RESUMEN
Autosomal recessive (AR) gene defects are the leading genetic cause of intellectual disability (ID) in countries with frequent parental consanguinity, which account for about 1/7th of the world population. Yet, compared to autosomal dominant de novo mutations, which are the predominant cause of ID in Western countries, the identification of AR-ID genes has lagged behind. Here, we report on whole exome and whole genome sequencing in 404 consanguineous predominantly Iranian families with two or more affected offspring. In 219 of these, we found likely causative variants, involving 77 known and 77 novel AR-ID (candidate) genes, 21 X-linked genes, as well as 9 genes previously implicated in diseases other than ID. This study, the largest of its kind published to date, illustrates that high-throughput DNA sequencing in consanguineous families is a superior strategy for elucidating the thousands of hitherto unknown gene defects underlying AR-ID, and it sheds light on their prevalence.
Asunto(s)
Genes Recesivos/genética , Discapacidad Intelectual/genética , Adulto , Consanguinidad , Exoma/genética , Familia , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Homocigoto , Humanos , Irán , Masculino , Persona de Mediana Edad , Mutación/genética , Linaje , Mapas de Interacción de Proteínas/genética , Secuenciación del Exoma/métodos , Secuenciación Completa del Genoma/métodosRESUMEN
BACKGROUND: Countries with culturally accepted consanguinity provide a unique resource for the study of rare recessively inherited genetic diseases. Although hereditary hearing loss (HHL) is not uncommon, it is genetically heterogeneous, with over 85 genes causally implicated in non-syndromic hearing loss (NSHL). This heterogeneity makes many gene-specific types of NSHL exceedingly rare. We sought to define the spectrum of autosomal recessive HHL in Iran by investigating both common and rarely diagnosed deafness-causing genes. DESIGN: Using a custom targeted genomic enrichment (TGE) panel, we simultaneously interrogated all known genetic causes of NSHL in a cohort of 302 GJB2-negative Iranian families. RESULTS: We established a genetic diagnosis for 67% of probands and their families, with over half of all diagnoses attributable to variants in five genes: SLC26A4, MYO15A, MYO7A, CDH23 and PCDH15. As a reflection of the power of consanguinity mapping, 26 genes were identified as causative for NSHL in the Iranian population for the first time. In total, 179 deafness-causing variants were identified in 40 genes in 201 probands, including 110 novel single nucleotide or small insertion-deletion variants and three novel CNV. Several variants represent founder mutations. CONCLUSION: This study attests to the power of TGE and massively parallel sequencing as a diagnostic tool for the evaluation of hearing loss in Iran, and expands on our understanding of the genetics of HHL in this country. Families negative for variants in the genes represented on this panel represent an excellent cohort for novel gene discovery.
Asunto(s)
Pérdida Auditiva/genética , Conexina 26 , Conexinas , Consanguinidad , Efecto Fundador , Frecuencia de los Genes , Genes Recesivos , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Pérdida Auditiva/patología , Humanos , IránRESUMEN
OBJECTIVES: We investigated the cause of autosomal recessive nonsyndromic hearing loss (ARNSHL) that segregated in 2 consanguineous Iranian families. METHODS: Otologic and audiometric examinations were performed on affected members of each family. Genome-wide parametric multipoint linkage mapping using a recessive model was performed with Affymetrix 50K GeneChips or short tandem repeat polymorphisms. Direct sequencing was used to confirm the causative mutation in each family. RESULTS: In 2 Iranian families, L-1651 and L-8600606, with ARNSHL that mapped to the DFNB7/11 locus, homozygosity for a reported splice site mutation (c.776+1G>A), and a novel deletion (c.1589_1590delCT; p.S530*) were identified in the TMC1 gene, respectively. CONCLUSIONS: Consistent with the previously reported phenotype in DFNB7/11 families, the 2 Iranian families had segregated congenital, profound hearing impairment. However, in family L-1651, one affected family member (IV:3) has milder hearing impairment than expected, suggesting a potential genetic modifier effect. These results indicate that DFNB7/11 is a common form of genetic hearing loss in Iran, because this population is the source of 6 of the 29 TMC1 mutations reported worldwide.