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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]
  • A novel SMAD3 mutation caused multiple aneurysms in a patient without
           osteoarthritis symptoms
    • Abstract: Publication date: Available online 7 February 2017
      Source:European Journal of Medical Genetics
      Author(s): Audrey Courtois, Wouter Coppieters, Vincent Bours, Jean-Olivier Defraigne, Alain Colige, Natzi Sakalihasan
      Heterozygous mutations in the SMAD3 gene were recently described as the cause of a form of non-syndromic familial aortic thoracic aneurysm and dissection (FTAAD) transmitted as an autosomal dominant disorder and often associated with early-onset osteoarthritis. This new clinical entity, called aneurysms-osteoarthritis syndrome (AOS) or Loeys-Dietz syndrome 3 (LDS3), is characterized by aggressive arterial damages such as aneurysms, dissections and tortuosity throughout the arterial tree. We report, here, the case of a 45 year-old man presenting multiple visceral arteries and abdominal aortic aneurysms but without dissection of the thoracic aorta and without any sign of osteoarthritis. Exome-sequencing revealed a new frameshift heterozygous c.455delC (p.Pro152Hisfs*34) mutation in the SMAD3 gene. This deletion is located in the exon 3 coding for the linker region of the protein and causes a premature stop codon at positions 556–558 in the exon 4. The same mutation was found in the proband's mother and sister who had open surgery for abdominal aortic aneurysm and in one of his children who was 5 year-old and did not present aneurysm yet.

      PubDate: 2017-02-11T00:34:41Z
       
  • A case of Feingold type 2 syndrome associated with keratoconus refines
           keratoconus type 7 locus on chromosome 13q
    • Abstract: Publication date: Available online 31 January 2017
      Source:European Journal of Medical Genetics
      Author(s): Fabio Sirchia, Eleonora Di Gregorio, Gabriella Restagno, Enrico Grosso, Patrizia Pappi, Flavia Talarico, Elisa Savin, Simona Cavalieri, Elisa Giorgio, Cecilia Mancini, Barbara Pasini, Jodhbir S. Mehta, Alfredo Brusco
      We report on a 58-year old woman with microcephaly, mild dysmorphic features, bilateral keratoconus, digital abnormalities, short stature and mild cognitive delay. Except for keratoconus, the phenotype was suggestive for Feingold syndrome type 2 (FGLDS2, MIM 614326), a rare autosomal dominant disorder described in six patients worldwide, due to the haploinsufficiency of MIR17HG, a micro RNA encoding gene. Karyotype showed a de novo deletion on chromosome 13q, further defined by array-Comparative Genomic Hybridization (a-CGH) to a 17.2-Mb region. The deletion included MIR17HG, as expected by the FGLDS2 phenotype, and twelve genes from the keratoconus type 7 locus. Because our patient presented with keratoconus, we propose she further refines disease genes at this locus. Among previously suggested candidates, we exclude DOCK9 and STK24, and propose as best candidates IPO5, DNAJC3, MBNL2 and RAP2A. In conclusion, we report a novel phenotypic association of Feingold syndrome type 2 and keratoconus, a likely contiguous gene syndrome due to a large genomic deletion on 13q spanning MIR17HG and a still to be identified gene for keratoconus.

      PubDate: 2017-02-05T22:32:48Z
       
  • Reassessment of the 12q15 deletion syndrome critical region
    • Abstract: Publication date: Available online 31 January 2017
      Source:European Journal of Medical Genetics
      Author(s): Alesi Viola, Loddo Sara, Grispo Marta, Riccio Simona, Montella Andrea Costantino, Dallapiccola Bruno, Ulgheri Lucia, Novelli Antonio
      Interstitial deletions of the long arm of chromosome 12 are rare and only few cases have been reported in literature so far, with different phenotypic features related to size and gene content of deleted regions. Five patients reported a 12q15-q21 deletion, sharing a 1.3 Mb small region of overlap (SRO) and presenting with developmental delay, nasal speech and mild dysmorphic features. We identified by microarray analysis a new case of 12q15 deletion. Our patient clinical features allow the refinement of the SRO to CNOT2, KCNMB4, and PTPRB genes, improving genotype-phenotype correlations.

      PubDate: 2017-02-05T22:32:48Z
       
  • A de novo mutation in the X-linked PAK3 gene is the underlying cause of
           intellectual disability and macrocephaly in monozygotic twins
    • Abstract: Publication date: Available online 24 January 2017
      Source:European Journal of Medical Genetics
      Author(s): Jozef Hertecant, Makanko Komara, Aslam Nagi, Olfat Al-Zaabi, Waseem Fathallah, Hong Cui, Yaping Yang, Christine M. Eng, Mohammad Al Sorkhy, Mohammad A. Ghattas, Lihadh Al-Gazali, Bassam R. Ali
      Pathogenic variants in theP21 protein (Cdc42/Rac)-activated kinase 3gene (PAK3) lead to a rare non syndromic X-linked intellectual disability. The protein encoded by this gene forms an activated complex with GTP-bound RAS-like (P21), CDC2 and RAC1 proteins which then mediates a variety of cellular processes. So far, mutations in PAK3 gene have been reported in few families affected with intellectual disability associated with neurological manifestations such as speech defect, behavioral problem, brain structural abnormalities, microcephaly and cerebral palsy. In this study whole exome sequencing revealed a de novo likely pathogenic variant in PAK3 gene in monozygotic twins presented with intellectual disability, speech delay, behavioral problems and macrocephaly. Macrocephaly was noticed in our patients from birth at 35 weeks of gestation. This aspect of the phenotype has not been previously reported in other documented cases with pathogenic mutations in PAK3 gene. Our findings extend the phenotype of this disorder to include macrocephaly and offers further clues to the importance of the serine/threonine-protein kinase 3 (PAK3) protein in brain development and function.

      PubDate: 2017-01-29T22:40:16Z
       
  • Ocular dermoid in Pai Syndrome: A review
    • Abstract: Publication date: Available online 23 January 2017
      Source:European Journal of Medical Genetics
      Author(s): Peter Tormey, Iva Bilic, Michael A. Boyle
      Pai Syndrome is a rare congenital malformation syndrome of unknown cause with hypertelorism, midline cleft lip, nasal and facial polyps, ocular anomalies and the presence of distinctive lipomas adjacent to the corpus callosum. Herein, we present an infant girl with Pai Syndrome diagnosed in the first week of life with typical facial findings and associated pericallosal lipoma identified on cranial ultrasound and brain MRI. These typical features identified included median cleft of the upper lip (in her case as a forme fruste) with a cleft alveolus and a mid-anterior alveolar process congenital polyp. In addition to these findings there was mild hypertelorism and an ocular abnormality on the right eye. An ophthalmology assessment on day 5 identified the ocular lesion as a limbal dermoid. Several ocular anomalies have been reported in association with Pai Syndrome, however, dermoids have not been frequently described in this Syndrome and not before in a limbal location. Increasing identification of previously unreported ocular abnormalities in Pai Syndrome may improve diagnosis and may prove useful in future work attempting to elucidate the aetiology of this rare syndrome.

      PubDate: 2017-01-29T22:40:16Z
       
  • Attitudes toward prenatal genetic testing and therapeutic termination of
           pregnancy among parents of offspring with Prader-Willi syndrome
    • Abstract: Publication date: Available online 22 January 2017
      Source:European Journal of Medical Genetics
      Author(s): Noa Even-Zohar Gross, Talia Geva-Eldar, Yehuda Pollak, Harry J. Hirsch, Itai Gross, Varda Gross-Tsur
      Introduction Prenatal diagnosis (PND) raises ethical dilemmas such as the option of termination of pregnancy (TOP) in cases with severe outcome. Prader-Willi Syndrome (PWS), a complex neurogenetic syndrome with high morbidity and mortality throughout life. Recently, a unique prenatal phenotype was reported and TOP becomes a possibility. Objective To explore factors influencing the attitudes of parents of PWS children toward PND and TOP concerning a hypothetical pregnancy with a PWS fetus. Methods All 85 parents of individuals with PWS were interviewed regarding their attitudes towards PND and TOP using semi-structured questionnaire. Results Fifty-seven parents were supportive of invasive PND and 28 of non-invasive tests only; none opposed PND. Thirty eight favored TOP, additional 31 supported TOP under certain conditions such as spiritual advice, 15 were categorically against TOP. Attitudes correlated with religiosity (p < 0.025), mother's education (p < 0.001), mother's work status (p < 0.001), current age of the child with PWS (p < 0.008). Couples had similar attitudes regarding PND and TOP. No correlation was found with gender, genetic subtype and parental age. Conclusions Most parents of individuals with PWS support PND, however less than half support TOP. Religiosity was the most influential factor. Familial worldview should be taken into account during prenatal counseling.

      PubDate: 2017-01-22T22:01:44Z
       
  • LRP5-linked osteoporosis-pseudoglioma syndrome mimicking isolated
           microphthalmia
    • Abstract: Publication date: Available online 19 January 2017
      Source:European Journal of Medical Genetics
      Author(s): Sezen Guntekin Ergun, Guvem Gumus Akay, Mehmet Ali Ergun, E. Ferda Perçin
      Microphthalmia is defined as the measurement of the total axial length of the eyeball to be below average of the two standard deviation according to the age. While several genes have been identified so far related to microphthalmia, the genetic etiology of the disease has not been fully understood because of genetic heterogeneity observed in this disease. After exclusion of the genes that had been known to be the cause of microphthalmia, we performed homozygosity mapping and exome sequencing to clarify the genetic etiology of the bilateral microphthalmia in this family. When the results of the exome and microarray data were considered together as a splice-site mutation in LRP5 gene [c.2827 + 1G > A], which is known to be important for eye development and Wnt receptor signaling pathway, was found to be the cause of microphthalmia in our family. It was understood that after finding this mutation, when bone mineral density was measured with DXA in the family whose ages range between 19 and 28 and who have no bone problem before, osteoporosis was diagnosed. It was also understood that microphthalmia found in this family is a clinical finding of OPPG syndrome.

      PubDate: 2017-01-22T22:01:44Z
       
  • Novel FREM1 mutations in a patient with MOTA syndrome: Clinical findings,
           mutation update and review of FREM1-related disorders literature
    • Abstract: Publication date: Available online 19 January 2017
      Source:European Journal of Medical Genetics
      Author(s): Oscar F. Chacon-Camacho, Martin Zenker, Denny Schanze, Jasbeth Ledesma Gill, Juan C. Zenteno
      Manitoba-oculo-tricho-anal (MOTA) syndrome is an uncommon condition arising from biallelic mutations of FREM1 gene and clinically characterized by a variable spectrum of eyelid malformations, aberrant hairline, bifid or broad nasal tip, and gastrointestinal anomalies. In this report, we describe a patient with a phenotype compatible with MOTA syndrome (aberrant anterior hair line, hypertelorism, unilateral anophthalmia, and bifid and broad nasal tip) in whom two novel FREM1 mutations (c.305 A > G, p.Asp102Gly; and c.2626delG, p.Val876Tyrfs*16) were identified in the compound heterozygous state, thus broadening the mutational spectrum of the disease. We performed a literature review of the clinical and genetic features of individuals carrying FREM1 mutations.

      PubDate: 2017-01-22T22:01:44Z
       
  • Brachydactyly type E in an Italian family with 6p25 trisomy
    • Abstract: Publication date: Available online 19 January 2017
      Source:European Journal of Medical Genetics
      Author(s): Paolo Fontana, Cristina Tortora, Roberta Petillo, Michela Malacarne, Simona Cavani, Martina Miniero, Paola D'Ambrosio, Davide De Brasi, Maria Antonietta Pisanti
      Brachydactyly type E is a congenital limb malformation characterized by small hands and feet as a result of shortened metacarpals and metatarsals. Genetic causes of this anomaly are heterogeneous and only partially characterized. In this report we describe an Italian family in which four subjects share brachydactyly type E and a 3 Mb microduplication in region 6p25. The duplication involves the gene FOXC1, expressed during the osteoblast differentiation, which appears a potential candidate gene for brachydactyly.

      PubDate: 2017-01-22T22:01:44Z
       
  • How the EUCERD joint action supported initiatives on rare diseases
    • Abstract: Publication date: Available online 10 January 2017
      Source:European Journal of Medical Genetics
      Author(s): Stephen Lynn, Victoria Hedley, Antonio Atalaia, Teresinha Evangelista, Kate Bushby
      Joint Actions are successful initiatives from the European Commission (EC) that have helped to raise awareness and to bring significant benefit to those suffering from a rare disease (RD). In this paper, we will focus on the activities developed by the EUCERD Joint Action (EJA) and by the Orphanet Joint Action (“Orphanet Europe”). EUCERD Joint Action was co-funded by the EC and the Member States between 2012 and 2015 to help to define the activities and policies in the field of Rare Diseases and foster exchange of experiences amongst Member States. This project is the continuation of previous efforts to turn RD a priority in the EC Health Programmes “Orphanet Europe” was a Joint Action co-funded by INSERM, the French Directorate General for Health and the EC to address the need for a common portal that would gather the most update information regarding RD. This need was identified in the European Commission report “Rare Diseases: Europe's challenge” and in the Recommendation of the Council for a European RD portal. These joint actions have supported the policy development work of the European Commission, through the support of their committees for rare diseases. In this paper, the authors aim to raise awareness of the work done by the EUCERD Joint Action on behalf of the rare disease community and the policies established.

      PubDate: 2017-01-16T09:28:59Z
       
  • Inflammatory myopathy in a patient with Aicardi-Goutières syndrome
    • Abstract: Publication date: Available online 9 January 2017
      Source:European Journal of Medical Genetics
      Author(s): Birutė Tumienė, Norine Voisin, Eglė Preikšaitienė, Donatas Petroška, Jurgita Grikinienė, Rūta Samaitienė, Algirdas Utkus, Alexandre Reymond, Vaidutis Kučinskas
      Aicardi–Goutières syndrome (AGS) is an inflammatory disorder belonging to the recently characterized group of type I interferonopathies. The most consistently affected tissues in AGS are the central nervous system and skin, but various organ systems and tissues have been reported to be affected, pointing to the systemic nature of the disease. Here we describe a patient with AGS due to a homozygous p.Arg114His mutation in the TREX1 gene. The histologically proven inflammatory myopathy in our patient expands the range of clinical features of AGS. Histological signs of muscle biopsies in the proband, and in two other AGS patients described earlier, are similar to those seen in various autoimmune myositises and could be ascribed to inapproapriate IFN I activation. In view of signs of possible mitochondrial damage in AGS, we propose that mitochondrial DNA could be a trigger of autoimmune responses in AGS.

      PubDate: 2017-01-16T09:28:59Z
       
  • Multiple HABP2 variants in familial papillary thyroid carcinoma:
           Contribution of a group of “thyroid-checked” controls
    • Abstract: Publication date: Available online 9 January 2017
      Source:European Journal of Medical Genetics
      Author(s): Benjamin Kern, Lucie Coppin, Pauline Romanet, Michel Crépin, Isabelle Szuster, Florence Renaud, Emmanuelle Leteurtre, Frédéric Frénois, Jean-Louis Wemeau, Bruno Carnaille, Catherine Cardot-Bauters, Christine Do Cao, Pascal Pigny
      A heterozygous germline variant in the HABP2 gene c.1601G > A (p.Gly534Glu), which negatively impacts its tumor suppressive activity in vitro, has been described in 4–14% of kindreds of European-American ancestry with familial papillary thyroid carcinoma (fPTC). But it is also found in ≈4% of Europeans and European/Americans from public databases that, however, did not provide information on the thyroid function of the controls. To get unbiased results, we decided to compare HABP2 genotypes of patients with fPTC with those of “thyroid-checked” controls. A control group consisting of 136 European patients who were thyroidectomised for medullary thyroid carcinoma and devoid of any histologically detectable PTC or follicular-deriving carcinoma was built. In parallel we recruited 20 patients with fPTC from eleven independent European kindreds. The entire coding region of HABP2 was analyzed by Sanger sequencing the germline DNAs of patients. Nucleotide variants were searched for by Snap Shot analysis in the controls. Two variants, c.1601G > A (p.Gly534Glu) and c.364C > T (p.Arg122Trp), were found in 2 and 3 patients at the heterozygous level respectively (minor allele frequency (MAF): 5.0% and 7.5%, respectively). In controls, the MAF was either similar for the c.1601G > A HABP2 variant (2.94%, ns) or significantly lower for the c.364C > T variant (0.73%, p = 0.016). The Arg122 residue lies in the EGF-3 domain of HABP2 which is important for its activation but, however, superposition of the predicted 3D structures of the wild type and mutated proteins suggests that this variant is tolerated at the protein level. In conclusion, our data do not support the pathogenicity of the HABP2 c.1601G > A variant but highlight the existence of a new one that should be more extensively searched for in fPTC patients and its pathogenicity more carefully evaluated.

      PubDate: 2017-01-16T09:28:59Z
       
  • The impact of thalidomide use in birth defects in Brazil
    • Abstract: Publication date: January 2017
      Source:European Journal of Medical Genetics, Volume 60, Issue 1
      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: 2016-12-30T05:34:06Z
       
  • Prevalence of alcohol consumption during pregnancy and Fetal Alcohol
           Spectrum Disorders among the general and Aboriginal populations in Canada
           and the United States
    • Abstract: Publication date: January 2017
      Source:European Journal of Medical Genetics, Volume 60, Issue 1
      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. The FAS and FASD pooled prevalence estimates presented here 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: 2016-12-30T05:34:06Z
       
  • Neurodevelopmental disorder associated with prenatal exposure to alcohol
           (ND-PAE): A proposed diagnostic method of capturing the neurocognitive
           phenotype of FASD
    • Abstract: Publication date: January 2017
      Source:European Journal of Medical Genetics, Volume 60, Issue 1
      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: 2016-12-30T05:34:06Z
       
  • Correlation between morphological MRI findings and specific diagnostic
           categories in fetal alcohol spectrum disorders
    • Abstract: Publication date: January 2017
      Source:European Journal of Medical Genetics, Volume 60, Issue 1
      Author(s): S. Boronat, A. Sánchez-Montañez, N. Gómez-Barros, 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: 2016-12-30T05:34:06Z
       
  • In silico analysis for predicting pathogenicity of five unclassified
           mitochondrial DNA mutations associated with mitochondrial cytophaties'
           phenotypes
    • Abstract: Publication date: Available online 24 December 2016
      Source:European Journal of Medical Genetics
      Author(s): Mafalda Bacalhau, João Pratas, Marta Simões, Cândida Mendes, Carolina Ribeiro, Maria J. Santos, Luisa Diogo, Maria Carmo Macário, Manuela Grazina
      Mitochondrial DNA (mtDNA) mutations have been assigned as a major cause of genetic disease. When a novel sequence variation is found, it is necessary to evaluate its functional impact, usually requiring functional molecular studies. Given the fact that this approach is difficult to put in practice in a routine basis, it is possible to take advantage of the in silico tools available and predict protein/RNA structure changes and therefore pathogenicity. Here, we describe the characterization of five undescribed mtDNA variants, upon detection of 23 unclassified alterations at Laboratory of Biochemical Genetics, from 2004 to 2014. Those five sequence variations are located in protein-encoding genes, in five patients with a diverse range of mitochondrial respiratory chain disease phenotypes including encephalopathy, optic neuropathy, developmental delay, deafness and epilepsy. According to the prediction established by in silico analysis using tools to predict structure and function changes (Clustalw2®, Polyphen2®, SIFT®, MutationAssessor®, PredictProtein®, Provean®, I-TASSER®, Haplogrep®), from the 23 variants analyzed, the five described are potentially pathogenic. This approach is inexpensive and compatible with a rapid first line response to clinical demanding, contributing to a more rationale genetic diagnosis concerning novel mutations and to clarify the mtDNA involvement in these pathologies.

      PubDate: 2016-12-30T05:34:06Z
       
  • Cleidocranial dysplasia: Clinical, endocrinologic and molecular findings
           in 15 patients from 11 families
    • Abstract: Publication date: Available online 24 December 2016
      Source:European Journal of Medical Genetics
      Author(s): Firdevs Dinçsoy Bir, Nuriye Dinçkan, Yeliz Güven, Firdevs Baş, Umut Altunoğlu, Senem S. Kuvvetli, Şükran Poyrazoğlu, Güven Toksoy, Hülya Kayserili, Z. Oya Uyguner
      Cleidocranial dysplasia (CCD) is an autosomal dominant disorder characterized by skeletal anomalies such as delayed closure of the cranial sutures, underdeveloped or absent clavicles, multiple dental abnormalities, short stature and osteoporosis. RUNX2, encoding Runt DNA-binding domain protein important in osteoblast differentiation, is the only known gene related to the disease and identified as responsible in 70% of the cases. Our clinical evaluations revealed that short stature present at a rate of 28.6%, osteoporosis at a rate of 57.1% and osteopenia at 21.4%. In this study, RUNX2 sequencing revealed nine different variations in 11 families, eight being pathogenic of which one was novel gross insertion (c.1271_1272ins20) and one other being predicted benign in frame gross deletion (c.241_258del).

      PubDate: 2016-12-30T05:34:06Z
       
  • A severe pulmonary complication in a patient with COL4A1-related disorder:
           A case report
    • Abstract: Publication date: Available online 23 December 2016
      Source:European Journal of Medical Genetics
      Author(s): Yoshiichi Abe, Atsuko Matsuduka, Kazuo Okanari, Hiroaki Miyahara, Mitsuhiro Kato, Satoko Miyatake, Hirotomo Saitsu, Naomichi Matsumoto, Maeda Tomoki, Kenji Ihara
      Patients with COL4A1 mutation-related disorders demonstrate a variety of disease phenotypes, which caused by small-vessel dysfunction in the brain, eyes, kidney, muscle, or heart. The involvement of organs mainly depends on the expression of the COL4A1 gene. Complication or dysfunction of the alveolar tissue has not been reported in the literature on COL4A1 mutation-related disorders. We herein report the case of a boy with schizencephaly, renovascular hypertension, and retinal arteriosclerosis of unknown origin, who suffered from severe and repetitive alveolar hemorrhage at 9 years of age. A novel COL4A1 mutation was finally identified as the genetic cause. The pulmonary complication in the present case represents an important pathophysiological mechanism COL4A1 mutation-related disorders; lung tissue with COL4A1 gene mutations may be vulnerable and environmental substances and microorganisms in the air could accumulate to cause chronic damage in the alveolar tissues, especially in patients with tracheostoma and renovascular hypertension.

      PubDate: 2016-12-30T05:34:06Z
       
  • Editorial: Updates in Teratology
    • Abstract: Publication date: Available online 20 December 2016
      Source:European Journal of Medical Genetics


      PubDate: 2016-12-23T03:00:20Z
       
  • 16p13 microduplication without CREBBP involvement: Moving toward a
           phenotype delineation
    • Abstract: Publication date: Available online 20 December 2016
      Source:European Journal of Medical Genetics
      Author(s): Claudia Ciaccio, Arianna Tucci, Giulietta Scuvera, Margherita Estienne, Susanna Esposito, Donatella Milani
      The short arm of chromosome 16 is one of the less stable regions of our genome, as over 10% of the euchromatic region of 16p is composed of highly complex low copy repeats that are known to be predisposed to rearrangements mediated by non-allelic homologous recombination. The 16p13.3p13.13 molecular region has been defined as the 16p duplication hotspot, and duplications of chromosome 16p13 have recently been confirmed to cause a recognizable syndrome, with CREBBP being the main phenotype-causing gene. To date, only one case report is present in the literature with a 16p13 duplication without CREBBP involvement; we describe here a second analogous case with a not previously reported 16p13.2p13.13 microduplication. This paper allows us to better delineate the clinical features of 16p13 microduplications that do not encompass CREBBP and, concurrently, to narrow the molecular region responsible for congenital heart defects in 16p duplications as well as to propose GRIN2A as a candidate gene for epilepsy.

      PubDate: 2016-12-23T03:00:20Z
       
  • Calcifying Nested Stromal-Epithelial Tumor (CNSET) of the liver in
           Beckwith-Wiedemann syndrome
    • Abstract: Publication date: Available online 10 December 2016
      Source:European Journal of Medical Genetics
      Author(s): Nasim Khoshnam, Haynes Robinson, Michael R. Clay, Lauren R. Schaffer, Scott E. Gillespie, Bahig M. Shehata
      Calcifying nested stromal-epithelial tumor (CNSET) is a rare neoplasm. In the 31 reported cases, CNSET is predominantly found in young girls and women. Beckwith-Wiedemann syndrome (BWS) (OMIM #130650) is an overgrowth syndrome with an increased risk to develop cancer. Associations have been seen between BWS and embryonal tumors, especially Wilms tumor, hepatoblastoma, and adrenocortical carcinoma. Here we report on a female patient with BWS who presented with CNSET. Two other cases with the same association have been reported, with our case representing the third such reported in the literature. Although we recognize a potential reporting bias we speculate that CNSET may represent an unrecognized addition to the spectrum of BWS tumorigenesis.

      PubDate: 2016-12-14T15:22:37Z
       
  • The M694I/M694I genotype: A genetic risk factor of AA-amyloidosis in a
           group of Algerian patients with familial Mediterranean fever
    • Abstract: Publication date: Available online 10 December 2016
      Source:European Journal of Medical Genetics
      Author(s): Djouher Ait-Idir, Bahia Djerdjouri, Faiza Bouldjennet, Rowaida Z. Taha, Hatem El-Shanti, Rawda Sari-Hamidou, Ghalia Khellaf, Mustapha Benmansour, Mohamed Benabadji, Farid Haddoum
      Familial Mediterranean fever (FMF, OMIM 249100) is the most common hereditary fever, resulting from mutations in MEFV. FMF is characterized by episodic febrile attacks and polyserositis. Renal AA-amyloidosis is a major complication, which often leads to end-stage renal disease in untreated patients. The data about the renal AA-amyloidosis secondary to FMF are scarce in North African countries and non-existent in Algeria. We aimed to investigate the MEFV mutations associated with this complication in an Algerian patient cohort. Molecular analysis included 28 unrelated Algerian FMF patients with ascertained amyloidosis, 23 of them were symptomatic and 5 were asymptomatic. For this study, a group of 20 FMF patients without renal amyloidosis were selected as controls according to their age, disease onset and disease duration. The mutations were detected by sequencing exon 10 of MEFV. A total of 87.5% (49/56) mutant alleles were identified in 27/28 analyzed patients; p.M694I was predominant and appeared with an allele frequency of 62.5%, followed by p.M694V (17.85%), p.M680I (5.35%) and p.I692Del (1.78%). Remarkably, only p.M694I mutation was observed among the asymptomatic patients. The M694I/M694I genotype, identified in 14/27 (52%) patients, was significantly associated with the development of amyloidosis compared to group of controls (p = 0.022). This study did not link the M694V/M694V genotype to the renal complication despite the fact that it has been observed only in the patients with amyloidosis (3/27; 11%) (p = 0.349). The association of other identified genotypes to this complication was statistically insignificant. The progression of amyloidosis led to end-stage renal disease in 14 patients with 6 deaths. This study shows that p.M694I homozygosity is a potential genetic risk factor for the development of renal AA-amyloidosis in Algerian FMF patients.

      PubDate: 2016-12-14T15:22:37Z
       
  • Stargardt disease-associated mutation spectrum of a Russian Federation
           cohort
    • Abstract: Publication date: Available online 9 December 2016
      Source:European Journal of Medical Genetics
      Author(s): Inna V. Zolnikova, Vladimir V. Strelnikov, Natalia A. Skvortsova, Alexander S. Tanas, Debmalya Barh, Elena V. Rogatina, Irina V. Egorova, Darja V. Levina, Olga N. Demenkova, Egor G. Prikaziuk, Marianna E. Ivanova
      ABCA4-associated mutation screening is extensively performed in European, African, American and several other populations for various retinopathies. However, it has not been well studied in a Russian cohort. Using next-generation (325 genes inherited disease panel) and Sanger sequencing technologies for the first time we documented the spectrum of genetic variations in a Russian retinopathy cohort of 51 patients from 10 ethnic groups. We found ABCA4 variations in 70.5% cases and one case with BEST1 variation. Multiple ABCA4 variations, ABCA4 + RDH12, and ABCA4 + BEST1 variations are also observed and the disease severity is found proportionate to the variation burden. Ten novel ABCA4 variations are detected of which 8 belongs to non-Slavonian population. Most of the detected known variations are found in European and American Stargardt disease populations. No retinopathy causing variation is detected in 14 (27%) cases suggesting that in this Russian retinopathies cohort the causal variants could be in genes that are not covered by our 325 gene panel. Therefore, whole genome/exome analysis is required to identify novel retinopathy associated genes and provide better disease management for this heterogeneous cohort.

      PubDate: 2016-12-14T15:22:37Z
       
  • Clinical features associated with CTNNB1 de novo loss of function
           mutations in ten individuals
    • Abstract: Publication date: Available online 30 November 2016
      Source:European Journal of Medical Genetics
      Author(s): Mira Kharbanda, Daniela T. Pilz, Susan Tomkins, Kate Chandler, Anand Saggar, Alan Fryer, Victoria McKay, Pedro Louro, Jill Clayton Smith, John Burn, Usha Kini, Anna De Burca, David R. FitzPatrick, Esther Kinning
      Loss of function mutations in CTNNB1 have been reported in individuals with intellectual disability [MIM #615075] associated with peripheral spasticity, microcephaly and central hypotonia, suggesting a recognisable phenotype associated with haploinsufficiency for this gene. Trio based whole exome sequencing via the Deciphering Developmental Disorders (DDD) study has identified eleven further individuals with de novo loss of function mutations in CTNNB1. Here we report detailed phenotypic information on ten of these. We confirm the features that have been previously described and further delineate the skin and hair findings, including fair skin and fair and sparse hair with unusual patterning.

      PubDate: 2016-12-07T14:38:47Z
       
  • Autosomal recessive spinocerebellar ataxia 20: Report of a new patient and
           review of literature
    • Abstract: Publication date: Available online 29 November 2016
      Source:European Journal of Medical Genetics
      Author(s): Anju Shukla, Priyanka Upadhyai, Jhanvi Shah, K. Neethukrishna, Stephanie Bielas, K.M. Girisha
      Inherited ataxias are an extremely heterogeneous group of disorders. Autosomal recessive spinocerebellar ataxia 20 (SCAR20) is a recently described disorder characterized by intellectual disability, ataxia, coarse facial features, progressive loss of Purkinje cells in the cerebellum and often hearing loss and skeletal abnormalities. Mutations in the gene SNX14, which plays an important role in autophagy, have been found to cause SCAR20. The unique clinical findings of progressive coarsening of facial features makes the clinical phenotype recognizable among the various hereditary ataxias. Here we report on a child with a novel missense mutation in the SNX14 gene that appears to be debilitating for protein conformation, function and review the previously reported cases from 15 families.

      PubDate: 2016-12-07T14:38:47Z
       
  • 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 predisposition and hematopoietic malignancies in children: Primary
           immunodeficiency
    • 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
       
  • 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 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
       
  • 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
           PNPLA6
    • 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
       
  • 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
       
  • 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
       
  • 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
       
  • 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
       
  • 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
       
  • 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
       
  • Interventions in fetal alcohol spectrum disorders: An international
           perspective
    • 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
       
  • 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
       
  • 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 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
       
  • 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
       
  • 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
       
  • 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
       
  • 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
       
 
 
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