Journal Article

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

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

2021

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: abnormal development / Age / Alleles / anterior pituitary / Aplasia / Bioinformatics / Child / Child, Preschool / Combined pituitary hormone deficiency / Congenital diseases / Diabetes insipidus / Female / Genes / Genetic counseling / Genomes / Genotype / Genotype & phenotype / Growth hormones / Heredity / heterozygosity / Holoprosencephaly / Homeobox / homeodomain proteins / Homeodomain Proteins - genetics / homozygosity / Human Growth Hormone - genetics / Humans / Hypopituitarism / Hypopituitarism - diagnostic imaging / Hypopituitarism - genetics / Infant / Laboratories / Magnetic Resonance Imaging / Male / males / Mutation / Patients / Pedigree / penetrance / Phenotype / Phenotypes / Pituitary (anterior) / Pituitary (posterior) / Pituitary hormones / Population / Puberty / Repressor Proteins - genetics / somatotropin / Sox3 protein / SOXB1 Transcription Factors - genetics