De novo variants in PLCG1 are associated with hearing impairment, ocular pathology, and cardiac defects

• DOI: 10.7554/elife.95887
• Publication Date: 2024-04-19T11:25:19Z
• Authors: Mengqi Ma; Yiming Zheng; Shenzhao Lu; Xueyang Pan; Kim C. Worley; Lindsay C. Burrage; Lauren S. Blieden; Aimee Allworth; Wei-Liang Chen; Giuseppe Merla; Barbara Mandriani; Jill A. Rosenfeld; David Li-Kroeger; Debdeep Dutta; Shinya Yamamoto; Michael F. Wangler; ; Ian A. Glass; Sam Strohbehn; Elizabeth Blue; Paolo Prontera; Seema R. Lalani; Hugo J. Bellen
• Keywords: Ectopic expression; Loss function

Phospholipase C isozymes (PLCs) hydrolyze phosphatidylinositol 4,5-bisphosphate into inositol 1,4,5-trisphosphate and diacylglycerol, important signaling molecules involved in many cellular processes. PLCG1 encodes the PLCγ1 isozyme that is broadly expressed. Hyperactive somatic mutations of are observed multiple cancers, but only one germline variant has been reported. Here we describe three unrelated individuals with de novo heterozygous missense variants (p.Asp1019Gly, p.His380Arg, p.Asp1165Gly) who exhibit variable phenotypes including hearing loss, ocular pathology cardiac septal defects. To model these vivo , generated analogous Drosophila ortholog, small wing ( sl ). We created a null allele T2A assessed expression pattern. expressed, discs, eye subset neurons glia. Loss causes size reductions, ectopic veins supernumerary photoreceptors. document mutant flies reduced lifespan age-dependent locomotor Expressing wild-type rescues loss-of-function whereas expressing lethality. Ubiquitous overexpression also reduces viability, suggesting toxic. Ectopic an established hyperactive (p.Asp1165His) pouch severe phenotypes, resembling those p.Asp1019Gly or p.Asp1165Gly variants, further arguing two gain-of-function variants. However, associated p.His380Arg mild. Our data suggest pathogenic contribute to features probands.