Heterozygous variants in affect hearing, vision, cardiac, and immune function.

Phospholipase C isozymes (PLCs) hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP) into inositol 1,4,5-trisphosphate (IP) and diacylglycerol (DAG), important signaling molecules involved in many cellular processes including Ca release from the endoplasmic reticulum (ER). encodes the PLCγ1 isozyme that is broadly expressed. Hyperactive somatic mutations of are observed in multiple cancers, but only one germline variant has been reported. Here, we describe seven individuals with heterozygous missense variants in [p.(Asp1019Gly), p.(His380Arg), p.(Asp1165Gly), and p.(Leu597Phe)] who present with hearing impairment (5/7), ocular pathology (4/7), cardiac septal defects (3/6), and various immunological issues (5/7). To model these variants , we generated the analogous variants in the Drosophila ortholog, (). We created a null allele and assessed its expression pattern. is broadly expressed, including wing discs, eye discs, and a subset of neurons and glia. mutant flies exhibit wing size reductions, ectopic wing veins, and supernumerary photoreceptors. We document that mutant flies also exhibit a reduced lifespan and age-dependent locomotor defects. Expressing wild-type in mutant flies rescues the loss-of-function phenotypes, whereas the variants increase lethality. Ectopic expression of an established hyperactive variant, p.(Asp1165His) in the wing pouch causes elevated Ca activity and severe wing phenotypes. These phenotypes are also observed when the p.(Asp1019Gly) or p.(Asp1165Gly) variants are overexpressed in the wing pouch, arguing that these are gain-of-function variants. However, the wing phenotypes associated with p.(His380Arg) or p.(Leu597Phe) overexpression are either mild or only partially penetrant. Our data suggest that the heterozygous missense variants reported here affect protein function differentially and contribute to the clinical features observed in the affected individuals.