Abstract
A high rate of consanguinity leads to a high prevalence of autosomal recessive disorders in inbred populations. One example of inbred populations is the Arab communities in Israel and the Palestinian Authority. In the Palestinian Authority in particular, due to limited access to specialized medical care, most patients do not receive a genetic diagnosis and can therefore neither receive genetic counseling nor possibly specific treatment. We used whole-exome sequencing as a first-line diagnostic tool in 83 Palestinian and Israeli Arab families with suspected neurogenetic disorders and were able to establish a probable genetic diagnosis in 51% of the families (42 families). Pathogenic, likely pathogenic or highly suggestive candidate variants were found in the following genes extending and refining the mutational and phenotypic spectrum of these rare disorders: ACO2, ADAT3, ALS2, AMPD2, APTX, B4GALNT1, CAPN1, CLCN1, CNTNAP1, DNAJC6, GAMT, GPT2, KCNQ2, KIF11, LCA5, MCOLN1, MECP2, MFN2, MTMR2, NT5C2, NTRK1, PEX1, POLR3A, PRICKLE1, PRKN, PRX, SCAPER, SEPSECS, SGCG, SLC25A15, SPG11, SYNJ1, TMCO1, and TSEN54. Further, this cohort has proven to be ideal for prioritization of new disease genes. Two separately published candidate genes (WWOX and PAX7) were identified in this study. Analyzing the runs of homozygosity (ROHs) derived from the Exome sequencing data as a marker for the rate of inbreeding, revealed significantly longer ROHs in the included families compared with a German control cohort. The total length of ROHs correlated with the detection rate of recessive disease-causing variants. Identification of the disease-causing gene led to new therapeutic options in four families.
Highlights
GeneticsConsanguinity is a deeply rooted cultural trait in Middle Eastern societies, especially in the Arab rural populations due to socio-cultural factors like maintenance of the family structure, property, or ease of marital arrangements [1]
Two independent genetic disorders were identified in one family (GPT2 and likely autosomal recessive deafness) as discussed elsewhere [20]
A considerably higher percentage of families with reported consanguinity received a genetic diagnosis and the runs of homozygosity (ROHs) were significantly longer in patients with identified pathogenic/likely pathogenic variants compared with patients that did not receive a genetic diagnosis
Summary
GeneticsConsanguinity is a deeply rooted cultural trait in Middle Eastern societies, especially in the Arab rural populations due to socio-cultural factors like maintenance of the family structure, property, or ease of marital arrangements [1]. Despite the fact that this type of marriages is discouraged by the major religions, recent studies estimated the prevalence of consanguineous marriages among the Palestinian Arab and Israeli Arab population to 44.3% and 25.9%, respectively, representing some of the highest rates in the world [2,3,4,5]. This high inbreeding rate leads to a high prevalence of autosomal recessive disorders. Most of the time a genetic diagnosis is not established
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