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

PMID 40816622 | DOI 10.1053/j.ajkd.2025.06.011 · American journal of kidney diseases : the official journal of the National Kidney Foundation · 2025

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RATIONALE & OBJECTIVE: Autosomal recessive polycystic kidney disease (ARPKD) is typically caused by biallelic PKHD1 variants. However, some patients with a clinical diagnosis remain without a molecular diagnosis. We identified cryptic pathogenic variants in Israeli Bedouin patients of Arabian Peninsula ancestry with ARPKD. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Twelve Bedouin patients of 5 unrelated families of Arabian Peninsula ancestry with ARPKD whose causative variant 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. Complementary DNA (cDNA) analysis of urine-derived tubular kidney epithelial cells confirmed aberrant splicing with pseudo-exon inclusion of 121 base pairs, introducing a premature stop codon. This variant was found in 2 of 100 ethnically matched Bedouin control individuals (carrier rate 1:50). Among all known PKHD1 splicing-disrupting variants, this variant 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 variant causing ARPKD in Israeli Bedouins of Arabian Peninsula ancestry. This PKHD1 variant 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 noncoding ARPKD variants. PLAIN-LANGUAGE SUMMARY: Autosomal recessive polycystic kidney disease (ARPKD) is a severe genetic disorder that affects the kidneys and liver, often presenting before birth. In some patients, standard genetic tests do not detect a causative variant. We examined affected families of Israeli Bedouins originating from the Arabian Peninsula and used whole-genome sequencing and RNA studies to search beyond the protein-coding regions of DNA. We discovered a variant deep within a noncoding region of the PKHD1 gene that interferes with RNA splicing and leads to disease. This variant is a common cause of ARPKD in this population, and its detection may be a useful screening test for ARPKD in this population. These findings highlight the potential importance of analyzing noncoding genomic regions and using population-specific data in genetic diagnosis.