Heterozygous variants inPLCG1affect hearing, vision, cardiac, and immune function

Phospholipase C isozymes (PLCs) hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG), important signaling molecules involved in many cellular processes including Ca²⁺release from the endoplasmic reticulum (ER).PLCG1encodes the PLCγ1 isozyme that is broadly expressed. Hyperactive somatic mutations ofPLCG1are observed in multiple cancers, but only one germline variant has been reported. Here we describe seven individuals with heterozygous missense variants inPLCG1[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 variantsin vivo, we generated the analogous variants in theDrosophilaortholog,small wing(sl). We created a null allelesl^T2Aand assessed its expression pattern.slis broadly expressed, including wing discs, eye discs, and a subset of neurons and glia.sl^T2Amutant 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-typeslinsl^T2Amutant flies rescues the loss-of-function phenotypes, whereas the variants increase lethality. Ectopic expression of an established hyperactivePLCG1variant, p.(Asp1165His) in the wing pouch causes elevated Ca²⁺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.