RT Journal Article SR Electronic T1 Mutations in phospholipase C eta-1 (PLCH1) are associated with holoprosencephaly JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2020-107237 DO 10.1136/jmedgenet-2020-107237 A1 Ichrak Drissi A1 Emily Fletcher A1 Ranad Shaheen A1 Michael Nahorski A1 Amal M Alhashem A1 Steve Lisgo A1 Alberto Fernández-Jaén A1 Katherine Schon A1 Kalthoum Tlili-Graiess A1 Sarah F Smithson A1 Susan Lindsay A1 Hayley J Sharpe A1 Fowzan S Alkuraya A1 Geoff Woods YR 2021 UL http://jmg.bmj.com/content/early/2021/04/04/jmedgenet-2020-107237.abstract AB Background Holoprosencephaly is a spectrum of developmental disorder of the embryonic forebrain in which there is failed or incomplete separation of the prosencephalon into two cerebral hemispheres. To date, dominant mutations in sonic hedgehog (SHH) pathway genes are the predominant Mendelian causes, and have marked interfamilial and intrafamilial phenotypical variabilities.Methods We describe two families in which offspring had holoprosencephaly spectrum and homozygous predicted-deleterious variants in phospholipase C eta-1 (PLCH1). Immunocytochemistry was used to examine the expression pattern of PLCH1 in human embryos. We used SHH as a marker of developmental stage and of early embryonic anatomy.Results In the first family, two siblings had congenital hydrocephalus, significant developmental delay and a monoventricle or fused thalami with a homozygous PLCH1 c.2065C>T, p.(Arg689*) variant. In the second family, two siblings had alobar holoprosencephaly and cyclopia with a homozygous PLCH1 c.4235delA, p.(Cys1079ValfsTer16) variant. All parents were healthy carriers, with no holoprosencephaly spectrum features. We found that the subcellular localisation of PLCH1 is cytoplasmic, but the p.(Cys1079ValfsTer16) variant was predominantly nuclear. Human embryo immunohistochemistry showed PLCH1 to be expressed in the notorcord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome, all tissues producing or responding to SHH. Furthermore, the embryonic subcellular localisation of PLCH1 was exclusively cytoplasmic, supporting protein mislocalisation contributing to the pathogenicity of the p.(Cys1079ValfsTer16) variant.Conclusion Our data support the contention that PLCH1 has a role in prenatal mammalian neurodevelopment, and deleterious variants cause a clinically variable holoprosencephaly spectrum phenotype.All data relevant to the study are included in the article or uploaded as supplementary information. GW's mail address: cw347@cam.ac.ukAddress: Cambridge Institute for Medical Research, University of Cambridge, Keith Peters Building, Addenbrookes Hospital, Hills Rd, Cambridge CB2 0QQ, UK.Website: https://www.cimr.cam.ac.uk/research/principal-investigators/woods.