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Abstract
Purpose
Congenital hypopituitarism (CH) disorders are phenotypically variable. Variants in multiple genes are associated with these disorders, with variable penetrance and inheritance.
Methods
We screened a large cohort (n=1,765) of patients with or at risk of CH using Sanger sequencing, selected according to phenotype, and conducted next generation sequencing (NGS) in 51 families within our cohort. We report the clinical, hormonal and neuroradiological phenotypes of patients with variants in known genes associated with CH.
Results
We have identified variants in 178 patients: GH1/GHRHR (51 patients/414 screened), PROP1 (17/253), POU1F1 (15/139), SOX2 (13/59), GLI2 (7/106), LHX3/LHX4 (8/110), HESX1 (8/724), SOX3 (9/354), OTX2 (5/59), SHH (2/64) and TCF7L1, KAL1, FGFR1, FGF8 (2/585 respectively). NGS identified 26 novel variants in 35 patients (from 24 families).MRI showed prevalent hypothalamo-pituitary (HP) abnormalities, present in all patients with PROP1, GLI2, SOX3, HESX1, OTX2, LHX3, and LHX4 variants. Normal HP anatomy was reported in 24/121; predominantly those with GH1, GHRHR, POU1F1 and SOX2 variants.
Conclusion
We have identified variants in 10% (178/1,765) of our CH cohort. NGS has revolutionised variant identification, and careful phenotypic patient characterization has improved our understanding of CH. We have constructed a flow-chart to guide genetic analysis in these patients, which will evolve upon novel gene discoveries.
Keywords
Article info
Publication history
Accepted:
April 30,
2023
Received in revised form:
April 28,
2023
Received:
August 4,
2022
Publication stage
In Press Accepted ManuscriptFootnotes
The authors have nothing to disclose and have no conflicts of interest.
Conflict of Interest
Disclosure: The authors declare no conflict of interest.
Identification
Copyright
© 2023 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.
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