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Journal Cover European Journal of Medical Genetics
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   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1769-7212
   Published by Elsevier Homepage  [3038 journals]
  • Two novel RFX6 variants in siblings with Mitchell-Riley syndrome with
           later diabetes onset and heterotopic gastric mucosa
    • Authors: Martina Skopkova; Miriam Ciljakova; Zuzana Havlicekova; Jarmila Vojtkova; Lucia Valentinova; Daniel Danis; Dalibor Murgas; Renata Szepeova; Juraj Stanik; Peter Banovcin; Iwar Klimes; Daniela Gasperikova
      Pages: 429 - 435
      Abstract: Publication date: Available online 12 August 2016
      Source:European Journal of Medical Genetics
      Author(s): Martina Skopkova, Miriam Ciljakova, Zuzana Havlicekova, Jarmila Vojtkova, Lucia Valentinova, Daniel Danis, Dalibor Murgas, Renata Szepeova, Juraj Stanik, Peter Banovcin, Iwar Klimes, Daniela Gasperikova
      Mitchell-Riley syndrome, an autosomal recessive disorder caused by mutations in the RFX6 gene, is defined as a combination of neonatal diabetes mellitus and serious congenital gastrointestinal defects. We describe Mitchell-Riley syndrome in two sisters with two novel compound heterozygous variants in the RFX6 gene: c.1154G > A, p.(Arg385Gln), and c.1316_1319delTCTA, p.(Ile439Thrfs*13). Both sisters present milder forms of the syndrome, likely due to possible residual activity of the p.Arg385Gln variant, which is localized in a dimerization domain of the RFX6 transcription factor. We propose that the prognosis is dependent on patient RFX6 genotype and possible residual activity of RFX6 transcription factor. Both sisters had atypical later onset of diabetes, at 2 years and 10 months and 2 years and 7 months, respectively. This supports the need of extending the definition of diabetes in Mitchell-Riley syndrome from neonatal to childhood onset and regular glyceamia check in patients with gastrointestinal tract malformations typical for Mitchell-Riley syndrome. The clinical course in both sisters improved significantly after surgical removal of parts of the small intestine with heterotopic gastric mucosa. We suggest that gastric mucosa heterotopy is an important actionable part of Mitchell-Riley syndrome and could have been responsible for the malabsorption, failure to thrive and severe anemia present in previously reported patients with Mitchell-Riley syndrome.

      PubDate: 2016-08-13T00:22:08Z
      DOI: 10.1016/j.ejmg.2016.08.005
      Issue No: Vol. 59, No. 9 (2016)
  • Copy number variation analysis in adults with catatonia confirms
           haploinsufficiency of SHANK3 as a predisposing factor
    • Authors: Jeroen Breckpot; Marieke Vercruyssen; Eddy Weyts; Sean Vandevoort; Greet D'Haenens; Griet Van Buggenhout; Lore Leempoels; Elise Brischoux-Boucher; Lionel Van Maldergem; Alessandra Renieri; Maria Antonietta Mencarelli; Carla D'Angelo; Veronica Mericq; Mariette J. Hoffer; Maithé Tauber; Catherine Molinas; Claudia Castiglioni; Nathalie Brison; Joris R. Vermeesch; Marina Danckaerts; Pascal Sienaert; Koenraad Devriendt; Annick Vogels
      Pages: 436 - 443
      Abstract: Publication date: Available online 9 August 2016
      Source:European Journal of Medical Genetics
      Author(s): Jeroen Breckpot, Marieke Vercruyssen, Eddy Weyts, Sean Vandevoort, Greet D'Haenens, Griet Van Buggenhout, Lore Leempoels, Elise Brischoux-Boucher, Lionel Van Maldergem, Alessandra Renieri, Maria Antonietta Mencarelli, Carla D'Angelo, Veronica Mericq, Mariette J. Hoffer, Maithé Tauber, Claudia Castiglioni, Nathalie Brison, Joris R. Vermeesch, Marina Danckaerts, Pascal Sienaert, Koenraad Devriendt, Annick Vogels
      Background Catatonia is a motor dysregulation syndrome co-occurring with a variety of psychiatric and medical disorders. Response to treatment with benzodiazepines and electroconvulsive therapy suggests a neurobiological background. The genetic etiology however remains largely unexplored. Copy Number Variants (CNV), known to predispose to neurodevelopmental disorders, may play a role in the etiology of catatonia. Methods This study is exploring the genetic field of catatonia through CNV analysis in a cohort of psychiatric patients featuring intellectual disability and catatonia. Fifteen adults admitted to a psychiatric inpatient unit and diagnosed with catatonia were selected for array Comparative Genomic Hybridization analysis at 200 kb resolution. We introduced a CNV interpretation algorithm to define detected CNVs as benign, unclassified, likely pathogenic or causal with regard to catatonia. Results Co-morbid psychiatric diagnoses in these patients were autism, psychotic or mood disorders. Eight patients were found to carry rare CNVs, which could not be classified as benign, comprising 6 duplications and 2 deletions. Microdeletions on 22q13.3, considered causal for catatonia, were detected in 2 patients. Duplications on 16p11.2 and 22q11.2 were previously implicated in psychiatric disorders, but not in catatonia, and were therefore considered likely pathogenic. Driven by the identification of a rare 14q11.2 duplication in one catatonic patient, additional patients with overlapping duplications were gathered to delineate a novel susceptibility locus for intellectual disability and psychiatric disorders on 14q11.2, harboring the gene SUPT16H. Three remaining variants respectively on 2q36.1, 16p13.13 and 17p13.3 were considered variants of unknown significance. Conclusion The identification of catatonia-related copy number changes in this study, underscores the importance of genetic research in patients with catatonia. We confirmed that 22q13.3 deletions, affecting the gene SHANK3, predispose to catatonia, and we uncover 14q11.2 duplications as a novel susceptibility factor for intellectual and psychiatric disorders.

      PubDate: 2016-08-13T00:22:08Z
      DOI: 10.1016/j.ejmg.2016.08.003
      Issue No: Vol. 59, No. 9 (2016)
  • Long-term clinical follow-up and molecular testing for diagnosis of the
           first Tunisian family with Alström syndrome
    • Authors: Amine Chakroun; Mariem Ben Said; Amine Ennouri; Imen Achour; Mouna Mnif; Mohamed Abid; Abdelmonem Ghorbel; Jan D. Marshall; Jürgen K. Naggert; Saber Masmoudi
      Pages: 444 - 451
      Abstract: Publication date: Available online 12 August 2016
      Source:European Journal of Medical Genetics
      Author(s): Amine Chakroun, Mariem Ben Said, Amine Ennouri, Imen Achour, Mouna Mnif, Mohamed Abid, Abdelmonem Ghorbel, Jan D. Marshall, Jürgen K. Naggert, Saber Masmoudi
      Alström syndrome is a clinically complex disorder characterized by progressive degeneration of sensory functions, resulting in visual and audiological impairment as well as metabolic disturbances. It is caused by recessively inherited mutations in the ALMS1 gene, which codes for a centrosomal/basal body protein. The purpose of this study was to investigate the genetic and clinical features of two Tunisian affected siblings with Alström syndrome. Detailed clinical examinations were performed including complete ophthalmic examination, serial audiograms and several biochemical and hormonal blood tests. For the molecular study, first genomic DNA was isolated using a standard protocol. Then, linkage analysis with microsatellite markers was performed and DNA array was used to detect known mutations. Subsequently, all ALMS1 exons were simultaneously sequenced for one affected patient with the TaGSCAN targeted sequencing panel. Finally, segregation of the causal variant was performed by Sanger sequencing. Both affected siblings had cone rod dystrophy with impaired visual acuity, sensorineural hearing loss and truncal obesity. One affected individual showed insulin resistance without diabetes mellitus. Other clinical features including cardiac and pulmonary dysfunction, hypothyroidism, hyperlipidemia, acanthosis nigricans, renal and hepatic dysfunction were absent. Genetic analysis showed the presence of a homozygous splice site mutation (c.10388-2A > G) in both affected siblings. Although Alström syndrome is relatively well characterized disease, this syndrome is probably misdiagnosed in Tunisia. Here, we describe the first report of Tunisian patients affected by this syndrome and carrying a homozygous ALMS1 mutation. The diagnosis was suspected after long-term clinical follow-up and confirmed by genetic testing.

      PubDate: 2016-08-13T00:22:08Z
      DOI: 10.1016/j.ejmg.2016.08.004
      Issue No: Vol. 59, No. 9 (2016)
  • Genetic testing and counseling in the case of an autism diagnosis: A
           caregivers perspective
    • Authors: Kristien Hens; Hilde Peeters; Kris Dierickx
      Pages: 452 - 458
      Abstract: Publication date: Available online 17 August 2016
      Source:European Journal of Medical Genetics
      Author(s): Kristien Hens, Hilde Peeters, Kris Dierickx
      The search for genes that can explain the development of autism is ongoing. At the same time, genetic counselling and genetic testing can be offered to families with a child diagnosed with autism. However, given the complexity of autism, both with respect to its aetiology as well as with respect to its heterogeneity, such genetic counselling and testing raises specific ethical questions regarding the aim and scope. In order to map these questions and opinions we interviewed 15 Belgian autism professionals. We found that they believed that genetic counselling and genetic testing have certain benefits for families confronted with an autism diagnosis, but also that direct benefit to the child is limited to those cases where a genetic finding offers a certain prognosis and intervention plan. In cases where autism is the result of a syndrome or a known genetic variant that is associated with other health problems, detection can also enable prevention of these health issues. Benefits of genetic testing, such as relief of guilt and reproductive choice, are primarily benefits to the parents, although indirectly they may affect the wellbeing of the person diagnosed. These benefits are associated with ethical questions.

      PubDate: 2016-08-21T14:46:11Z
      DOI: 10.1016/j.ejmg.2016.08.007
      Issue No: Vol. 59, No. 9 (2016)
  • Germinal mosaicism for a deletion of the FMR1 gene leading to fragile X
    • Authors: P. Jiraanont; R.J. Hagerman; G. Neri; M. Zollino; M. Murdolo; F. Tassone
      Pages: 459 - 462
      Abstract: Publication date: Available online 18 August 2016
      Source:European Journal of Medical Genetics
      Author(s): Poonnada Jiraanont, R.J. Hagerman, G. Neri, M. Zollino, M. Murdolo, F. Tassone
      Aberrant CGG trinucleotide amplification within the FMR1 gene, which spans approximately 38 Kb of genomic DNA is almost always what leads to fragile X syndrome (FXS). However, deletions of part or the entire FMR1 gene can also cause FXS. Both CGG amplification-induced silencing and deletions result in the absence of the FMR1 gene product, FMRP. Here, we report a rare case of germinal mosaicism of a deletion encompassing approximately 300 Kb of DNA, which by removing the entire FMR1 gene led to FXS. The male proband, carrying the deletion, presented in clinic with the typical features of FXS. His mother was analyzed by FISH on metaphase chromosomes with cosmid probe c22.3 spanning the FMR1 locus, and she was found not to carry the deletion on 30 analyzed cells from peripheral blood lymphocytes. Prenatal examination of the mother's third pregnancy showed that the male fetus also had the same deletion as the proband. Following this prenatal diagnosis, FISH analysis in the mother was expanded to 400 metaphases from peripheral lymphocytes, and a heterozygous FMR1 deletion was found in three. Although this result could be considered questionable from a diagnostic point of view, it indicates that the deletion is in the ovary's germinal cells.

      PubDate: 2016-08-21T14:46:11Z
      DOI: 10.1016/j.ejmg.2016.08.009
      Issue No: Vol. 59, No. 9 (2016)
  • The emerging microduplication 3q13.31: Expanding the genotype-phenotype
           correlations of the reciprocal microdeletion 3q13.31 syndrome
    • Authors: B. Hervé; D. Fauvert; R. Dard; J. Roume; S. Cognard; D. Goidin; F. Lozach; D. Molina-Gomes; F. Vialard
      Pages: 463 - 469
      Abstract: Publication date: Available online 26 August 2016
      Source:European Journal of Medical Genetics
      Author(s): B. Hervé, D. Fauvert, R. Dard, J. Roume, S. Cognard, D. Goidin, F. Lozach, D. Molina-Gomes, F. Vialard
      Microdeletion and microduplication syndromes are well-known causes of developmental delay and/or malformations of differing severity. It was recently reported that a microdeletion at the 3q13.31 locus is associated with a new syndrome combining developmental delay, postnatal overgrowth and dysmorphic features. However, the reciprocal microduplication has only been described in a few case reports displaying some clinical features of the microdeletion syndrome. Here, we report on a female infant with a 3.34 Mb microduplication of the 3q13.2q13.31 region inherited from her mother. The infant presented with severe intellectual disability, learning difficulties, intrauterine and postnatal growth retardation and skeletal particularities but no dysmorphic traits. This microduplication encompassed the previously described shortest region of overlap, which contains five genes (DRD3, ZNF80, TIGIT, MIR568 and ZBTB20). We reviewed the phenotypes described in the literature on microduplications and in the well-characterized 3q13.31 microdeletion syndrome. In agreement with the literature data, DRD3 and ZBTB20 appear to be strong candidate genes for neurodevelopmental defects and growth retardation. Lastly, we consider the putative mechanism of this rearrangement, which may involve a particular kind of nonallelic homologous recombination of human endogenous retrovirus elements.

      PubDate: 2016-08-26T15:42:34Z
      DOI: 10.1016/j.ejmg.2016.08.010
      Issue No: Vol. 59, No. 9 (2016)
  • Xq11.1-11.2 deletion involving ARHGEF9 in a girl with autism spectrum
    • Authors: Gifty Bhat; Danielle LaGrave; Alison Millson; John Herriges; Allen N. Lamb; Reuben Matalon
      Pages: 470 - 473
      Abstract: Publication date: Available online 27 May 2016
      Source:European Journal of Medical Genetics
      Author(s): Gifty Bhat, Danielle LaGrave, Alison Millson, John Herriges, Allen N. Lamb, Reuben Matalon
      We report an 8-year-old female with autism spectrum disorder (ASD), intellectual disability and speech delay who was found to carry a de novo 82 kb deletion of chromosome Xq11.1-11.2 involving the ARHGEF9 gene on chromosomal microarray. So far, 11 patients with point mutations, disruptions due to chromosomal rearrangements and deletions involving ARHGEF9 have been reported in the literature. ARHGEF9-related disorders comprise a wide phenotypic spectrum, including behavior disorders, autism spectrum disorder, intellectual disability, hyperekplexia and infantile epileptic encephalopathy. ARHGEF9 encodes for collybistin which plays an important role in post synaptic clustering of glycine and inhibitory gamma-aminobutyric acid receptors along with its scaffolding partner, gephyrin. The reduction of inhibitory receptor clusters in brain has been proposed as a plausible underlying pathophysiological mechanism. With this report, we provide further evidence for the role of ARHGEF9 in neurocognitive function, its implication in ASD, and review the clinical features of previously published individuals with ARHGEF9-related intellectual disability.

      PubDate: 2016-05-29T17:40:35Z
      DOI: 10.1016/j.ejmg.2016.05.014
      Issue No: Vol. 59, No. 9 (2016)
  • A case report of hereditary apolipoprotein A-I amyloidosis associated with
           a novel APOA1 mutation and variable phenotype
    • Authors: Birgitte G. Tougaard; Katja Venborg Pedersen; Søren Rasmus Krag; Janet A. Gilbertson; Dorota Rowczenio; Julian D. Gillmore; Henrik Birn
      Pages: 474 - 477
      Abstract: Publication date: Available online 27 May 2016
      Source:European Journal of Medical Genetics
      Author(s): Birgitte G. Tougaard, Katja Venborg Pedersen, Søren Rasmus Palmelund Krag, Janet A. Gilbertson, Dorota Rowczenio, Julian D. Gillmore, Henrik Birn
      Apolipoprotein A-I (apo A-I) amyloidosis is a non-AL, non-AA, and non-transthyretin type of amyloidosis associated with mutations in the APOA1 gene inherited in an autosomal dominant fashion. It is a form of systemic amyloidosis, but at presentation, can also mimic localized amyloidosis. The renal presentation generally involves interstitial and medullary deposition of apo A-I amyloid protein. We describe the identification of apo A-I amyloidosis by mass spectrometry in a 52-year old male, with no family history of amyloidosis, presenting with nephrotic syndrome and associated with heterozygosity for a novel APOA1 mutation (c.220 T > A) which encodes the known amyloidogenic Trp50Arg variant. Renal amyloid deposits in this case were confined to the glomeruli alone, and the patient developed progressive renal impairment. One year after diagnosis, the patient had a successful kidney transplant from an unrelated donor. Pathogenic mutations in the APOA1 gene are generally associated with symptoms of amyloidosis. In this family however, genotyping of family members identified several unaffected carriers suggesting a variable disease penetrance, which has not been described before in this form of amyloidosis and has implications when counselling those with APOA1 mutations.

      PubDate: 2016-05-29T17:40:35Z
      DOI: 10.1016/j.ejmg.2016.05.015
      Issue No: Vol. 59, No. 9 (2016)
  • MEF2C haploinsufficiency syndrome: Report of a new MEF2C mutation and
    • Authors: Helena Rocha; Mafalda Sampaio; Ruben Rocha; Susana Fernandes; Miguel Leão
      Pages: 478 - 482
      Abstract: Publication date: Available online 31 May 2016
      Source:European Journal of Medical Genetics
      Author(s): Helena Rocha, Mafalda Sampaio, Ruben Rocha, Susana Fernandes, Miguel Leão
      Introduction MEF2C haploinsufficiency syndrome is characterized by severe intellectual disability, epilepsy, stereotypic movements, minor dysmorphisms and brain abnormalities. We report the case of a patient with a new MEF2C mutation, comparing his clinical and imaging features to those previously reported in the literature. Case report A 10 year-old boy first came to pediatric neurology clinic at the age of 11 months because of severe psychomotor delay, without regression. He presented generalized hypotonia, poor eye contact, hand-mouth stereotypies, strabismus and minor facial dimorphisms. Epileptic seizures started at 26 months of age and were refractory. Brain MRI showed a slight increase in periventricular white matter signal and globally enlarged CSF spaces. Molecular analysis revealed a de novo, pathogenic and causative MEF2C mutation. Discussion MEF2C haploinsufficiency syndrome was recently recognized as a neurodevelopmental disorder. Severe intellectual disability with inability to speak and epilepsy are universal features in patients with MEF2C mutations, although mild cognitive and speech disorders have been reported to occur in patients with duplications. Epilepsy might be absent in patients with partial deletions. Abnormal movement patterns are very common in patients with MEF2C haploinsufficiency. Delayed myelination seems to be more commonly observed in patients with MEF2C mutations, while malformations of cortical development were only reported in patients with microdeletions. Although MEF2C haploinsufficiency prevalence is yet to be determined, it should be considered in the differential diagnosis of patients with severe intellectual disability and Rett-like features.

      PubDate: 2016-06-03T17:50:13Z
      DOI: 10.1016/j.ejmg.2016.05.017
      Issue No: Vol. 59, No. 9 (2016)
  • Association of structural and numerical anomalies of chromosome 22 in a
           patient with syndromic intellectual disability
    • Authors: Rania Naoufal; Marine Legendre; Dominique Couet; Brigitte Gilbert-Dussardier; Alain Kitzis; Frederic Bilan; Radu Harbuz
      Pages: 483 - 487
      Abstract: Publication date: Available online 21 July 2016
      Source:European Journal of Medical Genetics
      Author(s): Rania Naoufal, Marine Legendre, Dominique Couet, Brigitte Gilbert-Dussardier, Alain Kitzis, Frederic Bilan, Radu Harbuz
      Array comparative genomic hybridization (aCGH) is now widely adopted as a first-tier clinical diagnostic test for patients with developmental delay (DD)/intellectual disability (ID), autism spectrum disorders, and multiple congenital anomalies. Nevertheless, classic karyotyping still has its impact in diagnosing genetic diseases, particularly mosaic cases. We report on a 30 year old patient with syndromic intellectual disability, a 22q13.2 microdeletion and mosaic trisomy 22. The patient had the following clinical features: intrauterine growth retardation at birth, hypotonia, cryptorchidism, facial asymmetry, enophthalmus, mild prognathism, bifid uvula, hypoplastic upper limb phalanges, DD including speech delay, and ID. Whole genome aCGH showed a de novo 1 Mb interstitial heterozygous deletion in 22q13.2, confirmed by fluorescence in situ hybridization in all cells examined. Moreover, 18% cells had an extra chromosome 22 suggesting a trisomy 22 mosaicism. Almost all 22q13 deletions published so far have been terminal deletions with variable sizes (100 kb to over 9 Mb). Very few cases of interstitial 22q13.2 deletions were reported. In its mosaic form, trisomy 22 is compatible with life, and there are about 20 reports in the literature. It has a variable clinical presentation: growth restriction, dysmorphic features, cardiovascular abnormalities, hemihyperplasia, genitourinary tract anomalies and ID. Neurodevelopmental outcome ranges from normal to severe DD. The patient presents clinical features that are common to both the interstitial 22q13 deletion and the mosaic trisomy 22; characteristics related to the interstitial deletion alone and others explained solely by the mosaic trisomy. Our case points out the role of conventional cytogenetic tools in mosaic cases that could be missed by microarray technology. We therefore suggest the combination of both conventional and molecular karyotyping in the investigation of certain genetic diseases.

      PubDate: 2016-08-07T23:52:58Z
      DOI: 10.1016/j.ejmg.2016.07.001
      Issue No: Vol. 59, No. 9 (2016)
  • A novel MIP mutation in familial congenital nuclear cataracts
    • Authors: Litao Qin; Liangjie Guo; Hongdan Wang; Tao Li; Guiyu Lou; Qiannan Guo; Qiaofang Hou; Hongyan Liu; Shixiu Liao; Zhe Liu
      Pages: 488 - 491
      Abstract: Publication date: Available online 22 July 2016
      Source:European Journal of Medical Genetics
      Author(s): Litao Qin, Liangjie Guo, Hongdan Wang, Tao Li, Guiyu Lou, Qiannan Guo, Qiaofang Hou, Hongyan Liu, Shixiu Liao, Zhe Liu
      We screened 60 known genes which are involved in inherited cataract in a pregnant woman with a four-generation family history of autosomal dominant congenital nuclear cataract through next-generation sequencing (NGS) and identified a heterozygous mutation, c.508dupC (p.L170fs), in the major intrinsic protein (MIP) gene. This mutation results in a frame-shift in MIP and has not been previously reported. The correlation of the mutation with disease was validated by Sanger sequencing of DNA from the other affected or unaffected members of the family. Therefore, our data expand the mutation spectrum of MIP mutation, and suggest that NGS is an accurate, rapid, and cost-effective method in the genetic diagnosis of congenital nuclear cataract.

      PubDate: 2016-08-07T23:52:58Z
      DOI: 10.1016/j.ejmg.2016.07.002
      Issue No: Vol. 59, No. 9 (2016)
  • The molecular characterization of beta globin gene in thalassemia patients
           reveals rare and a novel mutations in Pakistani population.
    • Authors: Humaira Yasmeen; Sarmad Toma; Natalie Killeen; Shahida Hasnain; Letizia Foroni
      Pages: 355 - 362
      Abstract: Publication date: Available online 1 June 2016
      Source:European Journal of Medical Genetics
      Author(s): Humaira Yasmeen, Sarmad Toma, Natalie Killeen, Shahida Hasnain, Letizia Foroni
      Introduction A multicentre study (including four cities in Pakistan) aimed to investigate the frequency and spectrum of alpha and beta thalassemia genetic mutations and XmnI polymorphism of the Gamma Globin gene. Methods One hundred and sixty one beta thalassemia patients, identified on the ground of haematological parameters, were screened for mutations of the Alpha (HBA2 and HBA1) and Beta (HBB) Globin genes as well as Gamma (HBG2) Globin gene XmnI polymorphism using a combination of multiplex GAP polymerase chain reaction (PCR), Sanger sequencing and restriction fragment length polymerase (RFLP) based PCR. Results Mutations of at least one HBB gene was identified in 157 of 161 patients screened. Among 16 identified mutations in the beta gene, HBB:c.27_28insG (p. Ser10Valfs*14) was the most prevalent. α−3.7 and α−4.2 deletions were co-inherited with beta thalassemia mutations. Rare mutations such as HBB:c.–138C > T and HBB:c.315 + 1G > A were also identified. One novel variant (HBB:c.–148T > A), two rare mutations [HBB:c.332T > C (p.Leu111Pro); HBB:c.92G > C (p.Arg31Thr] and a novel association, HBB:c.[92G > C (p.Arg31Thr)] and [-92C > G], were reported for the first time in our study. HBG2:c.–211C > T base-pair substitution (historically described as -158 GγXmnI polymorphism) was present in 36% of the patients. Conclusion Heterogeneity in clinical and haematological parameters in TM, show that monogenic disorders can present with a wide spectrum of disease severity. Our studies identified rare and novel mutations that will be useful in the prevention of highly prevalent disease of thalassemia in Pakistan following nationwide awareness campaign.

      PubDate: 2016-06-03T17:50:13Z
      DOI: 10.1016/j.ejmg.2016.05.016
      Issue No: Vol. 59, No. 8 (2016)
  • A novel SMARCAL1 missense mutation that affects splicing in a severely
           affected Schimke immunoosseous dysplasia patient
    • Authors: Jimena Barraza-García; Carlos I. Rivera-Pedroza; Alberta Belinchón; Carlota Fernández-Camblor; Blanca Valenciano-Fuente; Pablo Lapunzina; Karen E. Heath
      Pages: 363 - 366
      Abstract: Publication date: Available online 6 June 2016
      Source:European Journal of Medical Genetics
      Author(s): Jimena Barraza-García, Carlos I. Rivera-Pedroza, Alberta Belinchón, Carlota Fernández-Camblor, Blanca Valenciano-Fuente, Pablo Lapunzina, Karen E. Heath
      Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive disease characterized by skeletal dysplasia, focal segmental glomerulosclerosis, renal failure and immunodeficiency. In this work, we report the molecular studies undertaken in a severely affected SIOD patient that died at six years old due to nephropathy. The patient was screened for mutations using a targeted skeletal dysplasias panel. A homozygous novel missense mutation was identified, c.1615C > G (p.[Leu539Val]) that was predicted as mildly pathogenic by in silico pathogenicity prediction tools. However, splicing prediction software suggested that this variant may create a new splicing donor site in exon 9, which was subsequently confirmed using a minigene assay in HEK293 cells. Thus, the splicing alteration, c.1615C > G; r.1615c > g, 1615_1644del; (p.[Leu539_Ile548del]), results in the loss of 10 amino acids of the HARP-ATPase catalytic domain and the RPA-binding domain. Several studies have demonstrated a weak genotype-phenotype correlation among such patients. Thus, the molecular characterization has helped us to understand why a predicted weakly pathogenic missense mutation results in severe SIOD and should be considered in similar scenarios.

      PubDate: 2016-06-08T18:04:12Z
      DOI: 10.1016/j.ejmg.2016.06.002
      Issue No: Vol. 59, No. 8 (2016)
  • Two male sibs with severe micrognathia and a missense variant in MED12
    • Authors: Trine E. Prescott; Mari Ann Kulseth; Ketil R. Heimdal; Barbro Stadheim; Einar Hopp; Tomasz Gambin; Zeynep H. Coban Akdemir; Shalini N. Jhangiani; Donna M. Muzny; Richard A. Gibbs; James R. Lupski; Asbjørg Stray-Pedersen
      Pages: 367 - 372
      Abstract: Publication date: Available online 7 June 2016
      Source:European Journal of Medical Genetics
      Author(s): Trine E. Prescott, Mari Ann Kulseth, Ketil R. Heimdal, Barbro Stadheim, Einar Hopp, Tomek Gambin, Zeynep H. Coban Akdemir, Shalini N. Jhangiani, Donna M. Muzny, Richard A. Gibbs, James R. Lupski, Asbjørg Stray-Pedersen
      Missense variants in MED12 cause three partially overlapping dysmorphic X-linked intellectual disability (XLID) syndromes: Lujan-Fryns syndrome (also known as Lujan syndrome), FG syndrome (also known as Opitz-Kaveggia syndrome) and X-linked Ohdo syndrome. We report a family with two severely micrognathic male sibs, a 10½ year old boy and a fetus, in which hemizygosity for a previously unreported missense variant in exon 13 of MED12 (NM_005120.2), c.1862G > A, p.(Arg621Gln) was detected by whole exome sequencing. The affected sibs shared no other rare variant with relevance to the phenotype. X-chromosome inactivation in blood was completely skewed (100:0) in the unaffected heterozygous mother, most likely as a result of preferential inactivation of the X-chromosome harbouring the missense variant in MED12. Neither the unaffected brother nor the unaffected maternal grandfather carried the missense variant in MED12. In the 10½ year old boy, upper airway obstruction secondary to Pierre Robin sequence necessitated a tracheostomy for the first 10 months of life. He has mild to moderate intellectual disability and some dysmorphic features seen in MED12-related syndromes. In addition, he has a horizontal gaze paresis, anomalies of the inner ear, and a cervical block vertebra. This report contributes to the expanding phenotypic range associated with MED12-mutations.

      PubDate: 2016-06-08T18:04:12Z
      DOI: 10.1016/j.ejmg.2016.06.001
      Issue No: Vol. 59, No. 8 (2016)
  • Duplications of SLC1A3: Associated with ADHD and autism
    • Authors: Claudia J.M. van Amen-Hellebrekers; Sandra Jansen; Rolph Pfundt; Janneke H. Schuurs-Hoeijmakers; David A. Koolen; Carlo L. Marcelis; Nicole de Leeuw; Bert B.A. de Vries
      Pages: 373 - 376
      Abstract: Publication date: Available online 11 June 2016
      Source:European Journal of Medical Genetics
      Author(s): Claudia J.M. van Amen-Hellebrekers, Sandra Jansen, Rolph Pfundt, Janneke H. Schuurs-Hoeijmakers, David A. Koolen, Carlo L. Marcelis, Nicole de Leeuw, Bert B.A. de Vries
      We report four patients with a similar gain in 5p13.2 encompassing a single gene: SLC1A3. Behavioural problems resembling ADHD and/or autism-like features are observed which is in line with the glial glutamate transporter role of SLC1A3. We consider an association between SLC1A3 and the behavioural problems which can also be considered a contributing factor to behavioural problems in larger duplications overlapping the 5p13 microduplication syndrome region.

      PubDate: 2016-06-13T18:20:45Z
      DOI: 10.1016/j.ejmg.2016.06.003
      Issue No: Vol. 59, No. 8 (2016)
  • Mutations in MSX1, PAX9 and MMP20 genes in Saudi Arabian patients with
           tooth agenesis
    • Authors: Mohammad Shahid; Hanan A. Balto; Nouf Al-Hammad; S. Joshi; Hesham Saleh Khalil; Ali Mohammed Somily; Nasr Abdul-Aziz Sinjilawi; Sameer Al-Ghamdi; Muhammad Faiyaz-Ul-Haque; Varinderpal S. Dhillon
      Pages: 377 - 385
      Abstract: Publication date: August 2016
      Source:European Journal of Medical Genetics, Volume 59, Issue 8
      Author(s): Mohammad Shahid, Hanan A. Balto, Nouf Al-Hammad, S. Joshi, Hesham Saleh Khalil, Ali Mohammed Somily, Nasr Abdul-Aziz Sinjilawi, Sameer Al-Ghamdi, Muhammad Faiyaz-Ul-Haque, Varinderpal S. Dhillon
      Tooth agenesis in human being is the most common congenital anomaly associated with dental development. Mutations in many genes such as MSH homeobox 1 (MSX1), paired box gene 9 (PAX9), ectodysplasin A (EDA) and EDA receptor (EDAR) have been associated with familial form of this condition. However, in large majority of patients, genetic cause could not be identified. The primary aim of present study was to identify the causative mutation(s) in these genes in Saudi Arabian families diagnosed with non-syndromic form of disease. Direct sequencing of coding regions, including exon-intron boundaries of these genes was carried out. All identified nucleotide variations were also tested to exclude possibility of being rare polymorphisms. The sequence analysis of exons and exon-intronic regions of these genes revealed five new mutations that include four in MSX1, one in PAX9 and one single nucleotide polymorphism (SNP) in majority of the patients in MMP20. One novel mutation in exon 1 of MSX1 gene (5354C > G; A40G) was found in three patients. In addition, another novel mutation was detected in two patients in exon 3 (PAX9) as g.10672A > T which changes asparagine to isoleucine at position 40. These mutations were not found in any of the control subjects. A single SNP in MMP20 genes (g.5066A > C) that changes lysine to threonine at position 18 was found in 10% controls as well. Our results for the first time demonstrates that mutations in MSX1 gene might play an important role in hypodontia cases involving pre-molars and is a risk factor for this ethnic population mainly of Arabs and is first report linking these mutations with tooth agenesis.

      PubDate: 2016-08-07T23:52:58Z
      DOI: 10.1016/j.ejmg.2016.06.004
  • MKS1 mutations cause Joubert syndrome with agenesis of the corpus callosum
    • Authors: Ingrid Bader; E. Decker; J.A. Mayr; V. Lunzer; J. Koch; E. Boltshauser; W. Sperl; P. Pietsch; B. Ertl-Wagner; H. Bolz; C. Bergmann; O. Rittinger
      Pages: 386 - 391
      Abstract: Publication date: August 2016
      Source:European Journal of Medical Genetics, Volume 59, Issue 8
      Author(s): Ingrid Bader, E. Decker, J.A. Mayr, V. Lunzer, J. Koch, E. Boltshauser, W. Sperl, P. Pietsch, B. Ertl-Wagner, H. Bolz, C. Bergmann, O. Rittinger
      Joubert syndrome (JS) is a clinically and genetically heterogeneous ciliopathy characterized by episodic hyperpnea and apnea, hypotonia, ataxia, cognitive impairment and ocular motor apraxia. The “molar tooth sign” is pathognomonic of this condition. Mutations in the MKS1 gene are a major cause of Meckel-Gruber syndrome (MKS), the most common form of syndromic neural tube defects, frequently resulting in perinatal lethality. We present the phenotype and genotype of a child with severe JS and agenesis of the corpus callosum (ACC). In our patient, a next generation sequencing (NGS) approach revealed the following two variants of the MKS1 gene: first, a novel missense variant [ c.240G > T (p.Trp80Cys)], which affects a residue that is evolutionarily highly conserved in mammals and ciliates; second, a 29 bp deletion in intron 15 [c.1408-35_1408-7del29], a founder mutation, which in a homozygous state constitutes the major cause of MKS in Finland. We review the MKS1-variants in all of the eleven JS patients reported to date and compare these patients to our case. To our knowledge, this is the first patient with Joubert syndrome and agenesis of the corpus callosum where a potentially causal genotype is provided.

      PubDate: 2016-08-07T23:52:58Z
      DOI: 10.1016/j.ejmg.2016.06.007
  • Lipid profiles in a large cohort of Italian children with Down syndrome
    • Authors: Paola Sabrina Buonuomo; Andrea Bartuli; Gerarda Mastrogiorgio; Annachiara Vittucci; Chiara Di Camillo; Simona Bianchi; Denise Pires Marafon; Alberto Villani; Diletta Valentini
      Pages: 392 - 395
      Abstract: Publication date: August 2016
      Source:European Journal of Medical Genetics, Volume 59, Issue 8
      Author(s): Paola Sabrina Buonuomo, Andrea Bartuli, Gerarda Mastrogiorgio, Annachiara Vittucci, Chiara Di Camillo, Simona Bianchi, Denise Pires Marafon, Alberto Villani, Diletta Valentini
      Objectives Results of epidemiological studies of lipid profiles in individuals with Down Syndrome (DS) in different settings showed discordant results but laboratory norms for this population has been lacking. The aim of our study is to evaluate lipid profiles in a large population of Italian children with DS. Methods Lipid profiles of 357 patients with diagnosis of DS were recorded. RESULTS: Multiple linear regression was employed to estimate models for each lipid fraction as a function of sex and age in patients with DS. Conclusions The main contribution of this paper is to provide data about lipid profile on a large cohort of people with Down syndrome. Long-term surveillance will be crucial to establish if this specific lipid profile may translate into increased morbidity and mortality from cardiovascular diseases (CVD)

      PubDate: 2016-08-07T23:52:58Z
      DOI: 10.1016/j.ejmg.2016.06.005
  • NCAM2 deletion in a boy with macrocephaly and autism: Cause, association
           or predisposition'
    • Authors: Caroline Scholz; Doris Steinemann; Madeleine Mälzer; Mandy Roy; Mine Arslan-Kirchner; Thomas Illig; Jörg Schmidtke; Manfred Stuhrmann
      Pages: 493 - 498
      Abstract: Publication date: Available online 2 September 2016
      Source:European Journal of Medical Genetics
      Author(s): Caroline Scholz, Doris Steinemann, Madeleine Mälzer, Mandy Roy, Mine Arslan-Kirchner, Thomas Illig, Jörg Schmidtke, Manfred Stuhrmann
      We report on an 8-year-old boy with autism spectrum disorder (ASD), speech delay, behavioural problems, disturbed sleep and macrosomia including macrocephaly carrying a microdeletion that contains the entire NCAM2 gene and no other functional genes. Other family members with the microdeletion show a large skull circumference but do not exhibit any symptoms of autism spectrum disorder. Among many ASD-candidate genes, NCAM2 has been assumed to play a pivotal role in the development of ASD because of its function in the outgrowth and bundling of neurites. Our reported case raises the questions whether the NCAM2-deletion is the true cause of the ASD or only a risk factor and whether there might be any connection in NCAM2 with skull-size Key words: autism spectrum disorder, macrocephaly, neural cell adhesion molecule 2 protein (NCAM2), array comparative genomic hybridization (microarray).

      PubDate: 2016-09-05T17:55:30Z
      DOI: 10.1016/j.ejmg.2016.08.006
  • Bilateral renal tumors in an adult man with Smith-Magenis syndrome: The
           role of the FLCN gene
    • Authors: Leila Dardour; Pieter Verleyen; Karl Lesage; Maureen Holvoet; Koen Devriendt
      Pages: 499 - 501
      Abstract: Publication date: Available online 12 September 2016
      Source:European Journal of Medical Genetics
      Author(s): Leila Dardour, Pieter Verleyen, Karl Lesage, Maureen Holvoet, Koen Devriendt
      Smith-Magenis syndrome (SMS) is a contiguous-gene disorder most commonly caused by a deletion of chromosome 17p11.2. We report a 57 year-old man with SMS who presents bilateral renal tumors. This is most likely related to haploinsufficiency of FLCN gene, located in the deleted region, and a known tumor suppressor gene. Haploinsufficiency of FLCN causes Birt-Hogg-Dubé syndrome (BHDS), characterized by pulmonary cysts, renal and skin tumors. The present observation suggests that the follow-up of patients with SMS should also focus on possible manifestations of BHDS.

      PubDate: 2016-09-15T19:01:14Z
      DOI: 10.1016/j.ejmg.2016.09.005
  • 7p22.1 microdeletions involving ACTB associated with developmental delay,
           short stature, and microcephaly
    • Authors: Keiko Shimojima; Satoshi Narai; Masami Togawa; Tomotsune Doumoto; Noriko Sangu; Olivier M. Vanakker; Anne de Paepe; Matthew Edwards; John Whitehall; Sally Brescianini; Florence Petit; Joris Andrieux; Toshiyuki Yamamoto
      Pages: 502 - 506
      Abstract: Publication date: Available online 12 September 2016
      Source:European Journal of Medical Genetics
      Author(s): Keiko Shimojima, Satoshi Narai, Masami Togawa, Tomotsune Doumoto, Noriko Sangu, Olivier M. Vanakker, Anne de Paepe, Matthew Edwards, John Whitehall, Sally Brescianini, Florence Petit, Joris Andrieux, Toshiyuki Yamamoto
      There are no published reports of patients harboring microdeletions involving the 7p22.1 region. Although 7p22.1 microdeletions are rare, some reports have shown microduplications encompassing this region. In this study, we report five patients with overlapping deletions of the 7p22.1 region. The patients exhibited clinical similarities including non-specific developmental delay, short stature, microcephaly, and other distinctive features. The shortest region of overlap within the 7p22.1 region includes five genes, FBXL18, ACTB, FSCN1, RNF216, and ZNF815P. Of these genes, only ACTB is known to be associated with an autosomal dominant trait. Dominant negative mutations in ACTB are responsible for Baraitser-Winter syndrome 1. We analyzed ACTB expression in immortalized lymphocytes derived from one of the patients and found that it was reduced to approximately half that observed in controls. This indicates that ACTB expression is linearly correlated with the gene copy number. We suggest that haploinsufficiency of ACTB may be responsible for the clinical features of patients with 7p22.1 microdeletions.

      PubDate: 2016-09-15T19:01:14Z
      DOI: 10.1016/j.ejmg.2016.09.008
  • Severe early onset retinitis pigmentosa in a Moroccan patient with Heimler
           syndrome due to novel homozygous mutation of PEX1 gene
    • Authors: Ilham Ratbi; Imane Cherkaoui Jaouad; Hamza Elorch; Nada Al-Sheqaih; Mustapha Elalloussi; Jaber Lyahyai; Amina Berraho; William G. Newman; Abdelaziz Sefiani
      Pages: 507 - 511
      Abstract: Publication date: Available online 12 September 2016
      Source:European Journal of Medical Genetics
      Author(s): Ilham Ratbi, Imane Cherkaoui Jaouad, Hamza Elorch, Nada Al-Sheqaih, Mustapha Elalloussi, Jaber Lyahyai, Amina Berraho, William G. Newman, Abdelaziz Sefiani
      Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. It is the mildest form known to date of peroxisome biogenesis disorder caused by hypomorphic mutations of PEX1 and PEX6 genes. We report on a second Moroccan family with Heimler syndrome with early onset, severe visual impairment and important phenotypic overlap with Usher syndrome. The patient carried a novel homozygous missense variant c.3140T > C (p.Leu1047Pro) of PEX1 gene. As standard biochemical screening of blood for evidence of a peroxisomal disorder did not provide a diagnosis in the individuals with HS, patients with SNHL and retinal pigmentation should have mutation analysis of PEX1 and PEX6 genes.

      PubDate: 2016-09-15T19:01:14Z
      DOI: 10.1016/j.ejmg.2016.09.004
  • 17p13.3 microduplication including CRK leads to overgrowth and elevated
           growth factors: A case report
    • Authors: Rohan K. Henry; Caroline Astbury; Constantine A. Stratakis; Scott E. Hickey
      Pages: 512 - 516
      Abstract: Publication date: Available online 12 September 2016
      Source:European Journal of Medical Genetics
      Author(s): Rohan K. Henry, Caroline Astbury, Constantine A. Stratakis, Scott E. Hickey
      17p13.3 microduplications classified as class I duplications involving YWHAE but not PAFAH1B1 (formerly LIS1) and class II duplications which extend to involve PAFAH1B1, are associated with diverse phenotypes including intellectual disability and structural brain malformations. We report a girl with an approximately 1.58 Mb apparently terminal gain of 17p13.3, which contains more than 20 genes including the YWHAE and CRK genes (OMIM: 164762). She had increased growth factors accompanied by pathologic tall stature. In addition to these, she developed central precocious puberty at 7 years old. In individuals with class I 17p13.3 microduplications including CRK, we recommend biochemical evaluation of the growth hormone axis. Providers caring for these patients should be aware of their possible risk for the development of central precocious puberty.

      PubDate: 2016-09-15T19:01:14Z
      DOI: 10.1016/j.ejmg.2016.09.006
  • Answer to Thiffault and Bernard regarding “Expert opinion and caution
           are imperative for interpretation of next generation sequencing data”
    • Authors: Mohamed Khalifa
      Pages: 517 - 518
      Abstract: Publication date: Available online 10 August 2016
      Source:European Journal of Medical Genetics
      Author(s): Mohamed Khalifa

      PubDate: 2016-08-13T00:22:08Z
      DOI: 10.1016/j.ejmg.2016.08.001
  • Expert opinion and caution are imperative for interpretation of next
           generation sequencing data
    • Authors: Isabelle Thiffault; Geneviève Bernard
      Pages: 519 - 521
      Abstract: Publication date: Available online 12 August 2016
      Source:European Journal of Medical Genetics
      Author(s): Isabelle Thiffault, Geneviève Bernard
      We comment on the recent publication by Khalifa and Naffa who are reporting a young girl with variants in both WDR45 and POLR3A, which they state contribute to her clinical manifestations. We are arguing in this letter that the clinical, MRI, and genetics findings are not compatible with 4H leukodystrophy and that this patient is not affected by this condition.

      PubDate: 2016-08-13T00:22:08Z
      DOI: 10.1016/j.ejmg.2016.08.002
  • Expanding phenotype of p.Ala140Val mutation in MECP2 in a 4 generation
           family with X-linked intellectual disability and spasticity
    • Authors: Sophie Lambert; Isabelle Maystadt; Sébastien Boulanger; Pascal Vrielynck; Anne Destrée; Damien Lederer; Stéphanie Moortgat
      Pages: 522 - 525
      Abstract: Publication date: Available online 25 July 2016
      Source:European Journal of Medical Genetics
      Author(s): Sophie Lambert, Isabelle Maystadt, Sébastien Boulanger, Pascal Vrielynck, Anne Destrée, Damien Lederer, Stéphanie Moortgat
      Mutations in MECP2 (MIM #312750), located on Xq28 and encoding a methyl CpG binding protein, are classically associated with Rett syndrome in female patients, with a lethal effect in hemizygous males. However, MECP2 mutations have already been reported in surviving males with severe neonatal-onset encephalopathy, or with X-linked intellectual disability associated with psychosis, pyramidal signs, parkinsonian features and macro-orchidism (PPM-X syndrome; MIM3 #300055). Here we report on the identification of the p.Ala140Val mutation in the MECP2 gene in 4 males and 3 females of a large Caucasian family affected with X-linked intellectual disability. Females present with mild cognitive impairment and speech difficulties. Males have moderate intellectual disability, impaired language development, friendly behavior, slowly progressive spastic paraparesis and dystonic movements of the hands. Two of them show microcephaly. The p.Ala140Val mutation is recurrent, as it was already described in 4 families with X-linked mental retardation and in three sporadic male patients with intellectual disability. We further delineate the phenotype associated with the p.Ala140Val mutation, illustrating a variable expressivity even within a given family, and we compare our patients with previous reported cases in the literature.

      PubDate: 2016-08-07T23:52:58Z
      DOI: 10.1016/j.ejmg.2016.07.003
  • High prevalence of DUOX2 gene mutations among children with congenital
           hypothyroidism in central China
    • Authors: Hong Jiang; Jinhua Wu; Shengzhong Ke; Yue Hu; Anxing Fei; Yan Zhen; Jin Yu; Kuichun Zhu
      Pages: 526 - 531
      Abstract: Publication date: Available online 3 August 2016
      Source:European Journal of Medical Genetics
      Author(s): Hong Jiang, Jinhua Wu, Shengzhong Ke, Yue Hu, Anxing Fei, Yan Zhen, Jin Yu, Kuichun Zhu
      Congenial hypothyroidism (CH) is the most common congenital endocrine disease and is treatable when recognized early enough. We investigated the genetic variants in 12 children diagnosed with CH by newborn screening in Huangshi area central China. Twelve genes commonly involved in CH development were studied. Genomic DNA from peripheral blood was used to amplify all exons of the selected genes, and the constructed sequencing libraries were subjected to next generation high throughput DNA sequencing (NGS). Analysis of the sequencing results identified rare genetic variants in 11 of the 12 patients (91.7%), and two novel rare variants were found in DUOX2 gene and two in TPO gene. Mutations in DUOX2 gene were identified in 10 patients (83.3%), and all these patients were found to carry bi-allelic, tri-allelic mutations or compound mutations with other genes. Recurrent DUOX2 mutations include K530X, R683L, R1110Q, and L1343F. Truncating, splicing, and proven deleterious DUOX2 missense mutations were detected in 50% of the patients. Mutations in TG gene were identified in four patients, and mutations in TPO, THSR, SLC26A4 genes were identified, one in each patient, respectively. The high prevalence of DUOX2 mutations in this cohort of children with CH appears striking and surprising. The clinical implications were discussed.

      PubDate: 2016-08-07T23:52:58Z
      DOI: 10.1016/j.ejmg.2016.07.004
  • Recent advance in the molecular genetics of Wilson disease and hereditary
    • Authors: Tingxia Lv; Xiaojin Li; Wei Zhang; Xinyan Zhao; Xiaojuan Ou; Jian Huang
      Pages: 532 - 539
      Abstract: Publication date: Available online 31 August 2016
      Source:European Journal of Medical Genetics
      Author(s): Tingxia Lv, Xiaojin Li, Wei Zhang, Xinyan Zhao, Xiaojuan Ou, Jian Huang
      Metabolic liver diseases such as Wilson disease (WD) and hereditary hemochromatosis (HH) possess complicated pathogenesis and typical hereditary characteristics with the hallmarks of a deficiency in metal metabolism. Mutations in genes encoding ATPase, Cu + transporting, beta polypeptide (ATP7B) and hemochromatosis (HFE) or several non-HFE genes are considered to be causative for WD and HH, respectively. Although the identification of novel mutations in ATP7B for WD and HFE or the non-HFE genes for HH has increased, especially with the application of whole genome sequencing technology in recent years, the biological function of the identified mutations, as well as genotype–phenotype correlations remain to be explored. Further analysis of the causative gene mutation would be critical to clarify the mechanisms underlying specific disease phenotypes. In this review, we therefore summarize the recent advances in the molecular genetics of WD and HH including the updated mutation spectrums and the correlation between genotype and phenotype, with an emphasis on biological functional studies of the individual mutations identified in WD and HH. The weakness of the current functional studies and analysis for the clinical association of the individual mutation was also discussed. These works are essential for the understanding of the association between genotypes and phenotypes of these inherited metabolic liver diseases.

      PubDate: 2016-09-05T17:55:30Z
      DOI: 10.1016/j.ejmg.2016.08.011
  • Whole exome sequencing identifies a homozygous POLG2 missense variant in
           an infant with fulminant hepatic failure and mitochondrial DNA depletion
    • Authors: Hemant Varma; Phyllis L. Faust; Alejandro D. Iglesias; Stephen M. Lagana; Karen Wou; Michio Hirano; Salvatore DiMauro; Mahesh M. Mansukani; Kirsten E. Hoff; Peter L. Nagy; William C. Copeland; Ali B. Naini
      Pages: 540 - 545
      Abstract: Publication date: Available online 31 August 2016
      Source:European Journal of Medical Genetics
      Author(s): Hemant Varma, Phyllis L. Faust, Alejandro D. Iglesias, Stephen M. Lagana, Karen Wou, Michio Hirano, Salvatore DiMauro, Mahesh M. Mansukani, Kirsten E. Hoff, Peter L. Nagy, William C. Copeland, Ali B. Naini
      Mitochondrial DNA (mtDNA) depletion syndrome manifests as diverse early-onset diseases that affect skeletal muscle, brain and liver function. Mutations in several nuclear DNA-encoded genes cause mtDNA depletion. We report on a patient, a 3-month-old boy who presented with hepatic failure, and was found to have severe mtDNA depletion in liver and muscle. Whole-exome sequencing identified a homozygous missense variant (c.544C > T, p.R182W) in the accessory subunit of mitochondrial DNA polymerase gamma (POLG2), which is required for mitochondrial DNA replication. This variant is predicted to disrupt a critical region needed for homodimerization of the POLG2 protein and cause loss of processive DNA synthesis. Both parents were phenotypically normal and heterozygous for this variant. Heterozygous mutations in POLG2 were previously associated with progressive external ophthalmoplegia and mtDNA deletions. This is the first report of a patient with a homozygous mutation in POLG2 and with a clinical presentation of severe hepatic failure and mitochondrial depletion.

      PubDate: 2016-09-05T17:55:30Z
      DOI: 10.1016/j.ejmg.2016.08.012
  • Do the exome: A case of Williams-Beuren syndrome with severe epilepsy due
           to a truncating de novo variant in GABRA1
    • Authors: Bernt Popp; Regina Trollmann; Christian Büttner; Almuth Caliebe; Christian T. Thiel; Ulrike Hüffmeier; André Reis; Christiane Zweier
      Pages: 549 - 553
      Abstract: Publication date: Available online 7 September 2016
      Source:European Journal of Medical Genetics
      Author(s): Bernt Popp, Regina Trollmann, Christian Büttner, Almuth Caliebe, Christian T. Thiel, Ulrike Hüffmeier, André Reis, Christiane Zweier
      Williams-Beuren syndrome (WBS) is a relatively common, clinically recognizable microdeletion syndrome. In most cases the typical heterozygous deletion of 1.5 Mb on chromosome 7q11.23 spanning about 26 genes can be identified. Also some larger or smaller atypical deletions have been reported and associated with additional or atypical phenotypic aspects. We report on an individual with typical WBS due to the common deletion and with refractory infantile spasms. Using trio-exome sequencing, we identified a de novo truncating variant c.1200del, p (Lys401Serfs*25) in GABRA1 as the likely cause of the early onset epilepsy. This unique case not only allows to further define the phenotypic spectrum of infantile epileptic encephalopathy associated with rare de novo GABRA1 variants but exemplifies the need for a sensitive review of unclear associations in clinically defined syndromes and for extended diagnostic work-up in individuals with unusual presentations of a genetically confirmed diagnosis.

      PubDate: 2016-09-10T18:27:21Z
      DOI: 10.1016/j.ejmg.2016.09.002
  • Concurrent occurrence of an inherited 16p13.11 microduplication and a de
           novo 19p13.3 microdeletion involving MAP2K2 in a patient with
    • Abstract: Publication date: Available online 14 October 2016
      Source:European Journal of Medical Genetics
      Author(s): Keiko Shimojima, Yumiko Ondo, Mayumi Matsufuji, Nozomi Sano, Hisashi Tsuru, Tatsuki Oyoshi, Nayuta Higa, Hiroshi Tokimura, Kazunori Arita, Toshiyuki Yamamoto
      A female patient presented with developmental delay, distinctive facial features, and congenital anomalies, including a heart defect and premature lambdoid synostosis. The patient showed a paternally inherited 16p13.11 microduplication and a de novo 19p13.3 microdeletion involving the mitogen-activated protein kinase kinase 2 gene (MAP2K2), in which mutations cause the cardio-facio-cutaneous (CFC) syndrome. Reports of patients with overlapping 19p13.3 microdeletions of this region describe similar clinical manifestations including distinctive facial features: prominent forehead, horizontal/down-slanting palpebral fissures, long midface, pointed chin/angular jaw, sparse eyebrows, and underdeveloped cheekbones. Some of these findings overlapped to that of the patients with 16p13.11 microduplications and CFC syndrome. Although craniosynostosis was occasionally observed in patients with dominant-negative mutations in RAS/MAP kinase signaling genes (RASopathies) related to CFC syndrome, it was also reported in two patients with 16p13.11 microduplications. Genetic contributions of both chromosomal aberrations were discussed.

      PubDate: 2016-10-16T14:08:04Z
  • A 23 years follow-up study identifies GLUT1 deficiency syndrome initially
           diagnosed as complicated hereditary spastic paraplegia
    • Authors: Marina Diomedi; Ziv Gan-Or; Fabio Placidi; Patrick A. Dion; Anna Szuto; Mario Bengala; Guy A. Rouleau; Gian Luigi Gigli
      Abstract: Publication date: Available online 8 October 2016
      Source:European Journal of Medical Genetics
      Author(s): Marina Diomedi, Ziv Gan-Or, Fabio Placidi, Patrick A. Dion, Anna Szuto, Mario Bengala, Guy A. Rouleau, Gian Luigi Gigli
      Glucose transporter 1 (GLUT1) deficiency syndrome (GLUT1DS) was initially described in the early 90s as a sporadic clinical condition, characterized by seizures, motor and intellectual impairment with variable clinical presentation, and without a known genetic cause. Although causative mutations in SLC2A1 were later identified and much more is known about the disease, it still remains largely underdiagnosed. In the current study, a previously described Italian family was re-analyzed using whole exome sequencing and clinically re-evaluated. Affected individuals presented with spastic paraplegia as a predominant symptom, with epilepsy and intellectual disability, inherited as an autosomal dominant trait with variable clinical presentation. While a novel variant of hereditary spastic paraplegia (HSP) was initially hypothesized in this family, previous linkage studies of known HSP genes did not identify the genetic cause. Exome-sequencing study identified a p.Arg126Cys mutation in the SLC2A1 gene, encoding GLUT1, which segregated with the affected members of the family. The diagnosis of GLUT1DS was further confirmed by cerebrospinal fluid analysis, and treatment was started with good initial response. The description of this large family provides further clinical information on this rare disease. It also offers an example of how GLUT1DS can be challenging to diagnose, and emphasizes the importance of lumbar puncture in the workflow of similar syndromes. Finally, it suggests that analysis of SLC2A1 should be considered in the diagnostic work up of HSP, especially if it is associated with epilepsy.

      PubDate: 2016-10-13T13:11:25Z
      DOI: 10.1016/j.ejmg.2016.10.003
  • A review of the physical features of the fetal alcohol spectrum disorders
    • Authors: Miguel del Campo; Kenneth Lyons Jones
      Abstract: Publication date: Available online 10 October 2016
      Source:European Journal of Medical Genetics
      Author(s): Miguel del Campo, Kenneth Lyons Jones
      The fetal alcohol spectrum of disorders (FASD) includes four diagnostic categories for the clinical consequences of prenatal alcohol exposure (PAE) in the unborn child. Physical features are necessary for the diagnosis of the fetal alcohol syndrome (FAS) and partial pFAS. Moreover, these features are specific and a diagnosis of FAS can be made even in the absence of knowledge of PAE. Not only growth deficits, microcephaly and the 3 facial features (short palpebral fissures, smooth philtrum and narrow vermillion of the upper lip) are characteristic, since other dysmorphic features particularly in the hands are key to the recognition of FAS. Most features can be explained by the damage to the brain during pregnancy and can be replicated in animal models. Many different diagnostic guidelines are used for the diagnosis of FASD and the physical features are considered differently in each of them. There is a need for universal clinical criteria for the diagnosis of FASD if our goal is to favor universal recognition.

      PubDate: 2016-10-13T13:11:25Z
      DOI: 10.1016/j.ejmg.2016.10.004
  • Interventions in fetal alcohol spectrum disorders: An international
    • Authors: Christie L.M. Petrenko; Michelle E. Alto
      Abstract: Publication date: Available online 11 October 2016
      Source:European Journal of Medical Genetics
      Author(s): Christie L.M. Petrenko, Michelle E. Alto
      Fetal alcohol spectrum disorders (FASD) are present across countries and cultures, with prevalence rates threatening to rise in the coming years. In order to support children and families with FASD around the world, researchers must work to disseminate and implement evidence-based interventions. However, each cultural context presents unique elements and barriers to the implementation process. This review considers the challenges of addressing FASD in an international context. It summarizes existing FASD interventions that have empirical support in the domains of parenting and education, attention and self-regulation, adaptive functioning, and nutrition and medication. It then outlines cultural barriers pertaining to FASD that may impede the implementation process and makes suggestions for using purveyors as cultural liaisons between researchers and local stakeholders. The review concludes with recommendations for moving forward with international dissemination and implementation of FASD interventions.

      PubDate: 2016-10-13T13:11:25Z
      DOI: 10.1016/j.ejmg.2016.10.005
  • Chornobyl 30 years later: Radiation, pregnancies, and developmental
           anomalies in Rivne, Ukraine
    • Authors: Wladimir Wertelecki; Christina D. Chambers; Lyubov Yevtushok; Natalya Zymak-Zakutnya; Zoriana Sosyniuk; Serhiy Lapchenko; Bogdana Ievtushok; Diana Akhmedzhanova
      Abstract: Publication date: Available online 30 September 2016
      Source:European Journal of Medical Genetics
      Author(s): Wladimir Wertelecki, Christina D. Chambers, Lyubov Yevtushok, Natalya Zymak-Zakutnya, Zoriana Sosyniuk, Serhiy Lapchenko, Bogdana Ievtushok, Diana Akhmedzhanova
      In the 30 years since the Chornobyl nuclear power plant disaster, there is evidence of persistent levels of incorporated ionizing radiation in adults, children and pregnant women in the surrounding area. Measured levels of Cesium-137 vary by region, and may be influenced by dietary and water sources as well as proximity to nuclear power plants. Since 2000, comprehensive, population-based birth defects monitoring has been performed in selected regions of Ukraine to evaluate trends and to generate hypotheses regarding potential causes of unexplained variations in defect rates. Significantly higher rates of microcephaly, neural tube defects, and microphthalmia have been identified in selected regions of Ukraine collectively known as Polissia compared to adjacent regions collectively termed non-Polissia, and these significantly higher rates were evident particularly in the years 2000–2009. The Polissia regions have also demonstrated higher mean whole body counts of Cesium-137 compared to values in individuals residing in other non-Polissia regions. The potential causal relationship between persistent ionizing radiation pollution and selected congenital anomaly rates supports the need for a more thorough, targeted investigation of the sources of persistent ionizing radiation and the biological plausibility of a potential teratogenic effect.

      PubDate: 2016-10-06T11:34:00Z
      DOI: 10.1016/j.ejmg.2016.09.019
  • Before and after–Nutritional transformation of dysmorphism in a case
           of Costello syndrome
    • Authors: Annie T.G. Chiu; Lixing Zhu; Gary T.K. Mok; Gordon K.C. Leung; C.B. Chow; Brian H.Y. Chung
      Abstract: Publication date: Available online 2 October 2016
      Source:European Journal of Medical Genetics
      Author(s): Annie T.G. Chiu, Lixing Zhu, Gary T.K. Mok, Gordon K.C. Leung, C.B. Chow, Brian H.Y. Chung
      Costello syndrome is a type of RASopathy mapped to HRAS gene in chromosome 11, characterized by prenatal overgrowth, postnatal failure to thrive, classic facial gestalt and multisystem involvement including cardiomyopathy and intellectual disability. We present a 7 months old child with severe failure to thrive whose “subtle” facial dysmorphism at the time eluded clinical recognition of the syndrome. It was only with optimization of his nutritional status that dysmorphic features became more apparent, which affirmed the molecular diagnosis of Costello syndrome from exome sequencing. The case illustrated how drastic failure to thrive can be in Costello syndrome, and how nutritional status can transform dysmorphic features in a child. It also highlights the importance of serial dysmorphic evaluation in difficult cases.

      PubDate: 2016-10-06T11:34:00Z
      DOI: 10.1016/j.ejmg.2016.10.001
  • A case of constitutional trisomy 3 mosaicism in a teenage patient with
           mild phenotype
    • Authors: Mariana Kekis; Sayaka Hashimoto; Carol Deeg; Inga Calloway; Aimee McKinney; Christine Shuss; Scott Hickey; Caroline Astbury
      Abstract: Publication date: Available online 4 October 2016
      Source:European Journal of Medical Genetics
      Author(s): Mariana Kekis, Sayaka Hashimoto, Carol Deeg, Inga Calloway, Aimee McKinney, Christine Shuss, Scott Hickey, Caroline Astbury
      Constitutional mosaicism for trisomy 3 is extremely rare, with only a few postnatally diagnosed cases reported in the literature. We report a case of constitutional trisomy 3 mosaicism in a 16-year-old female, who presented with chronic joint pain, easy bruising, joint hypermobility and dysmorphic features, including long, thin facies, over-folded dysplastic ears, and Pierre-Robin sequence (PRS) with cleft palate. The patient was small at birth, had cleft palate repair, developed chronic joint pain at age 12, and has a history of mild leukopenia and mild thrombocytopenia. Microarray analysis was consistent with a mosaic gain of an entire chromosome 3. FISH analysis of peripheral blood and buccal cells showed the presence of the supernumerary chromosome 3 in a low percentage of cells in both tissues, suggesting that the nondisjunction event occurred prior to the germ cell layer differentiation. Since trisomy 3 has been observed somatically in lymphoma, a Hematology/Oncology consultation was provided for the patient. The oncologist's evaluation for malignancy was unremarkable. A review of findings from other trisomy 3 patients reported in the literature reveals a diverse phenotypic spectrum and does not show a correlation between the proportion of abnormal cells observed in peripheral blood and the patients' clinical features or severity. This case demonstrates that the clinical presentation of an individual with trisomy 3 is highly individualized and the clinical course is difficult to predict.

      PubDate: 2016-10-06T11:34:00Z
      DOI: 10.1016/j.ejmg.2016.10.002
  • Non lethal Raine syndrome and differential diagnosis
    • Authors: Siham Chafai Elalaoui; Nada Al-Sheqaih; Ilham Ratbi; Jill E. Urquhart; James O'Sullivan; Sanjeev Bhaskar; Simon S. Williams; Mustapha Elalloussi; Jaber Lyahyai; Leila Sbihi; Imane Cherkaoui Jaouad; Abdelhafid Sbihi; William G. Newman; Abdelaziz Sefiani
      Abstract: Publication date: Available online 22 September 2016
      Source:European Journal of Medical Genetics
      Author(s): Siham Chafai Elalaoui, Nada Al-Sheqaih, Ilham Ratbi, Jill E. Urquhart, James O'Sullivan, Sanjeev Bhaskar, Simon S. Williams, Mustapha Elalloussi, Jaber Lyahyai, Leila Sbihi, Imane Cherkaoui Jaouad, Abdelhafid Sbihi, William G. Newman, Abdelaziz Sefiani
      Raine syndrome is a rare autosomal recessive bone dysplasia characterized by characteristic facial features with exophthalmos and generalized osteosclerosis. Amelogenesis imperfecta, hearing loss, seizures, and intracerebral calcification are apparent in some affected individuals. Originally, Raine syndrome was originally reported as a lethal syndrome. However, recently a milder phenotype, compatible with life, has been described. Biallelic variants inFAM20C, encoding aGolgi casein kinase involved in biomineralisation, have been identified in affected individuals. We report here a consanguineous Moroccan family with two affected siblingsa girl aged 18 and a boy of 15years. Clinical features, including learning disability, seizures and amelogenesis imperfecta, initially suggested a diagnosis of Kohlschutter-Tonz syndrome. However,a novel homozygous FAM20Cvariantc.676T > A, p.(Trp226Arg) was identified in the affected siblings. Our report reinforces that Raine syndrome is compatible with life, and that mild hypophosphatemia and amelogenesis imperfecta are key features of the attenuated form.

      PubDate: 2016-09-25T09:23:14Z
      DOI: 10.1016/j.ejmg.2016.09.018
  • Prader-Willi syndrome and atypical submicroscopic 15q11-q13 deletions with
           or without imprinting defects
    • Authors: Maaz Hassan; Merlin G. Butler
      Abstract: Publication date: Available online 19 September 2016
      Source:European Journal of Medical Genetics
      Author(s): Maaz Hassan, Merlin G. Butler
      We report a 20 year follow up on a Caucasian female, now 26 years of age, with Prader-Willi syndrome (PWS) harboring an atypical 15q11-q13 submicroscopic deletion of 100–200 kb in size first detected in 1996 involving the imprinting center, SNRPN gene and surrounding region. PWS is a rare complex disorder caused by the loss of paternally expressed genes in the 15q11-q13 region. With high resolution chromosomal microarray and methylation – specific MLPA analysis, we updated the genetic findings on our patient and found a 209,819bp deletion including the SNURF-SNRPN gene complex which includes the imprinting center and the SNORD116 region. We compared with four other similarly reported individuals in the literature with atypical submicroscopic deletions within this region but without imprinting center involvement to better characterize the specific genetic lesions causing PWS clinical findings. Clinically, our patient met the diagnostic criteria of PWS including infantile hypotonia, a poor suck with feeding difficulties, global developmental delays and later food foraging, childhood obesity, small hands and skin picking. Small atypical deletions of comparable sizes were seen in the 15q11-q13 region in all five cases and similar behavioral/physical characteristics were found despite an imprinting defect in our patient. These results further support an overlapping critical deletion region involving the non-coding snoRNA SNORD116 in common in the five individuals playing a key role in contributing to the PWS phenotype.

      PubDate: 2016-09-21T08:57:24Z
      DOI: 10.1016/j.ejmg.2016.09.017
  • Clinical and molecular characterization of a novel INS mutation identified
           in patients with MODY phenotype
    • Authors: Barbara Piccini; Rosangela Artuso; Lorenzo Lenzi; Monica Guasti; Giulia Braccesi; Federica Barni; Emilio Casalini; Sabrina Giglio; Sonia Toni
      Abstract: Publication date: Available online 19 September 2016
      Source:European Journal of Medical Genetics
      Author(s): Barbara Piccini, Rosangela Artuso, Lorenzo Lenzi, Monica Guasti, Giulia Braccesi, Federica Barni, Emilio Casalini, Sabrina Giglio, Sonia Toni
      Correct diagnosis of Maturity-Onset Diabetes of the Young (MODY) is based on genetic tests requiring an appropriate subject selection by clinicians. Mutations in the insulin (INS) gene rarely occur in patients with MODY. This study is aimed at determining the genetic background and clinical phenotype in patients with suspected MODY. 34 patients with suspected MODY, negative for mutations in the GCK, HNF1α, HNF4α, HNF1β and PDX1 genes, were screened by next generation sequencing (NGS). A heterozygous INS mutation was identified in 4 members of the same family. First genetic tests performed identified two heterozygous silent nucleotide substitutions in MODY3/HNF1α gene. An ineffective attempt to suspend insulin therapy, administering repaglinide and sulphonylureas, was made. DNA was re-sequenced by NGS investigating a set of 102 genes. Genes implicated in the pathway of pancreatic β-cells, candidate genes for type 2 diabetes mellitus and genes causative of diabetes in mice were selected. A novel heterozygous variant in human preproinsulin INS gene (c.125T > C) was found in the affected family members. The new INS mutation broadens the spectrum of possible INS phenotypes. Screening for INS mutations is warranted not only in neonatal diabetes but also in MODYx patients and in selected patients with type 1 diabetes mellitus negative for autoantibodies. Subjects with complex diseases without a specific phenotype should be studied by NGS because Sanger sequencing is ineffective and time consuming in detecting rare variants.

      PubDate: 2016-09-21T08:57:24Z
      DOI: 10.1016/j.ejmg.2016.09.016
  • Mycophenolate mofetil embryopathy: A newly recognized teratogenic syndrome
    • Authors: Antonio Perez-Aytes; Purificacion Marin-Reina; Virginia Boso; Ana Ledo; John C. Carey; Maximo Vento
      Abstract: Publication date: Available online 14 September 2016
      Source:European Journal of Medical Genetics
      Author(s): Antonio Perez-Aytes, Purificacion Marin-Reina, Virginia Boso, Ana Ledo, John C. Carey, Maximo Vento
      MMF is probably the most common employed immunosuppressant drug in recipients of solid organ transplant and in many autoimmune diseases. In vitro studies, a significant number of single clinical observations and a recent study from a group of different European teratogen information services have provided very consistent data supporting the existence of a specific MMF embryopathy. The typical malformative pattern of MMF embryopathy includes external ear anomalies ranging from hypoplastic pinna (microtia) to complete absence of pinna (anotia); cleft lip, with or without cleft palate, and ocular anomalies as iris or chorioretinal coloboma and anophthalmia/microphthalmia. Other less frequent features are congenital heart defects, distal limbs anomalies, esophageal atresia, vertebral malformations, diaphragmatic hernia, and kidney and central nervous system anomalies. Neurodevelopmental outcome seems favorable in the small number of patients where information about this issue is available, but neurological deficits have been documented. Physicians in charge of women under MMF therapy should be aware of the potential risk of this drug to cause a specific embryopathy and the need of interrupting the treatment at least six weeks before becoming pregnant.

      PubDate: 2016-09-15T19:01:14Z
      DOI: 10.1016/j.ejmg.2016.09.014
  • A novel missense mutation, p.(R102W) in WNT7A causes Al-Awadi
           Raas-Rothschild syndrome in a fetus
    • Authors: Mehmet Burak Mutlu; Arda Cetinkaya; Nermin Koc; Gulay Ceylaner; Bekir Erguner; Hatip Aydın; Selin Karaman; Oya Demirci; Kamber Goksu; Ali Karaman
      Abstract: Publication date: Available online 13 September 2016
      Source:European Journal of Medical Genetics
      Author(s): Mehmet Burak Mutlu, Arda Cetinkaya, Nermin Koc, Gulay Ceylaner, Bekir Erguner, Hatip Aydın, Selin Karaman, Oya Demirci, Kamber Goksu, Ali Karaman
      Al-Awadi-Raas-Rothschild syndrome (AARRS) is a rare autosomal recessive disorder which consists of severe malformations of the upper and lower limbs, abnormal genitalia and underdeveloped pelvis. Here, we present a fetus with severe limbs defects, including bilateral humeroradial synostosis, bilateral oligodactyly in hands, underdeveloped pelvis, short femora and tibiae, absence of fibulae, severely small feet, and absence of uterus. An autosomal recessively inherited novel mutation in WNT7A found in the fetus, c.304C > T, affects an evolutionarily well-conserved amino acid, causing the p.(R102W) missense change at protein level. The findings presented in this fetus are compatible with diagnosis of AARRS, expanding the mutational spectrum of limb malformations arising from defects in WNT7A.

      PubDate: 2016-09-15T19:01:14Z
      DOI: 10.1016/j.ejmg.2016.09.009
  • Seizures and electroencephalography findings in 61 patients with fetal
           alcohol spectrum disorders
    • Authors: S. Boronat; M. Vicente; E. Lainez; A. Sánchez-Montañez; E. Vázquez; L. Mangado; L. Martínez-Ribot; M. del Campo
      Abstract: Publication date: Available online 13 September 2016
      Source:European Journal of Medical Genetics
      Author(s): S. Boronat, M. Vicente, E. Lainez, A. Sánchez-Montañez, E. Vázquez, L. Mangado, L. Martínez-Ribot, M. del Campo
      Fetal alcohol spectrum disorders (FASD) cause neurodevelopmental abnormalities. However, publications about epilepsy and electroencephalographic features are scarce. In this study, we prospectively performed electroencephalography (EEG) and brain magnetic resonance (MR) imaging in 61 patients with diagnosis of FASD. One patient had multiple febrile seizures with normal EEGs. Fourteen children showed EEG anomalies, including slow background activity and interictal epileptiform discharges, focal and/or generalized, and 3 of them had epilepsy. In one patient, seizures were first detected during the EEG recording and one case had an encephalopathy with electrical status epilepticus during slow sleep (ESES). Focal interictal discharges in our patients did not imply the presence of underlying visible focal brain lesions in the neuroimaging studies, such as cortical dysplasia or polymicrogyria. However, they had nonspecific brain MR abnormalities, including corpus callosum hypoplasia, vermis hypoplasia or cavum septum pellucidum. The latter was significantly more frequent in the group with EEG abnormal findings (p < 0.01).

      PubDate: 2016-09-15T19:01:14Z
      DOI: 10.1016/j.ejmg.2016.09.012
  • The impact of thalidomide use in birth defects in Brazil
    • Authors: Fernanda Sales Luiz Vianna; Thayne Woycinck Kowalski; Lucas Rosa Fraga; Maria Teresa Vieira Sanseverino; Lavinia Schuler-Faccini
      Abstract: Publication date: Available online 13 September 2016
      Source:European Journal of Medical Genetics
      Author(s): Fernanda Sales Luiz Vianna, Thayne Woycinck Kowalski, Lucas Rosa Fraga, Maria Teresa Vieira Sanseverino, Lavinia Schuler-Faccini
      Although the thalidomide tragedy occurred more than 50 years ago, the medication is still being used worldwide for different reasons, and several aspects regarding its teratogenicity remain unsolved. Despite the strict regulation implemented, new cases of thalidomide embryopathy (TE) are still being registered in Brazil. Furthermore, the molecular processes that lead to malformations when the embryo is exposed to thalidomide have not yet been fully identified. In this article, we perform a critical analysis of thalidomide's history in Brazil, highlighting aspects of the occurrence of TE over the decades. Finally, we present the main perspectives and challenges for ongoing surveillance and prevention of TE in Brazil. The effective control of dispensing thalidomide, especially in areas where leprosy is endemic, is one of the most important and challenging points. Furthermore, the emergence of thalidomide analogues is fast approaching, and their availability would pose additional concerns. The understanding of the molecular mechanisms and targets of thalidomide in both experimental and human models is essential for generating new insights into teratogenic mechanisms, so that safer thalidomide analogues can be developed.

      PubDate: 2016-09-15T19:01:14Z
      DOI: 10.1016/j.ejmg.2016.09.015
  • Prevalence of alcohol consumption during pregnancy and Fetal Alcohol
           Spectrum Disorders among the general and aboriginal populations in Canada
           and the United States
    • Authors: Svetlana Popova; Shannon Lange; Charlotte Probst; Nino Parunashvili; Jürgen Rehm
      Abstract: Publication date: Available online 13 September 2016
      Source:European Journal of Medical Genetics
      Author(s): Svetlana Popova, Shannon Lange, Charlotte Probst, Nino Parunashvili, Jürgen Rehm
      Prenatal alcohol exposure may cause a number of health complications for the mother and developing fetus, including Fetal Alcohol Spectrum Disorders (FASD). This study aimed to estimate the pooled prevalence of i) alcohol use (any amount) and binge drinking (4 or more standard drinks on a single occasion) during pregnancy, and ii) Fetal Alcohol Syndrome (FAS) and FASD among the general and Aboriginal populations in Canada and the United States, based on the available literature. Comprehensive systematic literature searches and meta-analyses, assuming a random-effects model, were conducted. It was revealed that about 10% and 15% of pregnant women in the general population consume alcohol in Canada and the United States, respectively, and that about 3% of women engage in binge drinking during pregnancy in both countries. However, the prevalence of alcohol use during pregnancy in the Aboriginal populations of the United States and Canada were found to be approximately 3–4 times higher, respectively, compared to the general population. Even more alarmingly, it was estimated that approximately one in five women in the Aboriginal populations in both countries engage in binge drinking during pregnancy. Further, among the general population of Canada, the pooled prevalence was estimated to be about 1 per 1000 for FAS and 5 per 1000 for FASD. However, compared to the general population, the prevalence of FAS and FASD among the Aboriginal population in Canada was estimated to be 38 times and 16 times higher, respectively. With respect to the United States, the pooled prevalence of FAS and FASD was estimated to be about 2 per 1000 and 15 per 1,000, respectively, among the general population, and 4 per 1000 and 10 per 1,000, respectively, among the Aboriginal population. However, the FAS and FASD prevalence estimates should be used with caution due to the limited number of existing studies and their methodological limitations. Based on the results of the current study, it is evident that there is an urgent need for implementing more effective national prevention and surveillance strategies to monitor and lower the prevalence of alcohol consumption during pregnancy and FASD.

      PubDate: 2016-09-15T19:01:14Z
      DOI: 10.1016/j.ejmg.2016.09.010
  • Neurodevelopmental disorder associated with prenatal exposure to alcohol
           (ND-PAE): A proposed diagnostic method of capturing the neurocognitive
           phenotype of FASD
    • Authors: Julie A. Kable; Raja A.S. Mukherjee
      Abstract: Publication date: Available online 13 September 2016
      Source:European Journal of Medical Genetics
      Author(s): Julie A. Kable, Raja A.S. Mukherjee
      Neurobehavioral Disorder associated with Prenatal Alcohol Exposure (ND-PAE) was proposed as a diagnostic formulation intended to capture the range of mental health problems occurring in alcohol-affected individuals with a history of prenatal alcohol exposure. The proposed criteria for the disorder are reviewed as well as various factors considered in the development of the disorder and its associated criteria. The taxonomic research related to the disorder is reviewed with preliminary analyses indicating that clinicians are readily able to agree when applying the diagnostic criteria but that the adaptive functioning criteria may need to be modified to expand its coverage of alcohol-affected individuals and to aid in discriminating these individuals from others not alcohol-affected. Finally, the challenges with translating the diagnosis into European medical and mental healthcare systems are discussed and recommendations for facilitating implementation are made.

      PubDate: 2016-09-15T19:01:14Z
      DOI: 10.1016/j.ejmg.2016.09.013
  • Cognitive behavioral therapy in 22q11.2 microdeletion with psychotic
           symptoms: What do we learn from schizophrenia'
    • Authors: Caroline Demily; Nicolas Franck
      Abstract: Publication date: Available online 14 September 2016
      Source:European Journal of Medical Genetics
      Author(s): Caroline Demily, Nicolas Franck
      The 22q11.2 deletion syndrome (22q11.2DS) is one of the most common microdeletion syndromes, with a widely underestimated prevalence between 1 per 2000 and 1 per 6000. Since childhood, patients with 22q11.2DS are described as having difficulties to initiate and maintain peer relationships. This lack of social skills has been linked to attention deficits/hyperactivity disorder, anxiety and depression. A high incidence of psychosis and positive symptoms is observed in patients with 22q11.2DS and remains correlated with poor social functioning, anxiety and depressive symptoms. Because 22q11.2DS and schizophrenia share several major clinical features, 22q11.2DS is sometimes considered as a genetic model for schizophrenia. Surprisingly, almost no study suggests the use of cognitive and behavioral therapy (CBT) in this indication.

      PubDate: 2016-09-15T19:01:14Z
      DOI: 10.1016/j.ejmg.2016.09.007
  • Human teratogens and genetic phenocopies. Understanding pathogenesis
           through human genes mutation
    • Authors: Matteo Cassina; Giulia A. Cagnoli; Daniela Zuccarello; Elena Di Gianantonio; Maurizio Clementi
      Abstract: Publication date: Available online 14 September 2016
      Source:European Journal of Medical Genetics
      Author(s): Matteo Cassina, Giulia A. Cagnoli, Daniela Zuccarello, Elena Di Gianantonio, Maurizio Clementi
      Exposure to teratogenic drugs during pregnancy is associated with a wide range of embryo-fetal anomalies and sometimes results in recurrent and recognizable patterns of malformations; however, the comprehension of the mechanisms underlying the pathogenesis of drug-induced birth defects is difficult, since teratogenesis is a multifactorial process which is always the result of a complex interaction between several environmental factors and the genetic background of both the mother and the fetus. Animal models have been extensively used to assess the teratogenic potential of pharmacological agents and to study their teratogenic mechanisms; however, a still open issue concerns how the information gained through animal models can be translated to humans. Instead, significant information can be obtained by the identification and analysis of human genetic syndromes characterized by clinical features overlapping with those observed in drug-induced embryopathies. Until now, genetic phenocopies have been reported for the embryopathies/fetopathies associated with prenatal exposure to warfarin, leflunomide, mycophenolate mofetil, fluconazole, thalidomide and ACE inhibitors. In most cases, genetic phenocopies are caused by mutations in genes encoding for the main targets of teratogens or for proteins belonging to the same molecular pathways. The aim of this paper is to review the proposed teratogenic mechanisms of these drugs, by the analysis of human monogenic disorders and their molecular pathogenesis.

      PubDate: 2016-09-15T19:01:14Z
      DOI: 10.1016/j.ejmg.2016.09.011
  • Esophageal atresia with tracheoesophageal fistula in a patient with
           7q35–36.3 deletion including SHH gene
    • Authors: Tiffany Busa; Nicoleta Panait; Kathia Chaumoitre; Nicole Philip; Chantal Missirian
      Abstract: Publication date: Available online 7 September 2016
      Source:European Journal of Medical Genetics
      Author(s): Tiffany Busa, Nicoleta Panait, Kathia Chaumoitre, Nicole Philip, Chantal Missirian
      Terminal 7q deletion is rarely reported in the literature. Holoprosencephaly and sacral dysgenesis are found in association with this deletion, due to haploinsufficiency of SHH and HLBX9 genes respectively. We report on a 2-year-old boy with 7q35–36.3 deletion encompassing SHH identified by oligonucleotide array comparative genomic hybridization. In addition to other frequent features, the patient presented with esophageal atresia and tracheoeosophageal fistula diagnosed at birth. This case, together with two others previously described, one presenting with esophageal atresia, the other with congenital esophageal stenosis, confirms the possible association between congenital esophageal malformations and 7q terminal deletion including SHH.

      PubDate: 2016-09-10T18:27:21Z
      DOI: 10.1016/j.ejmg.2016.09.001
  • Correlation between morphological MRI findings and specific diagnostic
           categories in fetal alcohol spectrum disorders
    • Authors: S. Boronat; A. Sánchez-Montañez; N. Gómez-Barros; C. Jacas; L. Martínez-Ribot; E. Vázquez; M. del Campo
      Abstract: Publication date: Available online 9 September 2016
      Source:European Journal of Medical Genetics
      Author(s): S. Boronat, A. Sánchez-Montañez, N. Gómez, C. Jacas, L. Martínez-Ribot, E. Vázquez, M. del Campo
      Fetal alcohol spectrum disorders (FASD) include physical and neurodevelopmental abnormalities related to prenatal alcohol exposure. Some neuroimaging findings have been clearly related to FASD, including corpus callosum and cerebellar anomalies. However, detailed studies correlating with specific FASD categories, that is, the fetal alcohol syndrome (FAS), partial FAS (pFAS) and alcohol related neurodevelopmental disorders (ARND), are lacking. We prospectively performed clinical assessment and brain MR imaging to 72 patients with suspected FASD, and diagnosis was confirmed in 62. The most frequent findings were hypoplasia of the corpus callosum and/or of the cerebellar vermis. Additional findings were vascular anomalies, gliosis, prominent perivascular spaces, occipito-cervical junction and cervical vertebral anomalies, pituitary hypoplasia, arachnoid cysts, and cavum septum pellucidum.

      PubDate: 2016-09-10T18:27:21Z
      DOI: 10.1016/j.ejmg.2016.09.003
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