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Genomic Analysis of Inherited Hearing Loss in the Palestinian Population

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Genomic Analysis of Inherited Hearing Loss in the Palestinian Population Genomic analysis of inherited hearing loss in the Palestinian population Amal Abu Rayyana,b,c, Lara Kamala,b, Silvia Casadeid,e, Zippora Brownsteinc, Fouad Zahdeha,b, Hashem Shahina,b, Christina Canavatia,b, Dima Dweika,b, Tamara Jaraysaa,b, Grace Rabiea,b, Ryan J. Carlsond,e, Suleyman Gulsunerd,e, Ming K. Leed,e, Karen B. Avrahamc, Tom Walshd,e, Mary-Claire Kingd,e,1, and Moien N. Kanaana,b aDepartment of Biology, Bethlehem University, Bethlehem 72372, Palestine; bHereditary Research Laboratory, Bethlehem University, Bethlehem 72372, Palestine; cDepartment of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv 6997901, Israel; dDepartment of Medicine, School of Medicine, University of Washington, Seattle, WA 98195-7720; and eDepartment of Genome Sciences, School of Medicine, University of Washington, Seattle, WA 98195-5065 Contributed by Mary-Claire King, June 29, 2020 (sent for review May 15, 2020; reviewed by Christine Petit and Mustafa Tekin) The genetic characterization of a common phenotype for an entire Results population reveals both the causes of that phenotype for that Genetic Epidemiology of Hearing Loss. The project enrolled and place and the power of family-based, population-wide genomic sequenced 2,198 participants from 491 families (Table 1). The analysis for gene and mutation discovery. We characterized the families live in all parts of the West Bank and Gaza (Fig. 1). Of genetics of hearing loss throughout the Palestinian population, all families, 52% (254/491) included more than one child with enrolling 2,198 participants from 491 families from all parts of hearing loss (multiplex families) and 48% (237/491) included the West Bank and Gaza. In Palestinian families with no prior his- only one child with hearing loss (singleton families). In 9.1% (23/ tory of hearing loss, we estimate that 56% of hearing loss is ge- 254) of multiplex families and 4.2% (10/237) of singleton fami- netic and 44% is not genetic. For the great majority (87%) of lies, children with hearing loss also presented with syndromic families with inherited hearing loss, panel-based genomic DNA features. sequencing, followed by segregation analysis of large kindreds Genetic diagnoses were obtained for 87% (201/231) of mul- and transcriptional analysis of participant RNA, enabled identifica- tiplex families and 49% (111/227) of singleton families with tion of the causal genes and mutations, including at distant non- nonsyndromic hearing loss, and for 87% (20/23) of multiplex GENETICS coding sites. Genetic heterogeneity of hearing loss was striking families and 50% (5/10) of singleton families with syndromic with respect to both genes and alleles: The 337 solved families hearing loss (Fig. 2). Of the 337 families with genetic diagnoses, harbored 143 different mutations in 48 different genes. For one hearing loss was autosomal recessive in 323 families, X-linked in four solved families, a transcription-altering mutation was the recessive in 3 families, and autosomal dominant in 11 families (SI responsible allele. Many of these mutations were cryptic, either Appendix, Tables S1, S2A, and S2B). Severity and onset of exonic alterations of splice enhancers or silencers or deeply hearing loss were associated with recessive versus dominant in- intronic events. Experimentally calibrated in silico analysis of tran- heritance. Hearing loss was severe to profound and prelingual in scriptional effects yielded inferences of high confidence for effects onset in most children in families with recessive hearing loss, but on splicing even of mutations in genes not expressed in accessible mild to moderate and progressive in families with dominant tissue. Most (58%) of all hearing loss in the population was attrib- hearing loss. utable to consanguinity. Given the ongoing decline in consanguin- eous marriage, inherited hearing loss will likely be much rarer in Significance the next generation. The genetic characterization of a common phenotype for an hearing loss | human genetics | genomics | deafness | consanguinity entire population reveals both the genetic epidemiology of that phenotype and the power of family-based, population- he discovery of genes responsible for inherited hearing loss wide genomic analysis. We characterized the genetics of Thas revealed molecular mechanisms essential to the devel- hearing loss throughout the Palestinian population of the West opment and maintenance of hearing that will ultimately enable Bank and Gaza. In families with no prior history of hearing loss, prevention and treatment of its loss (1). In the short term, we estimate that 56% of hearing loss is genetic and 44% is not identification of the genetic cause of hearing loss in a child en- genetic. For most families with inherited hearing loss, causal ables parents to anticipate possible progression or syndromic genes and mutations were identified. Most inherited hearing effects (2), judge the potential effectiveness of cochlear implants loss in the population was attributable to consanguinity. Given (3), and, with pregestational diagnosis, to opt to preclude hear- the ongoing decline in consanguineous marriage, inherited ing loss in future children. hearing loss will likely be much rarer in the next generation. Families from regions with traditions of consanguinity have been particularly informative for discovery of genes responsible Author contributions: A.A.R., R.J.C., K.B.A., T.W., M.-C.K., and M.N.K. designed research; for recessive traits. In particular, over the past 20 y, families from A.A.R., L.K., S.C., Z.B., H.S., C.C., D.D., T.J., G.R., R.J.C., T.W., and M.-C.K. performed re- search; A.A.R., S.C., H.S., R.J.C., S.G., M.K.L., T.W., M.-C.K., and M.N.K. contributed new Palestinian communities with traditions of consanguineous mar- reagents/analytic tools; A.A.R., L.K., S.C., Z.B., F.Z., R.J.C., S.G., M.K.L., T.W., and M.-C.K. riages and large families have been instrumental to the discovery analyzed data; A.A.R., S.G., T.W., and M.-C.K. wrote the paper; and K.B.A., M.-C.K., and and characterization of genes responsible for hearing loss (4–11). M.N.K. supervised research. For this project, we characterized the genetics of inherited hearing Reviewers: C.P., Institut Pasteur; and M.T., University of Miami Miller School of Medicine. loss throughout the Palestinian population, ascertaining children The authors declare no competing interest. with hearing loss throughout the Palestinian West Bank and Gaza Published under the PNAS license. and evaluating responsible genes and mutations. Characterization 1To whom correspondence may be addressed. Email: [email protected]. of hearing loss for an entire population both reveals the epide- This article contains supporting information online at https://www.pnas.org/lookup/suppl/ miology of hearing loss for that region and provides valuable in- doi:10.1073/pnas.2009628117/-/DCSupplemental. formation to address the genetics of hearing loss worldwide. www.pnas.org/cgi/doi/10.1073/pnas.2009628117 PNAS Latest Articles | 1of7 Downloaded by guest on September 28, 2021 Table 1. Demographic and clinical features of Palestinian families with hearing loss 72 N Proportion Tulkarm Tubas Residence 22 2 Qalqilya Bethlehem 76 0.15 25 20 Gaza 24 0.05 Hebron 152 0.31 7 Salfeet Jenin 72 0.15 Jerusalem 66 0.13 Nablus 20 0.04 25 Qalqilya 25 0.05 66 Ramallah 25 0.05 Salfeet 7 0.01 76 Tubas 2 0.004 Tulkarem 22 0.04 152 Clinical features 24 Nonsyndromic hearing loss 458 0.93 Syndromic hearing loss 33 0.07 2+ affected children (multiplex) 254 0.52 1 affected child (singleton) 237 0.48 Prelingual onset 482 0.98 Postlingual onset 9 0.02 Fig. 1. Cities and towns of Palestinian families with hearing loss. The Total 491 1.00 number of families enrolled from each place is indicated in red. Heterogeneity of the genetic causes of inherited hearing loss For families with nonsyndromic hearing loss, the difference in has been recognized since its first genetic diagnoses (12). Ge- proportions of multiplex versus singleton families with genetic diag- netic heterogeneity with respect to both genes and alleles was = noses was highly significant: relative risk (RR) 1.78, 95% CI [1.54, striking in the Palestinian population. The 337 solved families P = 2.05], 5.02E-19. This difference likely reflects a higher prevalence harbored 143 different mutations in 48 different genes (Table 2 of nongenetic hearing loss among singleton families and can be used and Fig. 3). SI Appendix, Table S2B indicates the phenotypes and to estimate the proportion of hearing loss in singleton families caused genotypes of each of these 337 families. by nongenetic factors. That is, if hearing loss in all multiplex families has a genetic basis, of which 87% was identifiable by the gene panel, Effect of Consanguinity on the Prevalence of Hearing Loss. For the then an estimate of the proportion of nongenetic hearing loss among proband of each family, the proportion of homozygous loci singleton families is [227 − (111/0.87)]/227, or 44%. among all loci in the panel was calculated based on the proband’s For 13 families with children with apparently nonsyndromic genotypes at all single-nucleotide polymorphisms (SNPs) (com- hearing loss, damaging mutations were identified in genes associated mon or rare) at each locus. Then, for each proband, a Z score with syndromic conditions: ADGRV1, CLPP, GPSM2, HSD17B4, was calculated to normalize this proportion vis-à-vis all families LARS2, SLC26A4, USH1C,andUSH2A. Syndromic features due to in the cohort (Methods). Means and SDs of the Z distributions ± mutations in some of these genes may appear years after the onset of were 0.48 1.03 for families with documented consanguinity − ± hearing loss. In contrast, hearing loss of the five unresolved singleton and 0.88 0.63 for families with documented nonconsanguinity P = t cases of syndromic hearing loss all appeared in the context of de- ( 3.67E-5, two-tailed test).
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