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

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.

Case series.

Twelve Bedouin patients of 5 unrelated families of Arabian Peninsula ancestry with ARPKD whose causative variant was unknown despite standard genetic analyses.

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.

Functional studies were limited to urinary-derived epithelial cells, small cohort size.

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.

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.