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

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Nakaguma, Marilena ^[1] ; Bianchi Pereira Ferreira, Nathalia Garcia ^[1] ; Figueredo Benedetti, Anna Flavia ^{[1, 2]} ; Madi, Mariana Cotarelli ^[1] ; Silva, Juliana Moreira ^[1] ; Li, Jun Z. ^[3] ; Ma, Qianyi ^[3] ; Ozel, Ayse Bilge ^[3] ; Fang, Qing ^[3] ; Narcizo, Amanda de Moraes ^[2] ; Cardoso, Lais Cavalca ^[2] ; Montenegro, Luciana Ribeiro ^{[1, 2]} ; de Assis Funari, Mariana Ferreira ^{[1, 2]} ; Nishi, Mirian Yumie ^{[1, 2]} ; Prado Arnhold, Ivo Jorge ^[1] ; de Lima Jorge, Alexander Augusto ^[4] ; de Mendonca, Berenice Bilharinho ^{[1, 2]} ; Camper, Sally Ann ^[3] ; Carvalho, Luciani R. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo FMUSP, Div Endocrinol, Dev Endocrinol Unit, Lab Hormones & Mol Genet LIM 42, Hosp Clin, Fac Med, Av Dr Eneas de Carvalho Aguiar 155, 2 Andar, BR-05403000 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med FMUSP, Lab Sequenciamento Larga Escala SELA, BR-01246903 Sao Paulo - Brazil

^[3] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 - USA

^[4] Univ Sao Paulo FMUSP, Div Endocrinol, Genet Endocrinol Unit LIM25, Hosp Clin, Fac Med, BR-01246903 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: GENES; v. 12, n. 8 AUG 2021.
• Citações Web of Science: 0

Resumo

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 (Delta Delta G = 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. (AU)

• Processo FAPESP: 15/26563-7 - Diagnóstico genético molecular em pacientes com distúrbios do desenvolvimento hipofisário e gonadal e a utilização de modelos in vitro e in vivo para avaliar o efeito funcional das variantes alélicas identificadas por sequenciamento de larga escala
• Beneficiário: Luciani Renata Silveira de Carvalho
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/03236-5 - Novas abordagens e metodologias na investigação genético-molecular dos distúrbios de crescimento e desenvolvimento puberal
• Beneficiário: Alexander Augusto de Lima Jorge
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/02162-8 - Patogênese molecular e caracterização de doenças monogênicas do desenvolvimento: um caminho para a medicina translacional
• Beneficiário: Berenice Bilharinho de Mendonça
• Modalidade de apoio: Auxílio à Pesquisa - Temático