Pathogenic copy number variants in patients with congenital hypopituitarism associated with complex phenotypes

Autor(es):Mostrar menos -

Correa, Fernanda A. ^[1] ; Jorge, Alexander A. L. ^[2] ; Nakaguma, Marilena ^[1] ; Canton, Ana P. M. ^[1] ; Costa, Silvia S. ^[3] ; Funari, Mariana F. ^[1] ; Lerario, Antonio M. ^[1] ; Franca, Marcela M. ^[1] ; Carvalho, Luciani R. ^[1] ; Krepischi, Ana C. V. ^[3] ; Arnhold, Ivo J. P. ^[1] ; Rosenberg, Carla ^[3] ; Mendonca, Berenice B. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Unidade Endocrinol Desenvolvimento, Lab Hormonios & Genet Mol LIM42, Hosp Clin, Disciplina Endocrinol, Fac Med, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Unidade Endocrinol Genet, Lab Endocrinol Celular & Mol LIM25, Disciplina Endocrinol, Hosp Clin, Fac Med, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Dept Genet & Biol Evolut, Inst Biociencias, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: CLINICAL ENDOCRINOLOGY; v. 88, n. 3, p. 425-431, MAR 2018.
• Citações Web of Science: 1

Resumo

ObjectivesThe aetiology of congenital hypopituitarism (CH) is unknown in most patients. Rare copy number variants (CNVs) have been implicated as the cause of genetic syndromes with previously unknown aetiology. Our aim was to study the presence of CNVs and their pathogenicity in patients with idiopathic CH associated with complex phenotypes. Design and PatientsWe selected 39 patients with syndromic CH for array-based comparative genomic hybridization (aCGH). Patients with pathogenic CNVs were also evaluated by whole exome sequencing. ResultsTwenty rare CNVs were detected in 19 patients. Among the identified rare CNVs, six were classified as benign, eleven as variants of uncertain clinical significance (VUS) and four as pathogenic. The three patients with pathogenic CNVs had combined pituitary hormone deficiencies, and the associated complex phenotypes were intellectual disabilities: trichorhinophalangeal type I syndrome (TRPS1) and developmental delay/intellectual disability with cardiac malformation, respectively. Patient one has a de novo 1.6-Mb deletion located at chromosome 3q13.31q13.32, which overlaps with the region of the 3q13.31 deletion syndrome. Patient two has a 10.5-Mb de novo deletion at 8q23.1q24.11, encompassing the TRPS1 gene; his phenotype is compatible with TRPS1. Patient three carries a chromosome translocation t(2p24.3;4q35.1) resulting in two terminal alterations: a 2p25.3p24.3 duplication of 14.7Mb and a 4-Mb deletion at 4q35.1q35.2. ConclusionsCopy number variants explained the phenotype in 8% of patients with hypopituitarism and additional complex phenotypes. This suggests that chromosomal alterations are an important contributor to syndromic hypopituitarism. (AU)

• 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
• 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: 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: 14/50137-5 - Caracterização molecular de doenças monogênicas do desenvolvimento por sequenciamento em larga escala
• Beneficiário: Berenice Bilharinho de Mendonça
• Modalidade de apoio: Auxílio à Pesquisa - Programa Equipamentos Multiusuários