Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery

Abstract

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Gulf region, North Africa, and Central Asia 1–3, has resulted in an elevated burden of recessive disease4. Here we generated a whole exome GME variome from 1,111 unrelated subjects. We detected substantial diversity from sub-geographies, continental and subregional admixture, several ancient founder populations with little evidence of bottlenecks. Measured consanguinity was an order-of-magnitude above that of other sampled populations, and included an increased burden of runs of homozygosity (ROH), but no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved GME recessive conditions reduced the number of potential disease-causing variants by 4–7-fold. These results reveal the variegated GME genetic architecture and support future human genetic discoveries in Mendelian and population genetics.

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

“…The healthy parents and siblings tested were all heterozygous for the mutant alleles or homozygous for the wild-type allele, consistent with an AR mode of inheritance with full clinical penetrance. None of the 12 mutant alleles were found in any of the various public databases (Exome Aggregation Consortium, Human Gene Mutation Database, Ensembl, National Heart, Lung, and Blood Institute Grand Opportunity Exome Sequencing Project, and 1000 Genomes Project), our in-house WES database (>3,000 exomes), or the Greater Middle Eastern Variome (63), further suggesting that the mutant alleles were causal for CMCD. The p.D387N missense mutation affected a residue conserved throughout evolution.…”

A variant in LMX1A causes autosomal recessive severe-to-profound hearing impairment

“…1a). This variant is rare in the current genomic databases with no reported homozygotes [gnomAD allele frequency (AF) = 1.80 × 10 −5 ; GME and South Asian gnomAD AF = 0] (Lek et al 2016; Scott et al 2016). It is located in a conserved C-terminal region, changes a hydrophobic residue to a polar neutral residue, and is predicted damaging by various bioinformatic tools (Fig.…”

“…Variant filtering was performed using the coding region and splice region ± 12 bp based on Ensembl transcripts. For a variant to be retained, it must be a splice-site, missense, nonsense, or indel with a minor allele frequency (MAF) < 0.005 in every population with ≤ 1 homozygous or x-chromosomal hemizygous variant in the Genome Aggregation Database (gnomAD); Greater Middle East (GME) variome database; or the NHLBI Exome Sequencing Project (ESP6500) database, amongst others (Fu et al 2012; Auton et al 2015; Lek et al 2016; Scott et al 2016). The missense variants must also have a scaled Combined Annotation-Dependent Depletion (CADD) score > 15 (Kircher et al 2014).…”

Medical genetics and genomic medicine in Turkey: a bright future at a new era in life sciences

“…This translates to an impressive four‐ to sevenfold increase in the identification of potential disease‐causing variants for unsolved recessive conditions (Scott et al 2016; Özçelik and Onat 2016). …”