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Lookup NU author(s): Dr Steven LisgoORCiD, Emerita Professor Susan Lindsay
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ. 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.
Author(s): Drissi I, Fletcher E, Shaheen R, Nahorski M, Alhashem AM, Lisgo S, Fernandez-Jaen A, Schon K, Tlili-Graiess K, Smithson SF, Lindsay S, Sharpe HJ, Alkuraya FS, Woods G
Publication type: Article
Publication status: Published
Journal: Journal of Medical Genetics
Year: 2022
Volume: 59
Issue: 4
Pages: 358-365
Print publication date: 01/04/2022
Online publication date: 05/04/2021
Acceptance date: 24/01/2021
Date deposited: 30/11/2023
ISSN (print): 0022-2593
ISSN (electronic): 1468-6244
Publisher: BMJ Publishing Group
URL: https://doi.org/10.1136/jmedgenet-2020-107237
DOI: 10.1136/jmedgenet-2020-107237
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