Homozygous CDH2 variant may be associated with hypopituitarism without neurological disorders
Author:
Ferreira Nathalia G B P1, Madeira Joao L O1, Gergics Peter2, Kertsz Renata1, Marques Juliana M1, Trigueiro Nicholas S S1, Benedetti Anna Flavia Figueredo3, Azevedo Bruna V1, Fernandes Bianca H V14, Bissegatto Debora D1, Biscotto Isabela P1, Fang Qing2, Ma Qianyi2, Ozel Asye B2, Li Jun2, Camper Sally A2, Jorge Alexander A L5ORCID, Mendonça Berenice B1, Arnhold Ivo J P1ORCID, Carvalho Luciani R1ORCID
Affiliation:
1. Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, Brazil 2. Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil 3. University of Michigan Medical School, Department of Human Genetics, Ann Arbor, Michigan, United States 4. Universidade de São Paulo, Zebrafish Facility, São Paulo, São Paulo, Brazil 5. Unidade de Endocrinologia Genética, Laboratório de Endocrinologia Celular e Molecular LIM25, Disciplina de Endocrinologia da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Abstract
Context
Congenital hypopituitarism is a genetically heterogeneous condition. Whole exome sequencing (WES) is a promising approach for molecular diagnosis of patients with this condition.
Objectives
The aim of this study is to conduct WES in a patient with congenital hypopituitarism born to consanguineous parents, CDH2 screening in a cohort of patients with congenital hypopituitarism, and functional testing of a novel CDH2 variant.
Design
Genomic DNA from a proband and her consanguineous parents was analyzed by WES. Copy number variants were evaluated. The genetic variants were filtered for population frequency (ExAC, 1000 genomes, gnomAD, and ABraOM), in silico prediction of pathogenicity, and gene expression in the pituitary and/or hypothalamus. Genomic DNA from 145 patients was screened for CDH2 by Sanger sequencing.
Results
One female patient with deficiencies in growth hormone, thyroid-stimulating hormone, adrenocorticotropic hormone, luteinizing hormone, and follicle-stimulating hormone and ectopic posterior pituitary gland contained a rare homozygous c.865G>A (p.Val289Ile) variant in CDH2. To determine whether the p.Val289Ile variant in CDH2 affects cell adhesion properties, we stably transfected L1 fibroblast lines, labeled the cells with lipophilic dyes, and quantified aggregation. Large aggregates formed in cells expressing wildtype CDH2, but aggregation was impaired in cells transfected with variant CDH2 or non-transfected.
Conclusion
A homozygous CDH2 allelic variant was found in one hypopituitarism patient, and the variant impaired cell aggregation function in vitro. No disease-causing variants were found in 145 other patients screened for CDH2 variants. Thus, CDH2 is a candidate gene for hypopituitarism that needs to be tested in different populations.
Significance statement
A female patient with hypopituitarism was born from consanguineous parents and had a homozygous, likely pathogenic, CDH2 variant that impairs cell aggregation in vitro. No other likely pathogenic variants in CDH2 were identified in 145 hypopituitarism patients.
Subject
Endocrinology,Endocrinology, Diabetes and Metabolism,Internal Medicine
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