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Original research
Mutations in phospholipase C eta-1 (PLCH1) are associated with holoprosencephaly
  1. Ichrak Drissi1,
  2. Emily Fletcher1,
  3. Ranad Shaheen2,
  4. Michael Nahorski1,
  5. Amal M Alhashem3,
  6. Steve Lisgo4,
  7. Alberto Fernández-Jaén5,
  8. Katherine Schon1,
  9. Kalthoum Tlili-Graiess6,
  10. Sarah F Smithson7,
  11. Susan Lindsay4,
  12. Hayley J Sharpe8,
  13. Fowzan S Alkuraya9,10,
  14. Geoff Woods11
  1. 1Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
  2. 2Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
  3. 3Pediatrics, Prince Sultan Military Medical City, Riyadh, Al Riyadh, Saudi Arabia
  4. 4Human Developmental Biology Resource, Newcastle Institute of Genetic Medicine, Newcastle University, Newcastle, UK
  5. 5Especialista en Neurología Infantil, Hospital Universitario Quirónsalud de Madrid, Madrid, Spain
  6. 6Neuroradiology Section, Department of Radiology, Prince Sultan Military Medical, Riyadh, Saudi Arabia
  7. 7Department of Clinical Genetics, St Michaels Hospital Bristol, Bristol, UK
  8. 8Signalling Programm, Babraham Institute, Babraham Research Campus, Cambridge, UK
  9. 9Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  10. 10Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
  11. 11Cambridge Institute for Medical Research Cambridge, University of Cambridge, Cambridge, Cambridgeshire, UK
  1. Correspondence to Dr Geoff Woods, Cambridge Institute for Medical Research Cambridge, University of Cambridge, Cambridge CB2 0XY, UK; cw347{at}cam.ac.uk

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.

  • cerebellar diseases
  • congenital
  • hereditary
  • and neonatal diseases and abnormalities
  • genetics
  • mutation

Data availability statement

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.

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Data availability statement

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.

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Footnotes

  • ID, EF and RS are joint first authors.

  • Contributors EF and ID conceived and performed experiments and were involved in writing the paper. RS, AF-J, SFS, KS, KT-G, FSA and GW produced clinical and experimental data. SLis and SLin produced the human embryo sections used in the paper, and were involved in the immunohistochemistry analysis. MN, HS, GW and FSA conceived and planned aspects of the project, and were involved in writing the paper.

  • Funding ID, EF and GW acknowledge funding by the 2017 Cambridge NIHR Cambridge Biomedical Research Centre award. MN by a Wellcome Trust Collaborative award (200183/Z/15/Z). A joint MRC/Wellcome Trust award (MR/R006237/1 and 099175/Z/12/Z) funds SLis and SLin. RS and FSA are supported by King Salman Centre for Disability Research and King Abdulaziz City for Science and Technology (13-BIO1113-20) and Saudi Human Genome Programme.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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