Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Allelic Variants in Established Hypopituitarism Genes Expands Our Knowledge of Phenotypic Spectrum

Version 1 : Received: 17 May 2021 / Approved: 21 May 2021 / Online: 21 May 2021 (11:13:02 CEST)

A peer-reviewed article of this Preprint also exists.

Nakaguma, M.; Ferreira, N.G.B.P.; Benedetti, A.F.F.; Madi, M.C.; Silva, J.M.; Li, J.Z.; Ma, Q.; Ozel, A.B.; Fang, Q.; Narcizo, A.M.; Cardoso, L.C.; Montenegro, L.R.; Funari, M.F.A.; Nishi, M.Y.; Arnhold, I.J.P.; Jorge, A.A.L.; Mendonca, B.B.; Camper, S.A.; Carvalho, L.R. Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum. Genes 2021, 12, 1128. Nakaguma, M.; Ferreira, N.G.B.P.; Benedetti, A.F.F.; Madi, M.C.; Silva, J.M.; Li, J.Z.; Ma, Q.; Ozel, A.B.; Fang, Q.; Narcizo, A.M.; Cardoso, L.C.; Montenegro, L.R.; Funari, M.F.A.; Nishi, M.Y.; Arnhold, I.J.P.; Jorge, A.A.L.; Mendonca, B.B.; Camper, S.A.; Carvalho, L.R. Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum. Genes 2021, 12, 1128.

Journal reference: Genes 2021, 12, 1128
DOI: 10.3390/genes12081128

Abstract

We report four allelic variants (3 novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p. Phe 57Leufs * 43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (ΔΔG = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in 3 genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.

Keywords

GH1, SOX3, TGIF1, HYPOPITUITARISM, ALLELIC VARIANTS

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