PIGA related disorder as a range of phenotypes rather than two distinct subtypes.

Patients with germline phosphatidylinositol glycan biosynthesis class A (PIGA) related disorder have historically been categorized into one of two distinct subtypes: a severe form which is often fatal, and a less severe form. However, the increasing number of cases with features indicative of both subtypes raise the possibility of a phenotypic spectrum associated with PIGA disorder. In order to further characterize this phenotypic spectrum, we present two patients with features of both the severe and less severe subtypes with a review of phenotypes reported to date in the literature. In eight year old patient 1, a maternally inherited PIGA likely pathogenic variant was discovered using exome sequencing. He presented with myoclonic epilepsy, mild intellectual disability, spastic diplegia, developmental motor delay, and autism spectrum disorder. Patient 2 is a 13 year old with focal epilepsy, profound developmental delay, coarse facial features, severe intellectual disability and autism spectrum disorder. A de novo PIGA likely pathogenic variant was found through exome sequencing. Both patients had normal alkaline phosphatase levels and are without related organ abnormalities. We conclude that pathogenic PIGA variants cause a spectrum of phenotypes rather than the categories of "severe" and "less severe" as previously posited.

Mutations in PLS1, encoding fimbrin, cause autosomal dominant nonsyndromic hearing loss.

Nonsyndromic hearing loss (NSHL), a common sensory disorder, is characterized by high clinical and genetic heterogeneity (i.e., approximately 115 genes and 170 loci so far identified). Nevertheless, almost half of patients submitted for genetic testing fail to receive a conclusive molecular diagnosis. We used next-generation sequencing to identify causal variants in PLS1 (c.805G>A, p.[E269K]; c.713G>T, p.[L238R], and c.383T>C, p.[F128S]) in three unrelated families of European ancestry with autosomal dominant NSHL. PLS1 encodes Plastin 1 (also called fimbrin), one of the most abundant actin-bundling proteins of the stereocilia. In silico protein modeling suggests that all variants destabilize the structure of the actin-binding domain 1, likely reducing the protein's ability to bind F actin. The role of PLS1 gene in hearing function is further supported by the recent demonstration that Pls1-/- mice show a hearing loss phenotype similar to that of our patients. In summary, we report PLS1 as a novel gene for autosomal dominant NSHL, suggesting that this gene is required for normal hearing in humans and mice.