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.
What's Already Known About This Topic?
Cell‐free fetal DNA reports include analysis of fetal sex chromosomes.
What Does This Study Add?
In patients that have non-invasive prenatal testing performed, ultrasound determination of fetal genitalia can lead to prenatal diagnosis of anomalies affecting the urogenital system.
(Abstracted from Genet Med 2020;22:1296–1302)
Spinal muscular atrophy (SMA) is a neurodevelopmental disorder that is associated with muscle weakness and atrophy. There are several subtypes that are categorized as SMA type 1 (presenting in early infancy), where infants are unable to sit unassisted; SMA type 2 (presenting between 6 and 18 months of age), where patients are unable to walk independently; SMA type 3 (presenting after 18 months of age), where some patients were able to walk independently, but others lose this ability; and SMA type 4 (presenting in adulthood), which is rare and less severe.
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