Abstract
Purpose
Disorders/differences of sex development (DSD) result from variants in many different human genes but, frequently, have no detectable molecular cause.
Methods
Detailed clinical and genetic phenotyping was conducted on a family with three children. A Sec31a animal model and functional studies were used to investigate the significance of the findings.
Results
By trio whole-exome DNA sequencing we detected a heterozygous de novo nonsense SEC31A variant, in three children of healthy non-consanguineous parents. The children had different combinations of disorders that included complete gonadal dysgenesis and multiple pituitary hormone deficiency. SEC31A encodes a component of the COPII coat protein complex, necessary for intracellular anterograde vesicle-mediated transport between the endoplasmic reticulum (ER) and Golgi. CRISPR-Cas9 targeted knockout of the orthologous Sec31a gene region resulted in early embryonic lethality in homozygous mice. mRNA expression of ER-stress genes ATF4 and CHOP was increased in the children, suggesting defective protein transport. The pLI score of the gene, from gnomAD data, is 0.02.
Conclusions
SEC31A might underlie a previously unrecognised clinical syndrome comprising gonadal dysgenesis, multiple pituitary hormone deficiencies, dysmorphic features and developmental delay. However, a variant that remains undetected, in a different gene, may alternatively be causal in this family.
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Acknowledgements
We are grateful to the staff of the sequencing facilities of Glasgow Polyomics, Edinburgh Genomics and the West of Scotland Centre for Genomic Medicine. In addition, we thank Sara Wells, Lydia Teboul, Joffrey Mianné, Gemma Codner and their team for CRISPR-Cas9 mutagenesis. We also thank the husbandry team in Ward 5 of the Mary Lyon Centre (MLC) at Harwell, particularly Jackie Harrison, Gemma Atkins, Anju Paudyal and Michelle Sandell. Additionally, we thank Martin Fray and the FESA and Gene Delivery teams of the MLC transgenic facility.
Funding
The next generation sequencing was facilitated by grants from the Wellcome Trust ISSF and Scottish Genomes Partnership. This Scottish Genomes Partnership is funded by the Chief Scientist Office of the Scottish Government Health Directorates [SGP/1] and The Medical Research Council Whole Genome Sequencing for Health and Wealth Initiative (MC/PC/15080). AKLH is funded by an NES/CSO Clinical Lectureship (PCL/21/05).
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EST, RM and SFA planned the project, obtained ethics approval and led the writing and analysis. AKLH prepared drafts of the report, acquired blood samples and undertook analysis and interpretation of the data. DS and AG undertook the mouse model work. ACM, FJR, LDLC and RMT undertook and supervised the ER stress work. GH, SGP, LAW, NW, PH and GG were responsible for genetic and proteomic analysis and interpretation. All authors reviewed the final manuscript.
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West of Scotland Ethics approval (14/WS/0036) and R&D permission (GN14KH079) were obtained from the respective committees for whole exome and whole genome sequencing and for the data storage and analysis.
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Tobias, E.S., Lucas-Herald, A.K., Sagar, D. et al. SEC31A may be associated with pituitary hormone deficiency and gonadal dysgenesis. Endocrine 84, 345–349 (2024). https://doi.org/10.1007/s12020-024-03701-x
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DOI: https://doi.org/10.1007/s12020-024-03701-x