Intronic and Coding Genetic Variants in Autosomal Recessive Polycystic Kidney Disease Among Israeli Bedouins of Arabian Peninsula Ancestry.

Abstract

RATIONALE & OBJECTIVE Autosomal recessive polycystic kidney disease (ARPKD) is typically caused by biallelic PKHD1 mutations. However, some clinically diagnosed patients remain without a molecular diagnosis. We aimed to identify cryptic pathogenic variants in Israeli Bedouin patients of Arabian Peninsula ancestry with ARPKD. STUDY DESIGN Case series. SETTING &PARTICIPANTS Twelve Bedouin patients of five unrelated families of Arabian Peninsula ancestry with ARPKD whose causative mutation was unknown despite standard genetic analyses. OBSERVATIONS Whole-genome sequencing (WGS), including short- and long-read platforms, followed by bioinformatics filtration and transcript analysis, identified a pathogenic PKHD1 variant confirmed by functional analysis: a deep-intronic PKHD1 variant (6:51,757,883 C>T (hg38), ENST00000340994.4: c.8643-2945 G>A) was identified in 12 patients with ARPKD within 5 families of Israeli Negev Bedouins originating from the Arabian Peninsula. Variant segregation within affected kindreds was consistent with autosomal recessive inheritance. cDNA analysis of urine-derived tubular kidney epithelial cells confirmed aberrant splicing with pseudo-exon inclusion of 121 bp, introducing a premature stop codon. This variant was found in 2 of 100 ethnically matched Bedouin controls (carrier rate 1:50). Among all known PKHD1 splicing-disrupting variants, this mutation received the lowest and most benign scores across splicing prediction tools. We also delineate 12 other PKHD1 variants in Negev Bedouins. LIMITATIONS Functional studies were limited to urinary-derived epithelial cells, small cohort size. CONCLUSIONS We describe a deep-intronic truncating PKHD1 variant, as a common founder mutation causing ARPKD in Israeli Bedouins of Arabian Peninsula ancestry. This PKHD1 mutation caused pseudo-exon inclusion through a donor-gain mechanism, without directly introducing a splice site. These findings highlight the diagnostic utility of WGS and transcript analysis in identifying pathogenic non-coding ARPKD variants.