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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  [3039 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)
  • 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
      Issue No: Vol. 59, No. 10 (2016)
  • 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
      Issue No: Vol. 59, No. 10 (2016)
  • 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
      Issue No: Vol. 59, No. 10 (2016)
  • 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
      Issue No: Vol. 59, No. 10 (2016)
  • 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
      Issue No: Vol. 59, No. 10 (2016)
  • 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
      Issue No: Vol. 59, No. 10 (2016)
  • 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
      Issue No: Vol. 59, No. 10 (2016)
  • 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
      Issue No: Vol. 59, No. 10 (2016)
  • 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
      Issue No: Vol. 59, No. 10 (2016)
  • 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
      Issue No: Vol. 59, No. 10 (2016)
  • 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
      Issue No: Vol. 59, No. 10 (2016)
  • 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
      Issue No: Vol. 59, No. 10 (2016)
  • Treatment of acute leukemia in children with ataxia telangiectasia (A-T)
    • Abstract: Publication date: December 2016
      Source:European Journal of Medical Genetics, Volume 59, Issue 12
      Author(s): M.H.D. Schoenaker, F. Suarez, T. Szczepanski, N. Mahlaoui, J.L. Loeffen
      Early onset ataxia telangiectasia (A-T) is a neurodegenerative DNA-instability disorder, which presents early in childhood. Hallmarks of A-T are progressive ataxia and a dramatic increased risk of developing malignancies (25%), especially of hematological origin. In children these malignancies mainly concern aggressive Non-Hodgkin lymphoma, acute leukemias and Hodgkin lymphoma. Of the acute leukemias, T-cell lymphoblastic leukemia (T-ALL) is by far the most common. Since patients with A-T experience increased toxicity to radio- and chemotherapeutic treatment, the optimal treatment strategy of acute leukemia remains subject of debate. Review of literature of treatment of T-ALL in patients with A-T (n = 18) showed that many patients are not diagnosed with A-T at time of presentation of T-ALL. This implicates that physicians must be aware of symptoms of A-T in young patients presenting with T-ALL. Complete remission rates are high following upfront modified as well as unmodified treatment strategies. Treatment of ALL in children with A-T is feasible and should be performed. Definitive treatment strategy must be determined by shared decision making with patient, caretakers and medical team. Future prospective studies are needed to elucidate optimal treatment strategy.

      PubDate: 2016-11-30T13:41:40Z
  • Genetic testing among Spanish pediatric neurologists: Knowledge, attitudes
           and practices
    • Abstract: Publication date: Available online 25 November 2016
      Source:European Journal of Medical Genetics
      Author(s): J. Domínguez-Carral, F.J. López-Pisón, A. Macaya, M. Bueno Campaña, M.A. García-Pérez, D. Natera-de Benito
      Advances in genetic testing applied to child neurology have enabled the development of genetic tests with greater sensitivity in elucidating an etiologic diagnosis for common neurological conditions. The objective of the current study was to examine child neurologists’ perspectives and insights into genetic testing. We surveyed 118 Spanish child neurologists, exploring their knowledge, attitudes, and practices concerning genetic tests. All of them had requested at least one genetic test in the past six months. Global developmental delay or intellectual disability in absence of a strong specific etiologic suspicion and autism spectrum disorders were the disorders for which genetic testing was most frequently requested. The most commonly requested genetic test was CGH-array. Overall, child neurologist perception of readiness for making genetic-related decisions was not bad, although many would like to have a greater support from geneticists and were interested in increasing the time dedicated to genetics within their continuing education program. These data have important implications for future practice, research, and education.

      PubDate: 2016-11-30T13:41:40Z
  • Treatment-related toxicities in children with acute lymphoblastic
           leukaemia predisposition syndromes
    • Abstract: Publication date: December 2016
      Source:European Journal of Medical Genetics, Volume 59, Issue 12
      Author(s): Kjeld Schmiegelow
      Although most children with acute lymphoblastic leukaemia (ALL) do not harbor germline mutations that strongly predispose them to development of this malignancy, large syndrome registries and detailed mapping of exomes or whole genomes of familial leukaemia kindreds have revealed that 3–5% of all childhood ALL cases are due to such germline mutations, but the figure may be higher. Most of these syndromes are primarily characterized by their non-malignant phenotype, whereas ALL may be the dominating or even only striking manifestation of the syndrome in some families. Identification of such ALL patients is important in order to adjust therapy and offer genetic counseling and cancer surveillance to mutation carriers in the family. In the coming years large genomic screening projects are expected to reveal further hitherto unrecognised familial ALL syndromes. The treatment of ALL cases harboring cancer predisposing mutations can be challenging for both the physician and the patient due to their preexisting symptoms, their reduced tolerance to radio- and/or chemotherapy with enhanced risk of life-threatening organ toxicities, and the paucity of data from ALL patients with the same or similar syndromes being treated by contemporary protocols. Recent studies clearly indicate that many of these patients stand a good chance of cure, and that they should be offered chemotherapy with the intention to cure. Some of these syndromes are characterized by reduced tolerance to radiotherapy and/or specific anticancer agents, while others are not. This review summarises our current knowledge on the risk of acute toxicities for these ALL patients and provides guidance for treatment adjustments.

      PubDate: 2016-11-30T13:41:40Z
  • Genetic predisposition and hematopoietic malignancies in children: Primary
    • Abstract: Publication date: December 2016
      Source:European Journal of Medical Genetics, Volume 59, Issue 12
      Author(s): Jutte van der Werff ten Bosch, Machiel van den Akker
      It is assumed that patients with some forms of primary immunodeficiency (PID) have a markedly increased risk of cancer as compared to the healthy population. This increased incidence is seen in children as well as adult patients. The type of malignancy depends on the underlying genetic defect, but hematopoietic cancers are most frequent in almost any subtype of PID. In some patients, a malignancy can even be the first or only symptom of an underlying genetic defect. The possibility of an underlying PID is important for the pediatric oncologist as this might influence the treatment. Also, patients with a known PID should be screened for the occurrence of cancer. It is therefore important to raise awareness on this subject among clinicians involved in the treatment of children with cancer as well as in the treatment of children with PID.

      PubDate: 2016-11-30T13:41:40Z
  • Novel ELN mutation in a family with supravalvular aortic stenosis and
           intracranial aneurysm
    • Abstract: Publication date: Available online 16 November 2016
      Source:European Journal of Medical Genetics
      Author(s): Anne Marie Jelsig, Zsolt Urban, Vishwanathan Hucthagowder, Henrik Nissen, Lilian Bomme Ousager
      Pathogenic germline mutations in ELN can be detected in patients with supravalvular aortic stenosis. The mutation might occur de novo or be inherited following an autosomal dominant pattern of inheritance. In this report we describe a three-generation family suffering from supravalvular aortic stenosis, various other arterial stenoses, sudden death, and intracranial aneurysms. A frameshift mutation in exon 12, not described before, was detected in the affected family members. This report emphasises the importance of family history, genetic counselling, and demonstrates the great variability in the phenotype within a single SVAS family.

      PubDate: 2016-11-23T15:31:31Z
  • 7p22.1 microduplication syndrome: Refinement of the critical region
    • Abstract: Publication date: Available online 16 November 2016
      Source:European Journal of Medical Genetics
      Author(s): Luisa Ronzoni, Francesca Sofia Grassi, Lidia Pezzani, Arianna Tucci, Marco Baccarin, Susanna Esposito, Donatella Milani
      7p22.1 microduplication syndrome is mainly characterized by developmental and speech delay, craniofacial dysmorphisms and skeletal abnormalities. The minimal critical region includes two OMIM genes: ACTB and RNF216. Here, we report on a girl carrying the smallest 7p22.1 microduplication detected to date, contributing to the delineation of the clinical phenotype of the 7p22.1 duplication syndrome and to the refinement of the minimal critical region. Our patient shares several major features of the 7p22.1 duplication syndrome, including craniofacial dysmorphisms and speech and motor delay, but she also presents with renal anomalies. Based on present and published dup7p22.1 patients we suggest that renal abnormalities might be an additional feature of the 7p22.1 microduplication syndrome. We also pinpoint the ACTB gene as the key gene affecting the 7p22.1 duplication syndrome phenotype.

      PubDate: 2016-11-23T15:31:31Z
  • Boucher Neuhäuser Syndrome – A rare cause of inherited hypogonadotropic
           hypogonadism. A case of two adult siblings with two novel mutations in
    • Abstract: Publication date: Available online 16 November 2016
      Source:European Journal of Medical Genetics
      Author(s): Jakob H. Langdahl, Anja L. Frederiksen, Nina Nguyen, Klaus Brusgaard, Claus B. Juhl
      Boucher Neuhäuser Syndrome (BNS) is a rare clinical syndrome with autosomal recessive inheritance defined by early-onset ataxia, hypogonadism and chorioretinal dystrophy. We present two siblings diagnosed with BNS in late adult life identified with compound heterozygous state of two novel PNPLA6 mutations. Five healthy siblings were non- or heterozygous carriers of the mutations. The cases, which presented with ataxia in childhood and hypogonadotropic hypogonadism (HH), were diagnosed at age 17 and 25, respectively, when examined for delayed puberty. The youngest case, a 55-year old male, was referred to our department in 2006 for evaluation of secondary causes of osteoporosis, which he developed despite adequate testosterone replacement therapy. The unusual medical history with childhood ataxia and hypogonadotropic hypogonadism lead to further examinations and eventually the diagnosis of BNS. The older sister of the proband also displayed the triad of ataxia, HH and chorioretinal dystrophy accompanied by cerebellar atrophy and in 2014, we found the mutations in PNPLA6. BNS is a rare cause of HH and secondary osteoporosis, but should be considered in patients presenting with one or more of the key features. Genetic screening is becoming increasingly available and inexpensive and accordingly this may be considered earlier and by broader indication in unusual phenotypic presentations. The increasing knowledge of causes for inherited diseases should extend the use of genetic screening, as the correct diagnosis will benefit the patients.

      PubDate: 2016-11-23T15:31:31Z
  • Mutation spectrum of NF1 gene in Italian patients with neurofibromatosis
           type 1 using Ion Torrent PGM™ platform
    • Abstract: Publication date: Available online 9 November 2016
      Source:European Journal of Medical Genetics
      Author(s): Francesco Calì, Valeria Chiavetta, Giuseppa Ruggeri, Maria Piccione, Angelo Selicorni, Daniela Palazzo, Maria Bonsignore, Anna Cereda, Maurizio Elia, Pinella Failla, Maria Grazia Figura, Agata Fiumara, Silvia Maitz, Giuseppa Maria Luana Mandarà, Teresa Mattina, Alda Ragalmuto, Corrado Romano, Martino Ruggieri, Roberto Salluzzo, Antonino Saporoso, Carmelo Schepis, Giovanni Sorge, Maria Spanò, Gaetano Tortorella, Valentino Romano
      Neurofibromatosis type 1 (NF1) is caused by mutations of the NF1 gene and is one of the most common human autosomal dominant disorders. The patient shows different signs on the skin and other organs from early childhood. The best known are six or more café au lait spots, axillary or inguinal freckling, increased risk of developing benign nerve sheath tumours and plexiform neurofibromas. Mutation detection is complex, due to the large gene size, the large variety of mutations and the presence of pseudogenes. Using Ion Torrent PGM™ Platform, 73 mutations were identified in 79 NF1 Italian patients, 51% of which turned out to be novel mutations. Pathogenic status of each variant was classified using "American College of Medical Genetics and Genomics" guidelines criteria, thus enabling the classification of 96% of the variants identified as being pathogenic. The use of Next Generation Sequencing has proven to be effective as for costs, and time for analysis, and it allowed us to identify a patient with NF1 mosaicism. Furthermore, we designed a new approach aimed to quantify the mosaicism percentage using electropherogram of capillary electrophoresis performed on Sanger method.

      PubDate: 2016-11-16T14:32:47Z
  • “Serpentine-like syndrome”–A very rare multiple malformation
           syndrome characterised by brachioesophagus and vertebral anomalies
    • Abstract: Publication date: Available online 9 November 2016
      Source:European Journal of Medical Genetics
      Author(s): Ana Beleza-Meireles, Patricia Steenhaut, Catheline Hocq, Philippe Clapuyt, Pierre Bernard, Christian Debauche, Yves Sznajer
      “Serpentine-like syndrome” is a severe and rare association of multiple congenital malformations, characterised by brachioesophagus, secondary intrathoracic stomach, and vertebral anomalies. Other associated anomalies have been described such as malposition and herniation of abdominal organs. We report the natural history of a baby girl born at 29 weeks of gestation with intra uterine growth restriction, short neck, large rachischisis from cervical to thoracic spine, a very short oesophagus, thoracic stomach associated with a midline diaphragmatic hernia, malrotated gut and median cleft lip. Most of these anomalies were detected antenatally. Molecular karyotype was normal. She died at age 12 days. To Whom It May Concern: our knowledge, the present patient represents the 8th report of a case of “Serpentine-like syndrome”. Brachioesophagus and congenital vertebral anomalies, in particular rachischisis, are the cardinal features of this condition. All reported cases have been sporadic and the cause is still unknown. We believe that the specificity of the presentation as well as the similarities between available descriptions of patients suggests a common, yet to identify, molecular cause, possibly involving a developmental “toolkit”/homeobox gene or related pathways.

      PubDate: 2016-11-09T12:59:07Z
  • Associated anomalies in cases with anotia and microtia
    • Abstract: Publication date: Available online 3 November 2016
      Source:European Journal of Medical Genetics
      Author(s): Claude Stoll, Yves Alembik, Beatrice Dott, Marie-Paule Roth
      Infants with anotia and microtia (AM) often have other non-AM associated congenital anomalies. The purpose of this investigation was to assess the prevalence and the types of these associated anomalies in a defined population. The associated anomalies in infants with AM were collected in all livebirths, stillbirths and terminations of pregnancy during 29 years in 387,067 consecutive births in the area covered by our population-based registry of congenital malformations. Of the 146 cases with AM registered during this period, representing a prevalence of 3.77 per 10,000, 49.3% had associated anomalies. There were 14 (9.6%) cases with chromosomal abnormalities including 5 trisomies 18, and 18 (12.3%) nonchromosomal recognized dysmorphic conditions including 6 cases with oculo-auriculo-vertebral spectrum. However, numerous other recognized dysmorphic conditions were registered. Forty (27.4%) of the cases had multiple congenital anomalies (MCA). Anomalies especially in the cardiovascular, the musculoskeletal, the urogenital, the central nervous, and the digestive systems, and facial clefts were the most common other anomalies. This study included special strengths: each affected child was examined by a geneticist, all elective terminations were ascertained, and the surveillance for anomalies was continued until 2 years of age. In conclusion the overall prevalence of associated anomalies, which was one in every two cases, emphasizes the need for a thorough investigation of cases with AM. A routine screening for other anomalies may be considered in infants and in fetuses with AM.

      PubDate: 2016-11-09T12:59:07Z
  • Haplotype analysis of α-thalassemia chromosomes reveals heterogeneity and
           multiple founders in Ashkenazi Jews
    • Abstract: Publication date: November 2016
      Source:European Journal of Medical Genetics, Volume 59, Issue 11
      Author(s): Adir Shaulov, Dvora Filon, Deborah Rund
      α-Thalassemia (α-thal) is among the world's most common single gene disorders, generally attributed to a selective advantage of heterozygotes against malaria mortality. A high frequency of -α3.7 deletion heterozygosity has been previously reported in Ashkenazi Jews despite lack of obvious malarial selection pressure in this population. Using haplotype and -α3.7 subtype analysis we analyzed a subset of -α3.7 homozygotes from various Israeli ethnic groups. We found a high frequency of the common Ia haplotype in Yemenite Jews and Arabs (54% and 13% respectively). Ashkenazi Jews exhibited a high frequency of IIIb alleles (67%) previously reported only in Aboriginal Australians and not found in other Israeli ethnicities. Both Yemenites and Ashkenazim carried the rare IIh alleles (18% and 15% respectively). These results may suggest multiple founder effects in Ashkenazi Jews as well a common founder for both Yemenite and Ashkenazi Jews.

      PubDate: 2016-11-02T20:26:21Z
  • Williams syndrome and mature B-Leukemia: A random association?
    • Abstract: Publication date: Available online 19 October 2016
      Source:European Journal of Medical Genetics
      Author(s): Valentina Decimi, Grazia Fazio, Fabiola Dell'Acqua, Silvia Maitz, Marta Galbiati, Carmelo Rizzari, Andrea Biondi, Giovanni Cazzaniga, Angelo Selicorni
      Williams syndrome (WBS) is a rare neurodevelopmental disorder with specific phenotypic characteristics and cardiac abnormalities, but is not considered as a cancer predisposing condition. However, in rare cases, malignancies have been described in patients with WBS, with hematologic cancer (mainly Burkitt Lymphoma and Acute Lymphoblastic Leukemia) as the most represented. We report here the case of a boy with WS and B-NHL. This is the unique case within the large cohort of patients (n = 117) followed in our institution for long time (mean clinical follow-up, 13 years). We herewith propose that the BCL7B gene, located in the chromosomal region commonly deleted in Williams syndrome, could potentially have a role in this particular association.

      PubDate: 2016-11-02T20:26:21Z
  • Cytogenetic biomarkers in detection of genotoxic effects of gestagens in
           peripheral blood lymphocytes in vitro and in vivo
    • Abstract: Publication date: Available online 26 October 2016
      Source:European Journal of Medical Genetics
      Author(s): Darko Grujičić, Marina Radović, Slobodan Arsenijević, Olivera Milošević-Djordjević
      Gestagens are the most frequently used steroid hormones in hormone-replacement therapy in the treatment of threatened miscarriage during the first trimester of pregnancy. This therapy has been applied in a large number of women with threatened abortion, despite various degrees of success of its efficacy. Genetic factors play a key role in miscarriages, especially in the initial stages. Cytogenetic biomarkers such as micronucleus (MN) test, chromosomal aberrations (CAs), and sister chromatid exchanges (SCEs) provide information on DNA damage. Cytogenetic markers detecting DNA damage have become very popular and useful in analysing genetic risk associated with hormone-replacement therapy. Cytogenetic studies presented heterogenous information. In many in vitro studies synthetic gestagens have been shown to induce genotoxic effects, and it was evaluated using three cytogenetic biomarkers. Genotoxic effects of gestagens have also been confirmed in in vivo studies that were conducted involving patients who received gestagen therapy during pregnancy and their newborns. However, some studies have shown that hormone-replacement therapy does not have genotoxic effects. In this paper, we summarize the results from previous studies. We also describe the usefulness of these biomarkers in the detection of genotoxic effects of hormone-replacement therapy.

      PubDate: 2016-11-02T20:26:21Z
  • Constitutional 560.49 kb chromosome 2p24.3 duplication including the MYCN
           gene identified by SNP chromosome microarray analysis in a child with
           multiple congenital anomalies and bilateral Wilms tumor
    • Abstract: Publication date: Available online 27 October 2016
      Source:European Journal of Medical Genetics
      Author(s): Mark A. Micale, Bedford Embrey, Jacqueline K. Macknis, Cheryl E. Harper, David J. Aughton
      Fewer than 100 patients with partial chromosome 2p trisomy have been reported. Clinical features are variable and depend on the size of the duplicated segment, but generally include psychomotor delay, facial anomalies, congenital heart defect, and other abnormalities. We report a 560.49 kb duplication of chromosome 2p in a 13 month-old male with hydrocephaly, ventricular septal defect, partial agenesis of the corpus callosum, and bilateral Wilms tumor. After discovery of bilateral renal masses at four months of age, the child underwent neoadjuvant chemotherapy followed by right radical nephrectomy that revealed triphasic Wilms' tumor. A needle core biopsy on one of two lesions on the left kidney also revealed Wilms tumor. A partial left nephrectomy revealed focally positive margins that necessitated left flank radiotherapy. The tumor karyotype was 46,XY,t(7;8)(q36;p11)[8]/46,XY [12] while his constitutional karyotype was 46,XY, suggesting that the t(7;8)(q36;p11) was associated with the malignancy. Single nucleotide polymorphism (SNP) chromosome microarray analysis of peripheral blood identified a maternally-inherited 560.49 kb chromosome 2p24.3 duplication that involved four OMIM genes: NBAS, DDX1, MYCNOS, and MYCN. SNP array analysis of the tumor revealed the same 2p24.3 duplication. At present, the now 5-year-old boy continues to do well without clinical or radiographic evidence of recurrent disease. This case is instructive because the child's health insurer initially denied authorization for chromosome microarray analysis (CMA), and it took more than one year before such authorization was finally granted. That initial decision to deny coverage could have had untoward health implications for this child, as the identification of constitutional MYCN duplication necessitated surveillance imaging for a number of pediatric malignancies associated with MYCN overexpression/dysregulation.

      PubDate: 2016-11-02T20:26:21Z
  • Chiari I malformation as part of the Floating-Harbor syndrome?
    • Abstract: Publication date: Available online 1 November 2016
      Source:European Journal of Medical Genetics
      Author(s): Arthur R. Kurzbuch, Shailendra Magdum
      We report the first case of a patient diagnosed with Floating-Harbor syndrome (FHS) and Chiari I malformation. The 3-year-old girl was of proportional short stature, had delay of language development, conductive hearing loss and a high threshold of pain. Diagnosis of Chiari I malformation may be difficult in FHS patients who present with communication problems. Clinicians following patients with FHS should be aware of a possible relation between FHS and Chiari I malformation.

      PubDate: 2016-11-02T20:26:21Z
  • 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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