Genomic analysis of inherited hearing loss in the Palestinian population

Abstract

The genetic characterization of a common phenotype for an entire population reveals both the causes of that phenotype for that place and the power of family-based, population-wide genomic analysis for gene and mutation discovery. We characterized the genetics of hearing loss throughout the Palestinian population, enrolling 2,198 participants from 491 families from all parts of the West Bank and Gaza. In Palestinian families with no prior history of hearing loss, we estimate that 56% of hearing loss is genetic and 44% is not genetic. For the great majority (87%) of families with inherited hearing loss, panel-based genomic DNA sequencing, followed by segregation analysis of large kindreds and transcriptional analysis of participant RNA, enabled identification of the causal genes and mutations, including at distant noncoding sites. Genetic heterogeneity of hearing loss was striking with respect to both genes and alleles: The 337 solved families harbored 143 different mutations in 48 different genes. For one in four solved families, a transcription-altering mutation was the responsible allele. Many of these mutations were cryptic, either exonic alterations of splice enhancers or silencers or deeply intronic events. Experimentally calibrated in silico analysis of transcriptional effects yielded inferences of high confidence for effects on splicing even of mutations in genes not expressed in accessible tissue. Most (58%) of all hearing loss in the population was attributable to consanguinity. Given the ongoing decline in consanguineous marriage, inherited hearing loss will likely be much rarer in the next generation.

Keywords: consanguinity; deafness; genomics; hearing loss; human genetics.

Fig. 1.

Cities and towns of Palestinian families with hearing loss. The number of families enrolled from each place is indicated in red.

Fig. 2.

Families with hearing loss (HL), with and without genetic diagnoses.

Fig. 3.

Genes responsible for hearing loss in Palestinian families.

Fig. 4.

Families with hearing loss due to nonsense mutation in PCDH15 isoform CD2. (A) Families with hearing loss and homozygosity for PCDH15 p.(Q1756*). The chance of this degree of cosegregation occurring by chance is <10E-6. (B) PCDH15 isoforms, indicating exons encoding the transmembrane (TM) domain and cytoplasmic domains C-terminal to the TM domain. Exons outlined in boxes are present in some but not all transcripts. Of the three isoforms of PCDH15, only CD2 is critical to the development and maintenance of hearing. PCDH15 p.(Q1576*) is transcribed only on isoform CD2.

Fig. 5.

Mutation at MYO15A c.3609(+985), predicted to alter transcription of a cochlear and pituitary-specific isoform of myosin 15A. (A) Families with mutations at MYO15A c.3609(+985) (red V), MYO15A c.7207G>T (green V), and MYO15A c.9572G>A (blue V). MYO15A c.3609(+985) disrupts the splice donor of isoform-specific exon 1A, predicted to lead to complete loss of transcript for this isoform. Splice effects of MYO15A c.7207G>T and MYO15A c.9572G>A are described in SI Appendix, Table S5. The chance of this degree of cosegregation of MYO15A c.3609(+985) with hearing loss occurring by chance is less than 10E-20. (B) MYO15A isoform 1 (NM_010862.2), isoform 2 (NM_182698.2), and proposed isoform 3. Locations in isoform 3 of the alternate first exon and of MYO15A c.3609(+985) are indicated. (C) Expression of the alternate first exon in mouse cochlear RNA. (D) Transcript sequence from mouse cochlear RNA indicating expression of exon 1A and splicing to exon 3.