First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery

Holger Hengel, Rebecca Buchert, Marc Sturm, Tobias B. Haack, Yvonne Schelling, Muhammad Mahajnah, Rajech Sharkia, Abdussalam Azem, Ghassan Balousha, Zaid Ghanem, Mohammed Falana, Osama Balousha, Suhail Ayesh, Reinhard Keimer, Werner Deigendesch, Jimmy Zaidan, Hiyam Marzouqa, Peter Bauer, Ludger Schöls*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1034-1043
Number of pages10
JournalEuropean Journal of Human Genetics
Volume28
Issue number8
DOIs
StatePublished - 1 Aug 2020

Funding

FundersFunder number
Deutsche ForschungsgemeinschaftSCHO 754/5-1, 2554-0-0
Bundesministerium für Bildung und Forschung
Seventh Framework Programme

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