2. Academic Validation
  3. Mutations in phospholipase C eta-1 ( PLCH1) are associated with holoprosencephaly

Mutations in phospholipase C eta-1 ( PLCH1) are associated with holoprosencephaly

  • J Med Genet. 2022 Apr;59(4):358-365. doi: 10.1136/jmedgenet-2020-107237.
Ichrak Drissi 1,  Emily Fletcher 1,  Ranad Shaheen 2,  Michael Nahorski 1,  Amal M Alhashem 3,  Steve Lisgo 4,  Alberto Fernández-Jaén 5,  Katherine Schon 1,  Kalthoum Tlili-Graiess 6,  Sarah F Smithson 7,  Susan Lindsay 4,  Hayley J Sharpe 8,  Fowzan S Alkuraya 9 10,  Geoff Woods 11
Affiliations

Affiliations

  • 1 Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
  • 2 Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
  • 3 Pediatrics, Prince Sultan Military Medical City, Riyadh, Al Riyadh, Saudi Arabia.
  • 4 Human Developmental Biology Resource, Newcastle Institute of Genetic Medicine, Newcastle University, Newcastle, UK.
  • 5 Especialista en Neurología Infantil, Hospital Universitario Quirónsalud de Madrid, Madrid, Spain.
  • 6 Neuroradiology Section, Department of Radiology, Prince Sultan Military Medical, Riyadh, Saudi Arabia.
  • 7 Department of Clinical Genetics, St Michaels Hospital Bristol, Bristol, UK.
  • 8 Signalling Programm, Babraham Institute, Babraham Research Campus, Cambridge, UK.
  • 9 Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 10 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
  • 11 Cambridge Institute for Medical Research Cambridge, University of Cambridge, Cambridge, Cambridgeshire, UK [email protected].
PMID: 33820834 DOI: 10.1136/jmedgenet-2020-107237
Abstract

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.

Keywords

and neonatal diseases and abnormalities; cerebellar diseases; congenital; genetics; hereditary; mutation.

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