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Journal Cover European Journal of Medical Genetics
  [SJR: 0.934]   [H-I: 40]   [6 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1769-7212
   Published by Elsevier Homepage  [3042 journals]
  • Genotype-phenotype evaluation of MED13L defects in the light of a novel
           truncating and a recurrent missense mutation
    • Abstract: Publication date: Available online 21 June 2017
      Source:European Journal of Medical Genetics
      Author(s): Reza Asadollahi, Markus Zweier, Laura Gogoll, Raphael Schiffmann, Heinrich Sticht, Katharina Steindl, Anita Rauch
      A decade after the designation of MED13L as a gene and its link to intellectual disability (ID) and dextro-looped transposition of great arteries in 2003, we previously described a recognizable syndrome due to MED13L haploinsufficiency. Subsequent reports of 22 further patients diagnosed by genome-wide testing further delineated the syndrome with expansion of the phenotypic spectrum and showed reduced penetrance for congenital heart defects. We now report two novel patients identified by whole exome sequencing, one with a de novo MED13L truncating mutation and the other with a de novo missense mutation. The first patient indicates some facial resemblance to Kleefstra syndrome as a novel differential diagnosis, and the second patient shows, for the first time, recurrence of a MED13L missense mutation (p.(Asp860Gly)). Notably, our in silico modelling predicted this missense mutation to decrease the stability of an alpha-helix and thereby affecting the MED13L secondary structure, while the majority of published missense mutations remain variants of uncertain significance. Review of the reported patients with MED13L haploinsufficiency indicates moderate to severe ID and facial anomalies in all patients, as well as severe speech delay and muscular hypotonia in the majority. Further common signs include abnormal MRI findings of myelination defects and abnormal corpus callosum, ataxia and coordination problems, autistic features, seizures/abnormal EEG, or congenital heart defects, present in about 20–50% of the patients. With reference to facial anomalies, the majority of patients were reported to show broad/prominent forehead, low set ears, bitemporal narrowing, upslanting palpebral fissures, depressed/flat nasal bridge, bulbous nose, and abnormal chin, but macroglossia and horizontal eyebrows were also observed in ∼30%. The latter are especially important in the differential diagnosis of 1p36 deletion and Kleefstra syndromes, while the more common facial gestalt shows some resemblance to 22q11.2 deletion syndrome. Despite the fact that MED13L was found to be one of the most common ID genes in the Deciphering Developmental Disorders Study, further detailed patient descriptions are needed to explore the full clinical spectrum, potential genotype-phenotype correlations, as well as the role of missense mutations and potential mutational hotspots along the gene.

      PubDate: 2017-06-22T04:02:17Z
       
  • High-throughput sequencing of the entire genomic regions of CCM1/KRIT1,
           CCM2 and CCM3/PDCD10 to search for pathogenic deep-intronic splice
           mutations in cerebral cavernous malformations
    • Abstract: Publication date: Available online 20 June 2017
      Source:European Journal of Medical Genetics
      Author(s): Matthias Rath, Sönke E. Jenssen, Konrad Schwefel, Stefanie Spiegler, Dana Kleimeier, Christian Sperling, Lars Kaderali, Ute Felbor
      Cerebral cavernous malformations (CCM) are vascular lesions of the central nervous system that can cause headaches, seizures and hemorrhagic stroke. Disease-associated mutations have been identified in three genes: CCM1/KRIT1, CCM2 and CCM3/PDCD10. The precise proportion of deep-intronic variants in these genes and their clinical relevance is yet unknown. Here, a long-range PCR (LR-PCR) approach for target enrichment of the entire genomic regions of the three genes was combined with next generation sequencing (NGS) to screen for coding and non-coding variants. NGS detected all six CCM1/KRIT1, two CCM2 and four CCM3/PDCD10 mutations that had previously been identified by Sanger sequencing. Two of the pathogenic variants presented here are novel. Additionally, 20 stringently selected CCM index cases that had remained mutation-negative after conventional sequencing and exclusion of copy number variations were screened for deep-intronic mutations. The combination of bioinformatics filtering and transcript analyses did not reveal any deep-intronic splice mutations in these cases. Our results demonstrate that target enrichment by LR-PCR combined with NGS can be used for a comprehensive analysis of the entire genomic regions of the CCM genes in a research context. However, its clinical utility is limited as deep-intronic splice mutations in CCM1/KRIT1, CCM2 and CCM3/PDCD10 seem to be rather rare.

      PubDate: 2017-06-22T04:02:17Z
       
  • NGS panel analysis in 24 ectopia lentis patients; a clinically relevant
           test with a high diagnostic yield
    • Abstract: Publication date: Available online 19 June 2017
      Source:European Journal of Medical Genetics
      Author(s): E. Overwater, K. Floor, D. van Beek, K. de Boer, T. van Dijk, Y. Hilhorst-Hofstee, A.J.M. Hoogeboom, K.J. van Kaam, J.M. van de Kamp, M. Kempers, I.P.C. Krapels, H.Y. Kroes, B. Loeys, S. Salemink, C.T.R.M. Stumpel, V.J.M. Verhoeven, E. Wijnands-van den Berg, J.M. Cobben, J.P. van Tintelen, M.M. Weiss, A.C. Houweling, A. Maugeri
      Background Several genetic causes of ectopia lentis (EL), with or without systemic features, are known. The differentiation between syndromic and isolated EL is crucial for further treatment, surveillance and counseling of patients and their relatives. Next generation sequencing (NGS) is a powerful tool enabling the simultaneous, highly-sensitive analysis of multiple target genes. Objective The aim of this study was to evaluate the diagnostic yield of our NGS panel in EL patients. Furthermore, we provide an overview of currently described mutations in ADAMTSL4, the main gene involved in isolated EL. Methods A NGS gene panel was analysed in 24 patients with EL. Results A genetic diagnosis was confirmed in 16 patients (67%). Of these, four (25%) had a heterozygous FBN1 mutation, 12 (75%) were homozygous or compound heterozygous for ADAMTSL4 mutations. The known European ADAMTSL4 founder mutation c.767_786del was most frequently detected. Conclusion The diagnostic yield of our NGS panel was high. Causative mutations were exclusively identified in ADAMTSL4 and FBN1. With this approach the risk of misdiagnosis or delayed diagnosis can be reduced. The value and clinical implications of establishing a genetic diagnosis in patients with EL is corroborated by the description of two patients with an unexpected underlying genetic condition.

      PubDate: 2017-06-22T04:02:17Z
       
  • Digenic inheritance of mutations in the cardiac troponin (TNNT2) and
           cardiac beta myosin heavy chain (MYH7) as the cause of severe dilated
           cardiomyopathy
    • Abstract: Publication date: Available online 19 June 2017
      Source:European Journal of Medical Genetics
      Author(s): Evmorfia Petropoulou, Mohammadhossein Soltani, Ali Dehghani Firoozabadi, Seyedeh Mahdieh Namayandeh, Jade Crockford, Reza Maroofian, Yalda Jamshidi
      Familial dilated cardiomyopathy (DCM) is characterized by ventricular dilation and depressed myocardial performance. It is a genetically heterogeneous disorder associated with mutations in over 60 genes. We carried out whole exome sequencing in combination with cardiomyopathy-related gene-filtering on two affected family members to identify the possible causative mutation in a consanguineous Iranian family with DCM. Two novel variants in cardiomyopathy-related genes were identified: c.247 A > C; p.N83H in the Troponin T Type 2 gene (TNNT2) and c.2863G > A; p.D955N in the Myosin Heavy Polypeptide 7 gene (MYH7). Sanger sequencing and co-segregation analysis in the remaining family members supported the coexistence of these digenic mutations in affected members of the family. Carriers of either variant alone were asymptomatic. In summary, we find that digenic inheritance of two novel variants in DCM related genes is associated with a severe form of DCM. Exome sequencing has been shown to be very useful in identifying pathogenic mutations in cardiomyopathy families, and this report emphasizes the importance of comprehensive screening of DCM related genes, even after the identification of a single disease-causing mutation.

      PubDate: 2017-06-22T04:02:17Z
       
  • A novel missense variant (Gln220Arg) of GNB4 encoding guanine
           nucleotide-binding protein, subunit beta-4 in a Japanese family with
           autosomal dominant motor and sensory neuropathy
    • Abstract: Publication date: Available online 19 June 2017
      Source:European Journal of Medical Genetics
      Author(s): Shiroh Miura, Takuya Morikawa, Ryuta Fujioka, Kazuhito Noda, Kengo Kosaka, Takayuki Taniwaki, Hiroki Shibata
      Dominant intermediate Charcot–Marie–Tooth disease F (CMTDIF) is an autosomal dominant hereditary form of Charcot–Marie–Tooth disease (CMT) caused by variations in the guanine nucleotide-binding protein, subunit beta-4 gene (GNB4). We examined two Japanese familial cases with CMT. Case 1 was a 49-year-old male whose chief complaint was slowly progressive gait disturbance and limb dysesthesia that appeared at the age of 47. On neurological examination, he showed hyporeflexia or areflexia, distal limb muscle weakness, and distal sensory impairment with lower dominancy. Nerve conduction studies demonstrated demyelinating sensorimotor neuropathy with reduced action potentials in the lower limbs. Case 2 was an 80-year-old man, Case 1's father, who reported difficulty in riding a bicycle at the age of 76. On neurological examination, he showed areflexia in the upper and lower limbs. Distal sensory impairment in the lower limbs was also observed. Nerve conduction studies revealed mainly axonal involvement. Exome sequencing identified a novel heterozygous nonsynonymous variant (NM_021629.3:c.659T > C [p.Gln220Arg]) in GNB4 exon 8, which is known to be responsible for CMT. Sanger sequencing confirmed that both patients are heterozygous for the variation, which causes an amino acid substitution, Gln220Arg, in the highly conserved region of the WD40 domain of GNB4. The frequency of this variant in the Exome Aggregation Consortium Database was 0.000008247, and we confirmed its absence in 502 Japanese control subjects. We conclude that this novel GNB4 variant is causative for CMTDIF in these patients, who represent the first record of the disease in the Japanese population.

      PubDate: 2017-06-22T04:02:17Z
       
  • Familial epilepsy with anterior polymicrogyria as a presentation of
           COL18A1 mutations
    • Abstract: Publication date: Available online 8 June 2017
      Source:European Journal of Medical Genetics
      Author(s): Mark A. Corbett, Samantha J. Turner, Alison Gardner, Jeremy Silver, Jim Stankovich, Richard J. Leventer, Christopher P. Derry, Renée Carroll, Thuong Ha, Ingrid E. Scheffer, Melanie Bahlo, Graeme D. Jackson, David A. Mackey, Samuel F. Berkovic, Jozef Gecz
      Knobloch syndrome [OMIM: (KNO1) #267750] is a rare and clinically heterogeneous autosomal recessive disorder caused by mutations in COL18A1. Knobloch syndrome is characterised by abnormalities of the eye and occipital skull defects however the full phenotypic spectrum is yet to be defined. This report describes a family of four affected sisters with polymicrogyria, refractory seizures, and intellectual impairment of varying severity with a Lennox-Gastaut phenotype, and complex eye abnormalities where a syndromic diagnosis was not initially made. Whole exome sequencing of two affected sisters followed by filtering for rare and potentially disease causing variants in all genes identified compound heterozygous variants in NM_030582.3 (COL18A1): c.3690G > A: p.(Trp1230*) and NM_030582.3 (COL18A1): c.4063_4064delCT: p.(Leu1355Valfs*72). The two variants co-segregated with the affected individuals in the family. Identification of COL18A1 mutations in individuals with a Lennox-Gastaut phenotype and anterior polymicrogyria but lacking the classical occipital encephalocele expands the COL18A1 clinical spectrum.

      PubDate: 2017-06-12T01:39:46Z
       
  • Pachydermoperiostosis of the complete type: A novel missense mutation
           c.101T > C in the SLCO2A1 gene
    • Abstract: Publication date: Available online 8 June 2017
      Source:European Journal of Medical Genetics
      Author(s): Wenbin Ma, Shuqin Guo, Yan Li, Zhihong Li
      We report on a rare case of pachydermoperiostosis (PDP) in a 25-year-old male who was admitted to our hospital because of enlargement of fingers and toes. Through examination, we found some typical features on the patient including finger clubbing, periostosis, pachydermia, and cutis verticis gyrata (CVG). But laboratory tests were almost within normal ranges, which ruled out rheumatic arthritis, osteopulmonary arthropathy, thyroid acropathy, and acromegaly. Then, we diagnosed this case as PDP, which was confirmed by gene sequencing. The pathogenesis is concerned with abnormal rise of the level of PGE2 that results from the solute carrier organic anion transporter family member 2A1 (SLCO2A1) gene defect. Meanwhile, we found a novel missense mutation c.101T > C of the SLCO2A1 gene in the patient with PDP.

      PubDate: 2017-06-12T01:39:46Z
       
  • Postzygotic telomere capture causes segmental UPD, duplication and
           deletion of chromosome 8p in a patient with intellectual disability and
           obesity
    • Abstract: Publication date: Available online 8 June 2017
      Source:European Journal of Medical Genetics
      Author(s): Jeroen Knijnenburg, Madiek E.W. Uytdewilligen, Daniella A.C.M. van Hassel, Rianne Oostenbrink, Bert H.J. Eussen, Annelies de Klein, Alice S. Brooks, Laura J.C.M. van Zutven
      Using SNP array and FISH analysis, a patient with moderate intellectual disability and obesity was found to harbour an atypical 1.6 Mb inverted duplication on 8p23.1, directly flanked by a distally located interstitial deletion of 2.3 Mb and a terminal segmental uniparental disomy. The duplicated and deleted regions lie exactly between the two segmental duplication regions. These segmental duplications on chromosome 8p23.1 are known to be involved in chromosomal rearrangements because of mutual homology and homology to other genomic regions. Genomic instability mediated by these segmental duplications is generally caused by non-allelic homologous recombination, resulting in deletions, reciprocal duplications, inversions and translocations. Additional analysis of the parental origin of the fragments of this atypical inverted duplication/interstitial deletion shows paternal contribution in the maternal derivate chromosome 8. Combined with the finding that the normal chromosome 8 carries an inversion in 8p23.1 we hypothesize that a double strand break in 8p23.1 of the maternal chromosome was postzygotically repaired with the paternal inverted copy resulting in a duplication, deletion and segmental uniparental disomy, with no particular mediation of the 8p23.1 segmental duplication regions in recombination.

      PubDate: 2017-06-12T01:39:46Z
       
  • Recurrent elevated liver transaminases and acute liver failure in two
           siblings with novel bi-allelic mutations of NBAS
    • Abstract: Publication date: Available online 30 May 2017
      Source:European Journal of Medical Genetics
      Author(s): Frederico S. Regateiro, Serkan Belkaya, Nélson Neves, Sandra Ferreira, Paula Silvestre, Sónia Lemos, Margarida Venâncio, Jean-Laurent Casanova, Isabel Gonçalves, Emmanuelle Jouanguy, Luísa Diogo
      Background Acute liver failure (ALF) in children can be life-threatening. Although many causes are known, ALF remains unexplained in about half of the cases. Recently, bi-allelic mutations in NBAS were reported to underlie recurrent episodes of elevated liver transaminases (ELT) and ALF in the context of diverse extrahepatic phenotypes. Results We here describe two sisters, born to non-consanguineous Portuguese parents, who had short stature and presented with recurrent episodes of severe ELT triggered by febrile respiratory viral infections from early childhood. Patient 1 presented mild facial dysmorphism and died during the second ELT crisis at 3–11/12 years of age. Patient 2, currently 9 years old, had multiple episodes of ELT (>30), twice with ALF, often accompanied by extensive urticaria and facial angioedema. Whole-exome and Sanger sequencing revealed that both patients carried previously undescribed compound heterozygous mutations of NBAS (NM_015909.3): c.680A > C (p.His227Pro), affecting an evolutionarily conserved residue, and c.1749G > A (p.Trp583*), causing a premature stop codon. Both mutations are predicted to be highly damaging. The parents and two younger siblings are healthy and heterozygous for one or another mutant allele. Discussion This multiplex kindred with autosomal recessive NBAS deficiency expands the genotypic and phenotypic spectrum of this recently described clinical syndrome. Novel analytical and histological abnormalities here reported might contribute to a better understanding of the disease pathophysiology.

      PubDate: 2017-06-02T00:11:35Z
       
  • Novel splice mutation in LRP4 causes severe type of Cenani-Lenz syndactyly
           syndrome with oro-facial and skeletal symptoms
    • Abstract: Publication date: Available online 27 May 2017
      Source:European Journal of Medical Genetics
      Author(s): Muhammad Afzal, Qamar Zaman, Uwe Kornak, Stefan Mundlos, Sajid Malik, Ricarda Flöttmann
      Cenani-Lenz syndactyly syndrome (CLSS; MIM-212780) is a rare autosomal recessive limb malformation characterized by complete osseous fusion of all fingers and toes, disorganization of phalangeal elements and severe shortening of the radius and ulna. It is occasionally associated with renal hypoplasia, oro-facial defects, scoliosis of the thoracic spine, hearing loss, and genital anomalies. Here we describe a consanguineous Pakistani kindred with a severe form of CLSS characterized by complete syndactyly and disorganization of fingers, oligo-syndactyly of toes, shortening of limbs, frontal bossing, and hypoplasia/agenesis of left kidney. The affected individuals were additionally presented with short stature, cleft-lip and hypoplastic shoulder joint with restricted upper limb movement. A novel splice variant in LRP4 (c.316+1G > A) segregated with the phenotype in a five generations family. The mutation is predicted to add 29 non-native amino acids with a premature termination, resulting in approximately 90% length reduction of the wild-type transcript. These findings not only further expand the phenotypic variability of CLSS but also indicate that early truncated and loss-of-function mutations in LRP4 lead to a more severe CLSS phenotype.

      PubDate: 2017-05-27T23:31:33Z
       
  • A novel deletion of SNURF/SNRPN exon 1 in a patient with Prader-Willi-like
           phenotype
    • Abstract: Publication date: Available online 26 May 2017
      Source:European Journal of Medical Genetics
      Author(s): Yang Cao, Susan S. AlHumaidi, Eissa A. Faqeih, Beth A. Pitel, Patrick Lundquist, Umut Aypar
      Here we report the smallest deletion involving SNURF/SNRPN that causes major symptoms of Prader-Willi syndrome (PWS), including hypotonia, dysmorphic features, intellectual disability, and obesity. A female patient with the aforementioned and additional features was referred to the Mayo Clinic Cytogenetics laboratory for genetic testing. Chromosomal microarray analysis and subsequent Sanger sequencing identified a de novo 6.4 kb deletion at 15q11.2, containing exon 1 of the SNURF gene and exon 1 of the shortest isoform of the SNRPN gene. SNURF/SNRPN exon 1, which is methylated on the silent maternal allele, is associated with acetylated histones on the expressed paternal allele. This region also overlaps with the PWS-imprinting center (IC). Subsequent molecular methylation analysis was performed using methylation-specific MLPA (MS-MLPA), which characterized that the deletion of SNURF/SNRPN exon 1 was paternal in origin, consistent with the PWS-like phenotype. Since SNURF/SNRPN gene and the PWS-IC are known to regulate snoRNAs, it is likely that the PWS-like phenotype observed in patients with paternal SNURF/SNRPN deletion is due to the disrupted expression of SNORD116 snoRNAs.

      PubDate: 2017-05-27T23:31:33Z
       
  • Novel missense loss-of-function mutations of WNT1 in an autosomal
           recessive Osteogenesis imperfecta patient
    • Abstract: Publication date: Available online 17 May 2017
      Source:European Journal of Medical Genetics
      Author(s): Joon Yeon Won, Woo Young Jang, Hye-Ran Lee, Seon Young Park, Woo-Young Kim, Jong Hoon Park, Yonghwan Kim, Tae-Joon Cho
      Osteogenesis imperfecta (OI) is a heritable skeletal disorder characterized by bone fragility and low bone mass. Recently, loss-of-function mutations of WNT1 have been reported to be causative in OI or osteoporosis. We report an OI patient with novel compound heterozygous WNT1 missense mutations, p.Glu123Asp and p.Cys153Gly. Both mutations are found in the exon 3, and the p.Glu123Asp is the most proximal N-terminus missense mutation among the reported WNT1 missense mutations in OI patients. In vitro functional analysis reveals that while expression of wildtype WNT1 stimulates canonical WNT1-mediated β-catenin signaling, that of individual WNT1 mutant fails to do so, indicative of the pathogenic nature of the WNT1 variants. Although the pathogenic mechanism of WNT1 defects in OI has yet to be uncovered, these findings further contribute to the implications and importance of functional relevance of WNT1 in skeletal disorders.

      PubDate: 2017-05-17T20:35:12Z
       
  • A 'joint venture' model of recontacting in clinical genomics: Challenges
           for responsible implementation
    • Abstract: Publication date: Available online 10 May 2017
      Source:European Journal of Medical Genetics
      Author(s): Sandi Dheensa, Daniele Carrieri, Susan Kelly, Angus Clarke, Shane Doheny, Peter Turnpenny, Anneke Lucassen Dphil
      Advances in genomics often lead healthcare professionals (HCPs) to learn new information, e.g., about reinterpreted variants that could have clinical significance for patients seen previously. A question arises of whether HCPs should recontact these former patients. We present some findings interrogating the views of patients with a rare or undiagnosed condition about how such recontacting might be organised ethically and practically. Forty-one interviews with patients were analysed thematically. Participants suggested a 'joint venture' model in which efforts to recontact are shared with HCPs. Some proposed an ICT-approach involving an electronic health record that automatically alerts them to potentially relevant updates. The need for rigorous privacy controls and transparency about who could access their data was emphasised. Importantly, these findings highlight that the lack of clarity about recontacting is a symptom of a wider problem: the lack of necessary infrastructure to pool genomic data responsibly, to aggregate it with other health data, and to enable patients to receive updates. We hope that our findings will instigate a debate about the way responsibilities for recontacting under any joint venture model could be allocated, as well as the limitations and normative implications of using ICT as a solution to this intractable problem. As a first step to delineating responsibilities in the clinical setting, we suggest clinicians should routinely discuss recontacting with patients, including the new information that should trigger a clinician to initiate recontact, as part of the consent process for genetic testing.

      PubDate: 2017-05-12T20:01:25Z
       
  • The congenital great toe malformation of fibrodysplasia ossificans
           progressiva? - A close call
    • Abstract: Publication date: Available online 1 May 2017
      Source:European Journal of Medical Genetics
      Author(s): O. Will Towler, Eileen M. Shore, Meiqi Xu, Abbey Bamford, Ilse Anderson, Robert J. Pignolo, Frederick S. Kaplan
      Background Congenital bilateral hallux valgus with associated absence or fusion of the interphalangeal joint is a classic diagnostic feature of fibrodysplasia ossificans progressiva (FOP), a human genetic disease of extra-skeletal bone formation caused in nearly all cases by a gain-of-function mutation in Activin A Receptor I/Activin-like Kinase 2 (ACVR1/ALK2), which encodes a bone morphogenetic protein (BMP) Type 1 receptor. This toe malformation prompts the suspicion of FOP even before the appearance of extra-skeletal bone. Here we report the case of a four-month-old child who was suspected of having FOP on the basis of a great toe malformation identical to that seen in children with the disease. Methods The patient's genomic DNA of the coding region of ACVR1 was sequenced and analyzed for mutations known to cause FOP and novel mutations. Subsequent comparative genomic hybridization (CGH) and single nucleotide polymorphism (SNP) analyses were performed to detect mutations elsewhere in the genome. Results Genetic testing exonerated ACVR1 as culpable for the patient's toe malformation. CGH and SNP analyses identified a large intragenic deletion in a different BMP Type 1 receptor gene, BMP Receptor 1B/Activin-like kinase 6 (BMPR1B/ALK6), a gene associated with a variable spectrum of autosomal dominant brachydactyly phenotypes. Conclusions This report illustrates that while toe morphology remains the earliest indicator of FOP, toe morphology alone is not an unequivocal clinical diagnostic feature of FOP, and supports that embryonic development of the great toe is highly sensitive to dysregulated signaling from at least two BMP type I receptors.

      PubDate: 2017-05-02T17:01:02Z
       
  • Fetal costello syndrome with neuromuscular spindles excess and p.Gly12Val
           HRAS mutation
    • Abstract: Publication date: Available online 25 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Chloé Quélin, Philippe Loget, Céline Rozel, Dominique D'Hervé, Mélanie Fradin, Florence Demurger, Sylvie Odent, Laurent Pasquier, Hélène Cavé, Pascale Marcorelles
      Costello syndrome (CS) is a rare multiple congenital disorder caused by activating germline mutations in HRAS gene and is characterized by coarse facial features, severe feeding difficulties, failure to thrive, mild to severe intellectual disability, severe postnatal growth retardation, cardiac abnormalities or cancer predisposition. Phenotypic spectrum associated with HRAS mutations is broad, ranging from attenuated CS phenotype to neonatal and lethal forms with limited genotype-phenotype correlations. Congenital myopathy with neuromuscular spindle excess has been rarely described in the literature. We report a new severe fetal case of CS with distal arthrogryposis due to neuromuscular spindle excess, confirmed by the detection of the p.Gly12Val mutation in HRAS gene. This case emphasizes the fact that HRAS is the only gene responsible for neuromuscular spindle excess, underlines a correlation between p.Gly12Val mutation and severe CS phenotype and points out the importance of a muscle biopsy performed according to the suitable procedure in neuromuscular disorders for any fetal arthrogryposis.

      PubDate: 2017-05-02T17:01:02Z
       
  • Marshall-Smith Syndrome: Novel pathogenic variant and previously
           unreported associations with precocious puberty and aortic root dilatation
           
    • Abstract: Publication date: Available online 24 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Anjali Aggarwal, Joanne Nguyen, Michelle Rivera-Davila, David Rodriguez-Buritica
      Marshall-Smith Syndrome (MRSHSS) is a very rare genetic disorder characterized by failure to thrive and characteristic dysmorphic features associated with accelerated osseous maturation. We present a nine-year-old girl who was diagnosed with MRSHSS based on characteristic clinical features supported by the identification of a novel de novo pathogenic variant in the NFIX gene. The patient also presented with precocious puberty diagnosed at five years of age and had an abnormal GnRH stimulation test indicative of central precocious puberty. Central precocious puberty has not been described in association with MRSHSS previously in the medical literature and broadens our knowledge of the natural history of MRSHSS. The causes of advanced bone age in this syndrome are also reviewed. Additionally, the patient showed progressive dilatation of the aortic root. Although connective tissue abnormalities have been described in association with MRSHSS, aortic root dilatation has not. Understanding the mechanism of comorbidities such as advanced bone age and aortic root dilatation in MRSHSS patients enables future development of anticipatory guidance, preventative care measures, and treatment guidelines.

      PubDate: 2017-04-25T15:25:04Z
       
  • Association of autoimmune thyroiditis and celiac disease with Juvenile
           Polyposis due to 10q23.1q23.31 deletion: Potential role of PI3K/Akt
           pathway dysregulation
    • Abstract: Publication date: Available online 18 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Federica Guaraldi, Giovanni Di Nardo, Luigi Tarani, Luca Bertelli, Francesco Claudio Susca, Rosanna Bagnulo, Nicoletta Resta
      Juvenile Polyposis (JP) is a rare hereditary condition characterized by diffuse hamartomatous gastrointestinal polyposis, associated with a significantly increased risk of neoplastic transformation. Most of the cases are caused by SMAD and BMPR1A mutations, while 10q23 microdeletions, encompassing both PTEN and BMPR1A oncogenes, are extremely rare, typically associated with more aggressive JP, and extraintestinal features overlapping with PTEN Hamartoma Tumor Syndrome. We present the first case of a young female with multiple autoimmune disorders (i.e. thyroiditis and celiac disease), associated with JP, cardiac defects and epilepsy, who carries a de novo heterozygous 10q23.1q23.31 deletion. The dysregulation of the PI3K/Akt pathway is advanced as the putative mechanism connecting autoimmune, malformative and neoplastic disorders. A literature review of clinical manifestation, gene alterations and the treatment of patients with 10q23 deletion is also provided, highlighting the importance of comprehensive, long-term, multi-disciplinary management, aimed at early identification and treatment of both intestinal and extraintestinal disorders.

      PubDate: 2017-04-25T15:25:04Z
       
  • Identification of a novel and functional mutation in the TBX5 gene in a
           patient by screening from 354 patients with isolated ventricular septal
           defect
    • Abstract: Publication date: Available online 18 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Huan-Xin Chen, Xi Zhang, Hai-Tao Hou, Jun Wang, Qin Yang, Xiu-Li Wang, Guo-Wei He
      Ventricular septal defect (VSD) is the most frequently occurring congenital heart disease in newborns. A number of genetic studies have linked TBX5 mutations to cardiac abnormalities. We aimed to identify potential pathogenic mutations in TBX5 and to provide insights into the etiology of sporadic and isolated VSD. Case-control mutational and functional analyses were performed in 354 sporadic patients with isolated VSD and 341 controls. All the coding exons and intron-exon boundaries of TBX5 were first sequenced in a group of VSD patients and controls. Sanger sequencing with high-resolution melting (HRM) curve analysis in new patients and controls was then used to detect TBX5 mutation and frequency. Luciferase activities were measured to identify transcriptional regulation of TBX5 to MYH6 and ANF promoter. A novel heterozygous missense mutations c.40C > A (p.Pro14Thr) was identified in TBX5 gene exon-2, resulting proline to threonine substitution. TBX5 containing mutation reduced transcriptional activities of the MYH6 promoter but enhanced transcriptional activities of the ANF promoter, compared with the wild type. This novel heterozygous missense mutation in TBX5 gene exon-2 that causes significant changes of the activity of TBX5 is therefore highly possible to be the cause of the defect in the VSD patients.

      PubDate: 2017-04-25T15:25:04Z
       
  • Novel homozygous FANCL mutation and somatic heterozygous SETBP1 mutation
           in a Chinese girl with Fanconi Anemia
    • Abstract: Publication date: Available online 15 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Weiqing Wu, Yang Liu, Qinghua Zhou, Qin Wang, Fuwei Luo, Zhiyong Xu, Qian Geng, Peining Li, Hui Z. Zhang, Jiansheng Xie
      Fanconi Anemia (FA) is a rare genetically heterogeneous disorder with 17 known complement groups caused by mutations in different genes. FA complementation group L (FA-L, OMIM #608111) occurred in 0.2% of all FA and only eight mutant variants in the FANCL gene were documented. Phenotype and genotype correlation in FANCL associated FA is still obscure. Here we describe a Chinese girl with FA-L caused by a novel homozygous mutation c.822_823insCTTTCAGG (p.Asp275LeufsX13) in the FANCL gene. The patient's clinical course was typical for FA with progression to bone marrow failure, and death from acute myelomonocytic leukemia (AML-M4) at 9 years of age. Mutation analysis also detected a likely somatic c.2608G > A (p.Gly870Ser) in the SETBP1 gene. Consistent copy number losses of 7q and 18p and gains of 3q and 21q and accumulated non-clonal single cell chromosomal abnormalities were detected in blood leukocytes as her FA progressed. This is the first Chinese FA-L case caused by a novel FANCL mutation. The somatic gene mutation and copy number aberrations could be used to monitor disease progression and the clinical findings provide further information for genotype-phenotype correlation for FA-L.

      PubDate: 2017-04-18T14:50:35Z
       
  • A novel mitochondrial ATP6 frameshift mutation causing isolated complex V
           deficiency, ataxia and encephalomyopathy
    • Abstract: Publication date: Available online 13 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Christopher Benjamin Jackson, Dagmar Hahn, Barbara Schröter, Uwe Richter, Brendan Battersby, Thomas Schmitt-Mechelke, Paula Martinen, Jean-Marc Nuoffer, André Schaller
      We describe a novel frameshift mutation in the mitochondrial ATP6 gene in a 4-year-old girl associated with ataxia, microcephaly, developmental delay and intellectual disability. A heteroplasmic frameshift mutation in the MT-ATP6 gene was confirmed in the patient's skeletal muscle and blood. The mutation was not detectable in the mother's DNA extracted from blood or buccal cells. Enzymatic and oxymetric analysis of the mitochondrial respiratory system in the patients' skeletal muscle and skin fibroblasts demonstrated an isolated complex V deficiency. Native PAGE with subsequent immunoblotting for complex V revealed impaired complex V assembly and accumulation of ATPase subcomplexes. Whilst northern blotting confirmed equal presence of ATP8/6 mRNA, metabolic 35S-labelling of mitochondrial translation products showed a severe depletion of the ATP6 protein together with aberrant translation product accumulation. In conclusion, this novel isolated complex V defect expands the clinical and genetic spectrum of mitochondrial defects of complex V deficiency. Furthermore, this work confirms the benefit of native PAGE as an additional diagnostic method for the identification of OXPHOS defects, as the presence of complex V subcomplexes is associated with pathogenic mutations of mtDNA.

      PubDate: 2017-04-18T14:50:35Z
       
  • Metatropic dysplasia in third trimester of pregnancy and a novel causative
           variant in the TRPV4 gene
    • Abstract: Publication date: Available online 13 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Sara Bargiacchi, Matteo Della Monica, Roberto Biagiotti, Elena Andreucci, Serena Ciabattoni, Paolo Poggi, Marco Di Maurizio, Claudio Defilippi, Ettore Cariati, Sabrina Giglio
      Prenatal diagnosis of skeletal dysplasias is particularly difficult for many reasons and differentiating these disorders in the prenatal period can be challenging because they are rare and many of the ultrasound findings are not necessarily pathognomonic for a specific disorder. The diagnosis is often made just after birth or exitus. The prenatal diagnosis of osteochondrodysplasias is based predominantly upon fetal ultrasound findings and it focuses substantially on the possible lethality of the disorder, without always being able to find a specific name for the disorder. Metatropic dysplasia is a rare osteochondrodysplasia due to mutations in the TRPV4 gene: TRPV4 is a cation channel, non-selectively permeable to calcium, encoded by a gene on chromosome 12q24.11; it is widely expressed and involved in many different physiological processes through responses to several different stimuli (physical, chemical, and hormonal) in ciliated epithelial cells. The exact incidence of this disorder is not known, however less than a hundred cases have been reported at present, with only two prenatal reports but without any reference to the molecular test. We describe the first report of molecular diagnosis of metatropic dysplasia carried out in prenatal diagnosis: the molecular testing of the TRPV4 (transient receptor potential cation channel, subfamily V, member 4, MIM *605427) gene in our case, in fact, detected a causative variant, confirming the diagnostic suspicion, which was made possible thanks also to the utilization of MRI and CT scan. In our case different imaging methods together with the close cooperation of a multidisciplinary team and test availability, allowed an accurate diagnosis.

      PubDate: 2017-04-18T14:50:35Z
       
  • A case of splenomegaly in CBL syndrome
    • Abstract: Publication date: Available online 13 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Rachel R. Coe, Margaret L. McKinnon, Maja Tarailo-Graovac, Colin J. Ross, Wyeth W. Wasserman, Jan M. Friedman, Paul C. Rogers, Clara D.M. van Karnebeek
      Introduction We present a child with unexplained splenomegaly to highlight this feature as a presenting sign of the RASopathy CBL syndrome and to draw attention to the power and utility of next generation genomic sequencing for providing rapid diagnosis and critical information to guide care in the pediatric clinical setting. Clinical report A 7-year-old boy presented with unexplained splenomegaly, attention deficit hyperactivity disorder, mild learning difficulties, easy bruising, mild thrombocytopenia, and subtle dysmorphic features. Extensive haematological testing including a bone marrow biopsy showed mild megaloblastoid erythropoiesis and borderline fibrosis. There were no haematological cytogenetic anomalies or other haematological pathology to explain the splenomegaly. Metabolic testing and chromosomal microarray were unremarkable. Trio whole-exome sequencing (WES) identified a pathogenic de novo heterozygous germline CBL variant (c.1111T > C, p.Y371H), previously reported to cause CBL syndrome and implicated in development of juvenile myelomonocytic leukemia (JMML). Discussion CBL syndrome (more formally known as “Noonan-syndrome-like disorder with or without juvenile myelomonocytic leukemia”) has overlapping features to Noonan syndrome with significant variability. CBL syndrome and other RASopathy disorders—including Noonan syndrome, neurofibromatosis 1, and Costello syndrome—are important to recognize as these are associated with a cancer-predisposition. CBL syndrome carries a very high risk for JMML, thus accurate diagnosis is of utmost importance. The diagnosis of CBL syndrome in this patient would not have been possible based on clinical features alone. Through WES, a specific genetic diagnosis was made, allowing for an optimized management and surveillance plan, illustrating the power of genomics in clinical practice.

      PubDate: 2017-04-18T14:50:35Z
       
  • Gene expression profiling of bone marrow mesenchymal stem cells from
           Osteogenesis Imperfecta patients during osteoblast differentiation
    • Abstract: Publication date: Available online 7 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Carla Martins Kaneto, Patrícia S. Pereira Lima, Karen Lima Prata, Jane Lima dos Santos, João Monteiro de Pina Neto, Rodrigo Alexandre Panepucci, Houtan Noushmehr, Dimas Tadeu Covas, Francisco José Alburquerque de Paula, Wilson Araújo Silva
      Mesenchymal stem cells (MSCs) are precursors present in adult bone marrow that are able to differentiate into osteoblasts, adipocytes and chondroblasts that have gained great importance as a source for cell therapy. Recently, a number of studies involving the analysis of gene expression of undifferentiated MSCs and of MSCs in the differentiation into multiple lineage processes were observed but there is no information concerning the gene expression of MSCs from Osteogenesis Imperfecta (OI) patients. Osteogenesis Imperfecta is characterized as a genetic disorder in which a generalized osteopenia leads to excessive bone fragility and severe bone deformities. The aim of this study was to analyze gene expression profile during osteogenic differentiation from BMMSCs (Bone Marrow Mesenchymal Stem Cells) obtained from patients with Osteogenesis Imperfecta and from control subjects. Bone marrow samples were collected from three normal subjects and five patients with OI. Mononuclear cells were isolated for obtaining mesenchymal cells that had been expanded until osteogenic differentiation was induced. RNA was harvested at seven time points during the osteogenic differentiation period (D0, D+1, D+2, D+7, D+12, D+17 and D+21). Gene expression analysis was performed by the microarray technique and identified several differentially expressed genes. Some important genes for osteoblast differentiation had lower expression in OI patients, suggesting a smaller commitment of these patient's MSCs with the osteogenic lineage. Other genes also had their differential expression confirmed by RT-qPCR. An increase in the expression of genes related to adipocytes was observed, suggesting an increase of adipogenic differentiation at the expense osteogenic differentiation.

      PubDate: 2017-04-11T14:09:35Z
       
  • Elucidating the behavioral phenotype of patients affected with
           mucolipidosis IV: What can we learn from the parents?
    • Abstract: Publication date: Available online 6 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Perri Segal, Ben Pode-Shakked, Annick Raas-Rothschild
      Background Mucolipidosis type IV (ML-IV) is a rare autosomal recessive lysosomal storage disorder which presents with nonspecific developmental delay. Nowadays with the use of new tools such as next generation sequencing, more ML-IV affected patients are diagnosed. Still, identifying the behavioral phenotype might be of help for early diagnosis and anticipatory guidance, as well as for counseling of the families. Objective Identification of the behavioral characteristics of 12 ML-IV patients, aged from 2.5 to 34 years, based on their caregivers' observations. Methods The information was gathered from the patients' parents using an extensive semi-structured interview especially designed for this study. Each interview lasted approximately three hours. Results Patients were uniformly described as friendly and show explicit pleasure from both social interactions and music. They all presented delays in psychomotor development, while their general health was reported as good. Parents reported that the patients present deterioration of motor and communication skills over the years. Episodes of ocular pain, with ipsilateral flushing of the face and tearing were frequently reported, as was shortening of the Achilles tendon. Since the identification of the ML-IV gene, diagnosis is made earlier in life. Conclusion We suggest that ML-IV be considered in the differential diagnosis of patients with developmental delay, who present the behavioral phenotype reported here. This pattern could also be useful for the ancitipatory guidance in the care of ML-IV affected patients. Further clinical research is warranted to confirm these preliminary findings.

      PubDate: 2017-04-11T14:09:35Z
       
  • A familial case of severe infantile nephronophthisis explained by
           oligogenic inheritance
    • Abstract: Publication date: Available online 6 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Valentin Penchev, Anelia Boueva, Kunka Kamenarova, Dimitar Roussinov, Reni Tzveova, Mariya Ivanova, Violeta Dimitrova, Ivo Kremensky, Vanio Mitev, Radka Kaneva, Olga Beltcheva
      Renal cysts are common malformation during the prenatal and postnatal period and frequent cause of chronic kidney or ESRD. More than 70 genes have been shown to play role in their pathology. Part of them are responsible for the structure and function of the cilia, which assigns a large proportion of the renal cystic diseases in the ciliopathies. Another group of genes responsible for cystic kidneys encodes transcription factors with crucial role during organogenesis. We describe here a systematic approach for identifying the genetic cause(s) of an unusually severe form of renal cystic disease in a family with multiple affected siblings. High throughput mutations screening of the parents and one of the children was applied for identifying the genetic causes of the disease. The affected child was found to have inherited 3 deleterious mutations in two nephronophthisis genes, NPHP3 and NPHP4. The possibility for epistatic interaction of the NPHP mutations as well as the modifying effect of other inherited genetic variants is discussed.

      PubDate: 2017-04-11T14:09:35Z
       
  • Novel FSHβ mutation in a male patient with isolated FSH deficiency
           and infertility
    • Abstract: Publication date: Available online 6 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Junjie Zheng, Jiangfeng Mao, Mingxuan Cui, Zhaoxiang Liu, Xi Wang, Shuyu Xiong, Min Nie, Xueyan Wu
      Isolated follicle stimulating hormone (FSH) deficiency due to mutations in FSHβ is an extremely rare autosomal recessive disease that has only been reported in ten patients to date. Symptoms of the disease include amenorrhoea and hypogonadism in women and azoospermia and normal testosterone levels in men. This study describes a Chinese male patient who presented with cryptorchidism and infertility. His serum hormonal profile revealed low FSH, elevated LH and normal testosterone levels. Sequence analysis identified a novel homozygous mutation in the FSHβ gene (c.343C > T) predicted to result in a premature termination codon and a truncated FSH protein (p.R115X). Both parents were heterozygous carriers of the mutation with normal pubertal development and fertility. The patient's testicular volume increased after one year of exogenous FSH replacement therapy at which point spermatocytes were detected in seminal samples, indicating potential future spermatogenesis. The expanded spectrum of FSHβ mutations and associated clinical manifestations described in this study may improve the diagnosis and treatment of this disease.

      PubDate: 2017-04-11T14:09:35Z
       
  • De novo GRIN1 mutations: An emerging cause of severe early infantile
           encephalopathy
    • Abstract: Publication date: Available online 5 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Yoav Zehavi, Hanna Mandel, Arie Zehavi, Muhammad Abu Rashid, Rachel Straussberg, Banan Jabur, Avraham Shaag, Orly Elpeleg, Ronen Spiegel
      De novo GRIN1 mutations have recently been shown to cause severe intellectual disability, hypotonia, hyperkinetic and stereotyped movements, and epilepsy. We report two new cases of severe early onset encephalopathy associated with hyperkinetic and oculogyric-like movements, caused by mutations in the GRIN1 gene; both were identified by whole exome sequencing. One of the patients harbored the novel mutation p.Ser688Tyr and the other patient harbored the p.Gly827Arg mutation, which was previously reported in three patients. In silico studies suggested that the p.Se688Tyr mutation results in disruption of NMDA ligand binding and the p.Gly827Arg mutation results in disrupted gating of the ion channel. Our study highlights the importance of GRIN1 mutations in the etiology of isolated cases of early onset encephalopathy, and the valuable role of whole exome sequencing in identifying these mutations.

      PubDate: 2017-04-11T14:09:35Z
       
  • Caution in interpretation of disease causality for heterozygous
           loss-of-function variants in the MYH8 gene associated with autosomal
           dominant disorder
    • Abstract: Publication date: Available online 2 April 2017
      Source:European Journal of Medical Genetics
      Author(s): Zunyan Dai, Zachary Whitt, Lindsey C. Mighion, Alessandro Pontoglio, Lora J.H. Bean, Roberto Colombo, Madhuri Hegde
      To date, the NM_002472.2(MYH8):c.2021G>A (p.Arg674Gln) missense variant in the MYH8 gene is the only known genetic change in individuals with autosomal dominant trismus-pseudocamptodactyly syndrome with unknown molecular mechanism. Next-generation sequencing (NGS), including targeted gene panels and whole-exome sequencing, is routinely performed in many clinical diagnostic laboratories as standard-of-care testing aimed at identifying disease-causing genomic variants. Whole-exome sequencing has revealed loss-of-function variants in the MYH8 gene. To properly classify the MYH8 loss-of-function variants, we either retrieved them from public databases or retrospectively collected them from individuals genetically tested by custom NGS panels or by whole-exome sequencing and confirmed using Sanger sequencing. We further evaluated the respective clinical presentations of these individuals with the MYH8 loss-of-function variants. Heterozygous loss-of-function variants in the MYH8 gene were detected in 16 individuals without trismus-pseudocamptodactyly syndrome. Four of these 16 individuals had a pathogenic or likely pathogenic variant detected in another gene that could explain their clinical presentation. Moreover, there are ∼100 MYH8 heterozygous protein-truncating and splice site variants in the ExAC database in different populations. Our results, combined with the population data, indicate that loss-of-function variants in the MYH8 gene do not cause autosomal dominant trismus-pseudocamptodactyly syndrome, and the clinical significance of these variants remains unknown at present. This result highlights the importance of considering the molecular mechanism of disease, variants published in the medical literature, and population genomic data for the correct interpretation of loss-of-function variants in genes associated with autosomal dominant diseases.

      PubDate: 2017-04-04T13:07:36Z
       
  • Two females with mutations in USP9X highlight the variable expressivity of
           the intellectual disability syndrome
    • Abstract: Publication date: Available online 1 April 2017
      Source:European Journal of Medical Genetics
      Author(s): P.Y.B. Au, L. Huang, S. Broley, L. Gallagher, E. Creede, D. Lahey, S. Ordorica, K. Mina, K.M. Boycott, G. Baynam, D.A. Dyment
      The genetic causes of intellectual disability (ID) are heterogeneous and include both chromosomal and monogenic etiologies. The X-chromosome is known to contain many ID-related genes and males show a marked predominance for intellectual disability. Here we report two females with syndromic intellectual disability. The first individual was relatively mild in her presentation with mild-moderate intellectual disability, hydronephrosis and altered pigmentation along the lines of Blaschko without additional congenital anomalies. A second female presented shortly after birth with dysmorphic facial features, post-axial polydactyly and, on follow-up assessment, demonstrated moderate intellectual disability. Chromosomal studies for Individual 1 identified an X-chromosome deletion due to a de novo pericentric inversion; the inversion breakpoint was associated with deletion of the 5′UTR of the USP9X, a gene which has been implicated in a syndromic intellectual disability affecting females. The second individual had a de novo frameshift mutation detected by whole-exome sequencing that was predicted to be deleterious, NM_001039590.2 (USP9X): c.4104_4105del (p.(Arg1368Serfs*2)). Haploinsufficiency of USP9X in females has been associated with ID and congenital malformations that include heart defects, scoliosis, dental abnormalities, anal atresia, polydactyly, Dandy Walker malformation and hypoplastic corpus callosum. The extent of the congenital malformations observed in Individual 1 was less striking than Individual 2 and other individuals previously reported in the literature, and suggests that USP9X mutations in females can have a wider spectrum of presentation than previously appreciated.

      PubDate: 2017-04-04T13:07:36Z
       
  • Juvenile hemochromatosis and hepatocellular carcinoma in a patient with a
           novel mutation in the HJV gene
    • Abstract: Publication date: Available online 28 March 2017
      Source:European Journal of Medical Genetics
      Author(s): Khushnooda Ramzan, Faiqa Imtiaz, Hamad I. Al-Ashgar, Moeenaldeen AlSayed, Raashda A. Sulaiman
      Juvenile hemochromatosis is a rare but the most severe form of hereditary hemochromatosis which develops due to mutations in the HJV or HAMP genes. It presents in early adulthood mainly as cardiomyopathy, hypogonadism and liver fibrosis. Unlike hereditary hemochromatosis due to HFE mutation, hepatocellular carcinoma is not known to be associated with juvenile hemochromatosis. Here, we report a patient of Arab ancestry who presented with severe cardiomyopathy. Sequence analysis of the HJV gene followed by homozygosity mapping, identified a previously undescribed homozygous missense variation in exon 3 (c.497A > G; p.H166R) in both the proband and his clinically asymptomatic brother. The former later developed hepatocellular carcinoma. To the best of our knowledge, neither the mutation identified in our patient, nor a case of juvenile hemochromatosis with hepatocellular carcinoma has been reported before.

      PubDate: 2017-04-04T13:07:36Z
       
  • Wiedemann-Steiner Syndrome: Novel pathogenic variant and review of
           literature
    • Abstract: Publication date: Available online 27 March 2017
      Source:European Journal of Medical Genetics
      Author(s): Anjali Aggarwal, David F. Rodriguez-Buritica, Hope Northrup
      Wiedemann-Steiner syndrome (WDSTS) is a very rare genetic disorder characterized by short stature, intellectual disability and distinctive facial appearance. We present a five-year-old boy who was diagnosed with WDSTS based on identification of a novel de novo pathogenic variant in the KMT2A gene (OMIM: 159555) by Whole Exome Sequencing and supported by some characteristic clinical features. Genotype and phenotype of the patient is compared with the earlier reported patients in the literature, in an attempt to broaden our knowledge of this rare syndrome.

      PubDate: 2017-04-04T13:07:36Z
       
  • Expanding the cardiac spectrum of Noonan syndrome with RIT1 variant: Left
           main coronary artery atresia causing sudden death
    • Abstract: Publication date: Available online 25 March 2017
      Source:European Journal of Medical Genetics
      Author(s): Francis Ramond, Sébastien Duband, Pierre Croisille, Hélène Cavé, Georges Teyssier, Véronique Adouard, Renaud Touraine
      Noonan syndrome is a well-known genetic condition associating congenital heart defects, short stature, and distinctive facial features. Pulmonary valve stenosis and hypertrophic cardiomyopathy are the most frequent cardiac abnormalities, the latter being associated with a higher mortality. Here we report for the first time, a case of congenital left main coronary artery atresia in a Noonan syndrome associated with RIT1 variant, leading to unrescued sudden death. This case-report supports the already-suspected severity of the RIT1-related Noonan syndrome compared to average Noonan syndrome, and should encourage clinicians to be very cautious with these patients.

      PubDate: 2017-03-27T11:32:26Z
       
  • Arthrogryposis as neonatal presentation of Loeys-Dietz syndrome due to a
           novel TGFBR2 mutation
    • Abstract: Publication date: Available online 24 March 2017
      Source:European Journal of Medical Genetics
      Author(s): Irene Valenzuela, Paula Fernández-Alvarez, Francina Munell, Angel Sanchez-Montanez, Gemma Giralt, Teresa Vendrell, Eduardo Tizzano
      Loeys–Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized mainly by cardiovascular, craniofacial and skeletal features. We report on a patient with LDS, whose prenatal examination was compatible with the diagnosis of arthrogryposis multiplex congenita. Neonatal assessment showed craniofacial and cardiovascular findings suggestive of LDS whose diagnosis was confirmed by the detection of a novel mutation (HGVN: NM_003242.5 (TGFBR2): c.1381T > C (p.(Cys461Arg))) in the TGFBR2 gene. Few prenatal and neonatal cases of LDS have been reported in the literature. We reviewed all cases reported to date with perinatal onset to delineate the clinical manifestations that allow us to prompt diagnosis of this syndrome at an early stage to prevent fatal cardiovascular complications. Furthermore we discuss the multidisciplinary follow up required in these patients.

      PubDate: 2017-03-27T11:32:26Z
       
  • In silico prediction of the effects of mutations in the human triose
           phosphate isomerase gene: Towards a predictive framework for TPI
           deficiency
    • Abstract: Publication date: Available online 21 March 2017
      Source:European Journal of Medical Genetics
      Author(s): Conor Oliver, David J. Timson
      Triose phosphate isomerase (TPI) deficiency is a rare, but highly debilitating, inherited metabolic disease. Almost all patients suffer severe neurological effects and the most severely affected are unlikely to live beyond early childhood. Here, we describe an in silico study into well-characterised variants which are associated with the disease alongside an investigation into 79 currently uncharacterised TPI variants which are known to occur in the human population. The majority of the disease-associated mutations affected amino acid residues close to the dimer interface or the active site. However, the location of the altered amino acid residue did not predict the severity of the resulting disease. Prediction of the effect on protein stability using a range of different programs suggested a relationship between the degree of instability caused by the sequence variation and the severity of the resulting disease. Disease-associated variations tended to affect well-conserved residues in the protein's sequence. However, the degree of conservation of the residue was not predictive of disease severity. The majority of the 79 uncharacterised variants are potentially associated with disease since they were predicted to destabilise the protein and often occur in well-conserved residues. We predict that individuals homozygous for the corresponding mutations would be likely to suffer from TPI deficiency.

      PubDate: 2017-03-27T11:32:26Z
       
  • HERC1 mutations in idiopathic intellectual disability
    • Abstract: Publication date: Available online 18 March 2017
      Source:European Journal of Medical Genetics
      Author(s): G. Eda Utine, Ekim Z. Taşkıran, Can Koşukcu, Beren Karaosmanoğlu, Naz Güleray, Özlem Akgün Doğan, P. Özlem Şimşek Kiper, Koray Boduroğlu, Mehmet Alikaşifoğlu
      HERC1 is a member of HERC protein family of ubiquitin ligases and is a negative regulator of the mTOR pathway. It is also a guanine nucleotide exchange factor for ARF and Rab family GTPases. Biallelic mutations in HERC1 were recently shown to cause a human phenotype with overgrowth and intellectual disability as main features. Herein we describe clinical features in another patient with homozygous novel mutation in HERC1. Moderate to severe intellectual disability, hypotonia, macrocephaly, tall stature, and facial features appear as main clinical features of the condition. Kyphoscoliosis and seizures frequently accompany and autistic features might be another feature as recent studies also implicate. HERC1 mutations should be considered in differential diagnosis of severe intellectual disability and behavioural problems, particularly in patients testing negative for fragile X and KANSL1 mutations.

      PubDate: 2017-03-21T11:02:04Z
       
  • A mild form of stickler syndrome type II caused by mosaicism of COL11A1
    • Abstract: Publication date: Available online 14 March 2017
      Source:European Journal of Medical Genetics
      Author(s): Kathrine F. Lauritsen, Dorte L. Lildballe, Paul J. Coucke, Rikke Monrad, Dorte A. Larsen, Pernille A. Gregersen
      Stickler syndrome, a clinically as well as molecularly heterogeneous connective tissue disorder, is predominantly inherited in an autosomal dominant manner and is considered complete penetrant. Previously, mosaicism in Stickler syndrome has been reported in only a few cases. We describe a child with Stickler syndrome due to a novel splice site mutation in COL11A1. Initially, Sanger sequencing of both parents showed normal test results for the mutation. Due to mild phenotypic traits, the father was tested again using a more sensitive method (NGS), and was found to have low-grade mosaicism in various tissue samples (range 7–22% of the DNA). Therefore, we recommend using sensitive genetic testing when mosaicism is suspected. Furthermore, we support previous suggestions of parental testing even when the parents of an affected patient do not have obvious phenotypic signs of Stickler syndrome.

      PubDate: 2017-03-16T09:13:20Z
       
  • Complex postaxial polydactyly types A and B with camptodactyly,
           hypoplastic third toe, zygodactyly and other digit anomalies caused by a
           novel GLI3 mutation
    • Abstract: Publication date: Available online 14 March 2017
      Source:European Journal of Medical Genetics
      Author(s): Sara Mumtaz, Esra Yildiz, Karmoon Lal, Aslıhan Tolun, Sajid Malik
      Polydactyly is a phenotypically and genetically highly heterogeneous limb malformation with preaxial and postaxial subtypes and subtypes A and B. Most polydactyly entities are associated with GLI3 mutation. We report on 10 affected individuals from a large Pakistani kindred initially evaluated as a possible new condition. The phenotype is postaxial polydactyly types A and B associated with zygodactyly, postaxial webbing of toes and additional features not previously reported for isolated polydactyly such as camptodactyly, hypoplasia of third toe, and wide space between hallux and second toe. Hypothesizing that the disorder could have resulted from a mutation in a novel gene responsible for polydactyly, we launched a genetic investigation. By linkage mapping and exome sequencing in the most severe case, we identified novel heterozygous frameshift mutation NM_000168.5 (GLI3): c.3635delG (p.(Gly1212Alafs*18)) but did not detect any other possibly deleterious mutation that could explain the unusual features of camptodactyly, hypoplasia of third toe and wide space between first and second toes. Our findings further expand the phenotypic variability of GLI3 polydactyly. We also present a review of GLI3-associated isolated limb anomalies, which indicates that GLI3 mutation leads primarily to two well-established polydactyly types: postaxial types A and B and crossed polydactyly type I. In addition, a variety of other minor digit anomalies generally accompany polydactyly, and there is no straightforward genotype-polydactyly phenotype correlation.

      PubDate: 2017-03-16T09:13:20Z
       
  • The spectrum of infantile myofibromatosis includes both non-penetrance and
           adult recurrence
    • Abstract: Publication date: Available online 9 March 2017
      Source:European Journal of Medical Genetics
      Author(s): Natalia Murray, B. Hanna, Nicole Graf, He Fu, Veronneau Mylène, P.M. Campeau, Anne Ronan
      Infantile myofibromatosis is characterized by benign myofibroblastic tumors within skin, muscle, bone or viscera which have a characteristic staining pattern on immunohistochemistry. The condition typically presents in infancy and the tumors often disappear by the third year of life. Mutations in the PDGFRB gene and NOTCH3 genes have been identified in familial forms of the condition. We present two families with molecularly confirmed germline mutations in the PDGFRB gene, one demonstrating a phenotype ranging from complete non-penetrance to neonatal lethality; and the other illustrating adult recurrence of the tumors.

      PubDate: 2017-03-16T09:13:20Z
       
  • Sibling recurrence of total anomalous pulmonary venous drainage
    • Abstract: Publication date: Available online 7 March 2017
      Source:European Journal of Medical Genetics
      Author(s): J.H. McDermott, D.D.D. Study, J. Clayton-Smith
      Many childhood syndromic disorders are associated with congenital heart defects, but few present specifically with total anomalous pulmonary venous drainage (TAPVD). Here, we report two siblings presenting with TAPVD, tracheo-oesophageal fistula and dysmorphic features in the neonatal period. Careful examination of the mother revealed subtle facial asymmetry and a pre-auricular tag, suggesting a potential variable expression of a dominant disorder. Whole exome sequencing identified a pathogenic heterozygous mutation in EFTUD2, a gene, normally associated with mandibulofacial dystosis Guion-Almedia type (MFDGA), in both siblings and the mother. This is the first report of TAPVD occurring as part of the MFDGA phenotype. It serves to highlight the importance of modern sequencing panels in identifying causative mutations for heterogeneous syndromes such as MFDGA and familial congenital heart defects whilst emphasising the relevance of variable expression when counselling parents.

      PubDate: 2017-03-09T07:44:00Z
       
  • Chiari I malformation in a child with PTEN hamartoma tumor syndrome:
           Association or coincidence?
    • Abstract: Publication date: Available online 7 March 2017
      Source:European Journal of Medical Genetics
      Author(s): Veronica Saletti, Silvia Esposito, Angelo Maccaro, Sabrina Giglio, Laura Grazia Valentini, Luisa Chiapparini
      PTEN hamartoma tumor syndrome (PHTS) refers to a group of clinical conditions caused by germline mutations in the PTEN tumor suppressor gene. Increasing evidence has documented that PHTS may be associated with a broader spectrum of structural brain abnormalities, including dysplastic gangliocytoma of the cerebellum, brain tumors, vascular malformations, white matter abnormalities, dilated perivascular spaces and cortical dysplasia. We report a PTEN-mutated child showing macrocephaly, mild intellectual disability and epilepsy symptomatic of right occipital polymicrogyria, who also developed Chiari I Malformation (CIM) that repeatedly required surgical correction. We suppose that the association between PHTS and CIM could be not coincidental, thus extending the spectrum of neurological manifestations of PHTS and highlighting the role of brain MRI in the management of PHTS patients. We suggest that genes within the RAS-MAPK and PI3-AKT pathways might have a significant role in the pathogenesis of CIM in such patients.

      PubDate: 2017-03-09T07:44:00Z
       
  • A further case of brain-lung-thyroid syndrome with deletion proximal to
           NKX2-1
    • Abstract: Publication date: Available online 7 March 2017
      Source:European Journal of Medical Genetics
      Author(s): Mira Kharbanda, Pia Hermanns, Jeremy Jones, Joachim Pohlenz, Iain Horrocks, Malcolm Donaldson
      Brain-lung-thyroid syndrome (OMIM #610978) is associated with mutations in the NK2 homeobox 1 (NKX2-1) gene, a transcription factor important in development. 50% of patients are affected by the full triad, comprising congenital hypothyroidism, benign hereditary chorea and infant respiratory distress syndrome. Four cases have previously been reported where a patient has features consistent with brain-lung-thyroid syndrome and a chromosome 14q13 deletion adjacent to, but not disrupting, NKX2-1. We present a patient who has a phenotype consistent with brain-lung-thyroid syndrome, featuring congenital hypothyroidism and choreoathetoid movements with gross motor delay. Thyroid ultrasound showed a small-normal gland and spontaneous resolution of hypothyroidism. Array CGH revealed a de novo 14q13.2–3 deletion adjacent to but not directly involving NKX2-1. Sequencing of NKX2-1 was normal. This report highlights a further case of chromosomal deletion adjacent to NXK2-1 in a patient with a phenotype consistent with brain-lung-thyroid syndrome, and confirms that array-CGH is a useful test in the investigation of congenital hypothyroidism. Deletion of the adjacent gene MBIP in most reported cases so far may be relevant to the pathogenesis of brain-lung-thyroid syndrome. Deletion of nearby promoter or enhancer elements acting on NKX2-1 could also be an important factor. However, further work is needed to elucidate the pathogenesis of the brain-lung-thyroid phenotype in such cases.

      PubDate: 2017-03-09T07:44:00Z
       
  • Identification of a novel CNTNAP1 mutation causing arthrogryposis
           multiplex congenita with cerebral and cerebellar atrophy
    • Abstract: Publication date: Available online 27 February 2017
      Source:European Journal of Medical Genetics
      Author(s): Shenela Lakhani, Ryan Doan, Mariam Almureikhi, Jennifer N. Partlow, Muna Al Saffar, Mahmoud F. Elsaid, Nada Alaaraj, A. James Barkovich, Christopher A. Walsh, Tawfeg Ben-Omran
      Arthrogryposis multiplex congenital, the occurrence of multiple joint contractures at birth, can in some cases be accompanied by insufficient myelination of peripheral nerves, muscular hypotonia, reduced tendon reflexes, and respiratory insufficiency. Recently mutations in the CASPR/CNTN1 complex have been associated with similar severe phenotypes and CNTNAP1 gene mutations, causing loss of the CASPR protein, were shown to cause severe, prenatal onset arthrogryposis multiplex congenita in four unrelated families. Here we report a consanguineous Arab family from Qatar with three children having an early lethal form of arthrogryposis multiplex congenita and a novel frameshift mutation in CNTNAP1. We further expand the existing CNTNAP1-associated phenotype to include profound cerebral and cerebellar atrophy.

      PubDate: 2017-03-03T06:00:50Z
       
  • Novel splice site mutation in CNNM4 gene in a family with Jalili syndrome
    • Abstract: Publication date: Available online 27 February 2017
      Source:European Journal of Medical Genetics
      Author(s): Imane Cherkaoui Jaouad, Jaber Lyahyai, Soukaina Guaoua, Mustapha El Alloussi, Abdelali Zrhidri, Yassamine Doubaj, Abdelkrim Boulanouar, Abdelaziz Sefiani
      Jalili syndrome is a rare autosomal recessive genetic disease characterized by the association of amelogenesis imperfecta and cone-rod retinal dystrophy. This syndrome is caused by mutations in the CNNM4 gene. Different types of CNNM4 mutations have been reported; missense, nonsense, large deletions, single base insertion, and duplication. We used Sanger sequencing to analyze a large consanguineous family with three siblings affected with Jalili syndrome, suspected clinically after dental and ophthalmological examination. These patients are carrying a novel homozygous mutation in the splice site acceptor of intron 3 (c.1682-1G > C) in the CNNM4 gene. We compare the findings of the present family to those from literature, in order to further delineate Jalili syndrome.

      PubDate: 2017-03-03T06:00:50Z
       
  • Long QT syndrome and left ventricular noncompaction in 4 family members
           across 2 generations with KCNQ1 mutation
    • Abstract: Publication date: Available online 27 February 2017
      Source:European Journal of Medical Genetics
      Author(s): Mira Kharbanda, Amanda Hunter, Stephen Tennant, David Moore, Stephanie Curtis, Jules C. Hancox, Victoria Murday
      The association of long QT syndrome and left ventricular noncompaction is uncommon, with only a handful of previous reports, and only one reported case in association with a mutation in KCNQ1. Here we present genetic and phenotypic data for 4 family members across 2 generations who all have evidence of prolonged QT interval and left ventricular noncompaction in association with a pathogenic mutation in KCNQ1, and discuss the potential mechanisms of this association. In conclusion, we suggest that it may be helpful to consider looking for mutations in KCNQ1 in similar patients.

      PubDate: 2017-03-03T06:00:50Z
       
  • Altered body composition, lipedema, and decreased bone density in
           individuals with Williams syndrome: A preliminary report
    • Abstract: Publication date: Available online 27 February 2017
      Source:European Journal of Medical Genetics
      Author(s): Jessica L. Waxler, Cara Guardino, Richard S. Feinn, Hang Lee, Barbara R. Pober, Takara L. Stanley


      PubDate: 2017-03-03T06:00:50Z
       
  • 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
       
 
 
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