Homozygous cdh2 variant may be associated with hypopituitarism without neurological disorders

Abstract

Context: Congenital hypopituitarism is a genetically heterogeneous cond ition. Whole exome sequencing (WES) is a promising approach for molecular di agnosis of patients with this condition. Objectives: The aim of this study is to conduct WES in a patient with cong enital hypopituitarism born to consanguineous parents, CDH2 screening in a cohort of patients with congenital hypopituitarism, and functional testing of a no vel CDH2 variant. Design: Genomic DNA from a proband and her consanguineous parents was analyzed by WES. Copy number variants were evaluated. The genetic varian ts were filtered for population frequency (ExAC, 1000 genomes, gnomAD, and ABraOM), in silico prediction of pathogenicity, and gene expression in the pituitary and/or h ypothalamus. 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 fibrob last lines, labeled the cells with lipophilic dyes, and quantified aggregation. Large ag gregates formed in cells expressing wildtype CDH2, but aggregation was impaired in cells transfected with varian t 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 po pulations.