Accelerating Novel Candidate Gene Discovery in Neurogenetic Disorders via Whole-Exome Sequencing of Prescreened Multiplex Consanguineous FamiliesOur knowledge of disease genes in neurological disorders is incomplete. With the aim of closing this gap, we performed whole-exome sequencing on 143 multiplex consanguineous families in whom known disease genes had been excluded by autozygosity mapping and candidate gene analysis. This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS). We also encountered instances in which the phenotype departed significantly from the established clinical presentation of a known disease gene. Overall, a likely causal mutation was identified in >73% of our cases. This study contributes to the global effort toward a full compendium of disease genes affecting brain function.
TLE6 mutation causes the earliest known human embryonic lethalityBACKGROUND: Embryonic lethality is a recognized phenotypic expression of individual gene mutations in model organisms. However, identifying embryonic lethal genes in humans is challenging, especially when the phenotype is manifested at the preimplantation stage. RESULTS: In an ongoing effort to exploit the highly consanguineous nature of the Saudi population to catalog recessively acting embryonic lethal genes in humans, we have identified two families with a female-limited infertility phenotype. Using autozygosity mapping and whole exome sequencing, we map this phenotype to a single mutation in TLE6, a maternal effect gene that encodes a member of the subcortical maternal complex in mammalian oocytes. Consistent with the published phenotype of mouse Tle6 mutants, embryos from female patients who are homozygous for the TLE6 mutation fail to undergo early cleavage, with resulting sterility. The human mutation abrogates TLE6 phosphorylation, a step that is reported to be critical for the PKA-mediated progression of oocyte meiosis II. Furthermore, the TLE6 mutation impairs its binding to components of the subcortical maternal complex. CONCLUSION: In this first report of a human defect in a member of the subcortical maternal subcritical maternal complex, we show that the TLE6 mutation is gender-specific and leads to the earliest known human embryonic lethality phenotype.
Mutation in <i>ADAT3</i>, encoding adenosine deaminase acting on transfer RNA, causes intellectual disability and strabismusBACKGROUND: Intellectual disability (ID) is one of the most common forms of disability worldwide, displaying a wide range of aetiologies and affecting nearly 2% of the global population. OBJECTIVE: To describe a novel autosomal recessive form of ID with strabismus and its underlying aetiology. MATERIALS AND METHODS: Autozygosity mapping, linkage analysis and exome sequencing were performed in a large multiplex consanguineous family that segregates ID and strabismus. Exome sequencing was independently performed in three other consanguineous families segregating the same disease. Direct sequencing of the resulting candidate gene was performed in four additional families with the same phenotype. RESULTS: A single missense mutation was identified in ADAT3 in all studied families on an ancient ancestral haplotype. This gene encodes one of two eukaryotic proteins that are necessary for the deamination of adenosine at position 34 to inosine in t-RNA. Our results show the first human mutation in the t-RNA editing machinery and expand the landscape of pathways involved in the pathogenesis of ID.
A novel syndrome of Klippel-Feil anomaly, myopathy, and characteristic facies is linked to a null mutation in <i>MYO18B</i>Anas M. Alazami, Amal Y. Kentab, Eissa Faqeih et al.|Journal of Medical Genetics|2015 BACKGROUND: Klippel-Feil anomaly (KFA) can be seen in a number of syndromes. We describe an apparently novel syndromic association with KFA. METHODS: Clinical phenotyping of two consanguineous families followed by combined autozygome/exome analysis. RESULTS: Two patients from two apparently unrelated families shared a strikingly similar phenotype characterised by KFA, myopathy, mild short stature, microcephaly, and distinctive facies. They shared a single founder autozygous interval in which whole exome sequencing revealed a truncating mutation in MYO18B. There was virtually complete loss of the transcript in peripheral blood, indicative of nonsense-mediated decay. Electron microscopy of muscle confirms abnormal myosin filaments with accompanying myopathic changes. CONCLUSIONS: Deficiency of MYO18B is linked to a novel developmental disorder which combines KFA with myopathy. This suggests a widespread developmental role for this gene in humans, as observed for its murine ortholog.