RESUMO
Wolff-Parkinson-White (WPW) syndrome is a common cause of supraventricular tachycardia that carries a risk of sudden cardiac death. To date, mutations in only one gene, PRKAG2, which encodes the 5'-AMP-activated protein kinase subunit γ-2, have been identified as causative for WPW. DNA samples from five members of a family with WPW were analyzed by exome sequencing. We applied recently designed prioritization strategies (VAAST/pedigree VAAST) coupled with an ontology-based algorithm (Phevor) that reduced the number of potentially damaging variants to 10: a variant in KCNE2 previously associated with Long QT syndrome was also identified. Of these 11 variants, only MYH6 p.E1885K segregated with the WPW phenotype in all affected individuals and was absent in 10 unaffected family members. This variant was predicted to be damaging by in silico methods and is not present in the 1,000 genome and NHLBI exome sequencing project databases. Screening of a replication cohort of 47 unrelated WPW patients did not identify other likely causative variants in PRKAG2 or MYH6. MYH6 variants have been identified in patients with atrial septal defects, cardiomyopathies, and sick sinus syndrome. Our data highlight the pleiotropic nature of phenotypes associated with defects in this gene.
Assuntos
Exoma , Síndrome de Wolff-Parkinson-White/genética , Proteínas Quinases Ativadas por AMP/genética , Adulto , Miosinas Cardíacas/genética , Feminino , Loci Gênicos , Humanos , Masculino , Cadeias Pesadas de Miosina/genética , Linhagem , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Síndrome de Wolff-Parkinson-White/etiologiaRESUMO
Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymkinsT/insT zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits.
Assuntos
Proteínas de Membrana/genética , Síndrome de Möbius/genética , Morfogênese/genética , Proteínas Musculares/genética , Músculo Esquelético/metabolismo , Doenças Musculares/genética , Mutação , Mioblastos/metabolismo , Síndrome de Pierre Robin/genética , Proteínas de Peixe-Zebra/genética , Adulto , Sequência de Aminoácidos , Animais , Fusão Celular , Criança , Modelos Animais de Doenças , Embrião não Mamífero , Feminino , Expressão Gênica , Genes Recessivos , Teste de Complementação Genética , Humanos , Lactente , Masculino , Proteínas de Membrana/deficiência , Síndrome de Möbius/metabolismo , Síndrome de Möbius/patologia , Proteínas Musculares/deficiência , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/patologia , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Mioblastos/patologia , Linhagem , Síndrome de Pierre Robin/metabolismo , Síndrome de Pierre Robin/patologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Peixe-Zebra , Proteínas de Peixe-Zebra/deficiênciaRESUMO
BACKGROUND: A number of single gene defects have been identified in patients with isolated or nonsyndromic congenital heart defects (CHDs). However, due to significant genetic heterogeneity, candidate gene approaches have had limited success in finding high-risk alleles in most cases. The purpose of this study was to use exome sequencing to identify high-risk gene variants in a family with highly penetrant pleiotropic CHD. METHODS AND RESULTS: DNA samples from 2 members of a family with diverse CHD were analyzed by exome sequencing. Variants were filtered to eliminate common variants and sequencing artifacts and then prioritized based on the predicted effect of the variant and on gene function. The remainder of the family was screened using polymerase chain reaction, high-resolution melting analysis, and DNA sequencing to evaluate variant segregation. After filtering, >2000 rare variants (including single nucleotide substitutions and indels) were shared by the 2 individuals. Of these, 46 were nonsynonymous, 3 were predicted to alter splicing, and 6 resulted in a frameshift. Prioritization reduced the number of variants potentially involved in CHD to 18. None of the variants completely segregated with CHD in the kindred. However, 1 variant, Myh6 Ala290Pro, was identified in all but 1 affected individual. This variant was previously identified in a patient with tricuspid atresia and large secundum atrial septal defect. CONCLUSIONS: It is likely that next-generation sequencing will become the method of choice for unraveling the complex genetics of CHD, but information gained by analysis of transmission through families will be crucial.