Comprehensive Genetic Analysis of Druze Provides Insights into Carrier Screening

Abstract

Background: Druze individuals, like many genetically homogeneous and isolated populations, harbor recurring pathogenic variants (PV) in autosomal recessive (AR) disorders.

Methods: Variant calling of whole-genome sequencing (WGS) of 40 Druze from the Human Genome Diversity Project (HGDP) was performed (HGDP-cohort). Additionally, we performed whole exome sequencing (WES) of 118 Druze individuals: 38 trios and 2 couples, representing geographically distinct clans (WES-cohort). Rates of validated PV were compared with rates in worldwide and Middle Eastern populations, from the gnomAD and dbSNP datasets.

Results: Overall, 34 PVs were identified: 30 PVs in genes underlying AR disorders, 3 additional PVs were associated with autosomal dominant (AD) disorders, and 1 PV with X-linked-dominant inherited disorder in the WES cohort.

Conclusions: The newly identified PVs associated with AR conditions should be considered for incorporation into prenatal-screening options offered to Druze individuals after an extension and validation of the results in a larger study.

Keywords: druze; founder population; genetic isolate; recurring pathogenic variants; whole exome sequencing.

Figure 1

Methodology flow diagram: HGDP-derived data was filtered based on Druze ethnicity to create a Druze cohort of 40 individuals. Additionally, exome sequencing was performed on 118 Druze individuals from different clans in Israel, creating the WES cohort. Simultaneously, all the variants from ClinVar were filtered based on interpretation labeled as “pathogenic” or “likely pathogenic”. Then, the Druze-cohort variants and the WES-cohort variants were cross referenced with the catalogue of the pathogenic variants from ClinVar creating the Druze pathogenic-variants list. Only variants that were classified as “pathogenic” or “likely pathogenic” according to the ACMG-AMP guidelines were included in the list. We compared the allele frequency of each variant in our cohort and the allele frequency of the variants in worldwide populations based on the data from gnomAD and dbSNP. Using Fisher’s test, we identified the variants that were significantly different in Druze. After a literature review, we narrowed down the list to obtain a curated set of pathogenic variants that are enriched in the Druze population in comparison to other populations.

Figure 2

Bubble plot representing the AF of each PV according to the WES analysis and with respect to Druze, General, and Middle East populations. Missing allele frequencies are represented by missing bubbles.

Figure 3

Bubble plot representing the AF of each PV according to the HGDP analysis and with respect to Druze, General, and Middle East populations. Missing allele frequencies are represented by missing bubbles.