Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
PKD1L1-related situs inversus is an autosomal recessive disorder of left–right patterning characterized by mirror reversal of visceral organs. Initial whole-exome sequencing in two unrelated families identified homozygous PKD1L1 mutations in three affected individuals: a splice donor disruption c.6473+2_6473+3delTG in intron 42 in a fetus and a deceased child, and a missense variant c.5072G>C (p.Cys1691Ser) in a living individual with situs inversus totalis and congenital heart disease (PMID:27616478).
Subsequently, one additional non-PCD situs inversus case harbored the recurrent c.6473+2_6473+3del allele, confirming pathogenic recurrence in an independent cohort (PMID:32111882). In total, 4 probands across 3 families have been reported with bi-allelic PKD1L1 variants.
The spectrum includes the homozygous splice site deletion c.6473+2_6473+3delTG and the homozygous missense c.5072G>C (p.Cys1691Ser), both impacting a conserved GPS motif critical for protein folding (PMID:27616478). The splice variant recurs in unrelated cases, underscoring its pathogenic role (PMID:32111882).
Segregation is consistent with autosomal recessive inheritance; all obligate carriers are unaffected and no additional affected relatives beyond probands have been reported.
Functional studies demonstrate that Pkd1l1-null mouse and medaka models recapitulate laterality defects, and molecular modeling predicts that p.Cys1691Ser disrupts a key disulfide bridge in the GPS motif, supporting a loss-of-function mechanism (PMID:27616478).
These genetic and experimental data establish a Moderate clinical validity of PKD1L1 for autosomal recessive situs inversus, enabling molecular diagnosis and informed genetic counseling. Key Take-home: Biallelic PKD1L1 loss-of-function variants cause autosomal recessive situs inversus via disruption of ciliary signaling.
Gene–Disease AssociationModerate4 probands in 3 families with bi-allelic PKD1L1 variants; functional concordance in animal models Genetic EvidenceModerate4 AR probands with two variant classes (homozygous splicing and missense), including a recurrent splice variant in unrelated cases Functional EvidenceModeratePkd1l1-null mouse and medaka models recapitulate laterality defects; molecular modeling supports p.Cys1691Ser disruption |