Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in Humans

Abstract

Disruption of the establishment of left-right (L-R) asymmetry leads to situs anomalies ranging from situs inversus totalis (SIT) to situs ambiguus (heterotaxy). The genetic causes of laterality defects in humans are highly heterogeneous. Via whole-exome sequencing (WES), we identified homozygous mutations in PKD1L1 from three affected individuals in two unrelated families. PKD1L1 encodes a polycystin-1-like protein and its loss of function is known to cause laterality defects in mouse and medaka fish models. Family 1 had one fetus and one deceased child with heterotaxy and complex congenital heart malformations. WES identified a homozygous splicing mutation, c.6473+2_6473+3delTG, which disrupts the invariant splice donor site in intron 42, in both affected individuals. In the second family, a homozygous c.5072G>C (p.Cys1691Ser) missense mutation was detected in an individual with SIT and congenital heart disease. The p.Cys1691Ser substitution affects a highly conserved cysteine residue and is predicted by molecular modeling to disrupt a disulfide bridge essential for the proper folding of the G protein-coupled receptor proteolytic site (GPS) motif. Damaging effects associated with substitutions of this conserved cysteine residue in the GPS motif have also been reported in other genes, namely GPR56, BAI3, and PKD1 in human and lat-1 in C. elegans, further supporting the likely pathogenicity of p.Cys1691Ser in PKD1L1. The identification of bi-allelic PKD1L1 mutations recapitulates previous findings regarding phenotypic consequences of loss of function of the orthologous genes in mice and medaka fish and further expands our understanding of genetic contributions to laterality defects in humans.

Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome

“…Of the nine PKD1L1 variants (six missense, two splice‐site, and one chain‐terminating), eight have yet to be associated with a disease phenotype. The splice site mutation found in subject 3 (c.6473+2_6473+3delTG) was recently reported as a homozygous variant in 2 siblings with heterotaxy and severe congenital heart disease . The variants c.T2399C (p.I800T) and c.C6949T (p.R2317W) were both present in homozygous form in subject 1 and present as heterozygous alleles in subjects 2, 6, and 7 (Table ; Supporting Table ).…”

“…In particular, PKD1L1 , which encodes the polycystin 1‐like 1 protein (a member of the polycystin protein family), had potentially pathogenic biallelic and heterozygous variants in multiple BASM participants. Given the role of PKD1L1 in ciliary calcium signaling and laterality determination, its interactions with PKD2, and its identification as a cause of complex congenital heart disease in children, further investigations of PKD1L1 variants in this BASM cohort were pursued …”

Genetics and Genomics of Congenital Heart Disease

“…This triggers asymmetric gene expression in the lateral plate mesoderm, eventually leading to asymmetric heart looping. Due to the role of cilia in determining LR patterning, mutations affecting ciliary motility 100 and sensing 101 machinery result in HTX and CHD.…”

“…Some of the “unexplained CHD cases” could be due to mutations affecting the as of yet underexplored non-coding DNA, somatic mutations and gene-environment interactions as discussed below. In addition, CHD due to biallelic mutations has been underexplored, and thus far has largely focused on candidate gene analysis and familial CHD 101 . As new statistical approaches are coupled with larger CHD cohorts, the inherent challenges in an unbiased analysis of recessive mutations in sporadic CHD can be surmounted.…”

The genetics of congenital heart disease… understanding and improving long-term outcomes in congenital heart disease: a review for the general cardiologist and primary care physician

“…Such mutations most commonly affect genes for cardiac transcription factors, signaling molecules or cellular structures without significantly reducing reproductive potential (40, 41). For example, mutations in the NKX2.5 gene, a critical transcription factor that specifies cardiac mesoderm during embryogenesis, were some of the first mutations associated with inherited CHD.…”