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Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum

We report four allelic variants (three 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...

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Detalles Bibliográficos
Autores principales: Nakaguma, Marilena, Ferreira, Nathalia Garcia Bianchi Pereira, Benedetti, Anna Flavia Figueredo, Madi, Mariana Cotarelli, Silva, Juliana Moreira, Li, Jun Z., Ma, Qianyi, Bilge Ozel, Ayse, Fang, Qing, Narcizo, Amanda de Moraes, Cardoso, Laís Cavalca, Montenegro, Luciana Ribeiro, Funari, Mariana Ferreira de Assis, Nishi, Mirian Yumie, Arnhold, Ivo Jorge Prado, Jorge, Alexander Augusto de Lima, de Mendonca, Berenice Bilharinho, Camper, Sally Ann, Carvalho, Luciani R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394260/
https://www.ncbi.nlm.nih.gov/pubmed/34440302
http://dx.doi.org/10.3390/genes12081128
Descripción
Sumario:We report four allelic variants (three 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 hemizygous 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). This variant was previously reported in a patient with severe holoprosencephaly and shown to affect TGIF1 function. 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 three 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.