{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:16:40Z","timestamp":1784557000812,"version":"3.55.0"},"reference-count":57,"publisher":"Bioscientifica","issue":"8","license":[{"start":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T00:00:00Z","timestamp":1683763200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ec.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,7,5]]},"abstract":"<jats:sec>\n                    <jats:title>Context<\/jats:title>\n                    <jats:p>Congenital hypopituitarism is a genetically heterogeneous condition. Whole exome sequencing (WES) is a promising approach for molecular diagnosis of patients with this condition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>\n                      The aim of this study is to conduct WES in a patient with congenital hypopituitarism born to consanguineous parents,\n                      <jats:italic>CDH2<\/jats:italic>\n                      screening in a cohort of patients with congenital hypopituitarism, and functional testing of a novel\n                      <jats:italic>CDH2<\/jats:italic>\n                      variant.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design<\/jats:title>\n                    <jats:p>\n                      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),\n                      <jats:italic>in silico<\/jats:italic>\n                      prediction of pathogenicity, and gene expression in the pituitary and\/or hypothalamus. Genomic DNA from 145 patients was screened for\n                      <jats:italic>CDH2<\/jats:italic>\n                      by Sanger sequencing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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&gt;A (p.Val289Ile) variant in\n                      <jats:italic>CDH2.<\/jats:italic>\n                      To determine whether the p.Val289Ile variant in\n                      <jats:italic>CDH2<\/jats:italic>\n                      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\n                      <jats:italic>CDH2<\/jats:italic>\n                      , but aggregation was impaired in cells transfected with variant\n                      <jats:italic>CDH2<\/jats:italic>\n                      or non-transfected.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      A homozygous\n                      <jats:italic>CDH2<\/jats:italic>\n                      allelic variant was found in one hypopituitarism patient, and the variant impaired cell aggregation function\n                      <jats:italic>in vitro<\/jats:italic>\n                      . No disease-causing variants were found in 145 other patients screened for\n                      <jats:italic>CDH2<\/jats:italic>\n                      variants. Thus,\n                      <jats:italic>CDH2<\/jats:italic>\n                      is a candidate gene for hypopituitarism that needs to be tested in different populations.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance statement<\/jats:title>\n                    <jats:p>\n                      A female patient with hypopituitarism was born from consanguineous parents and had a homozygous, likely pathogenic,\n                      <jats:italic>CDH2<\/jats:italic>\n                      variant that impairs cell aggregation\n                      <jats:italic>in vitro<\/jats:italic>\n                      . No other likely pathogenic variants in\n                      <jats:italic>CDH2<\/jats:italic>\n                      were identified in 145 hypopituitarism patients.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1530\/ec-22-0473","type":"journal-article","created":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T10:10:02Z","timestamp":1683799802000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-10","source":"Crossref","is-referenced-by-count":4,"title":["Homozygous CDH2 variant may be associated with hypopituitarism without neurological disorders"],"prefix":"10.1530","volume":"12","author":[{"given":"Nathalia G B P","family":"Ferreira","sequence":"first","affiliation":[{"name":"Unidade de Endocrinologia do Desenvolvimento, Laborat\u00f3rio de Horm\u00f4nios e Gen\u00e9tica Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de S\u00e3o Paulo (FMUSP), S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joao L O","family":"Madeira","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia do Desenvolvimento, Laborat\u00f3rio de Horm\u00f4nios e Gen\u00e9tica Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de S\u00e3o Paulo (FMUSP), S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Gergics","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina FMUSP, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata","family":"Kertsz","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia do Desenvolvimento, Laborat\u00f3rio de Horm\u00f4nios e Gen\u00e9tica Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de S\u00e3o Paulo (FMUSP), S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana M","family":"Marques","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia do Desenvolvimento, Laborat\u00f3rio de Horm\u00f4nios e Gen\u00e9tica Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de S\u00e3o Paulo (FMUSP), S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas S S","family":"Trigueiro","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia do Desenvolvimento, Laborat\u00f3rio de Horm\u00f4nios e Gen\u00e9tica Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de S\u00e3o Paulo (FMUSP), S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Flavia Figueredo","family":"Benedetti","sequence":"additional","affiliation":[{"name":"University of Michigan Medical School, Department of Human Genetics, Ann Arbor, Michigan, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruna V","family":"Azevedo","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia do Desenvolvimento, Laborat\u00f3rio de Horm\u00f4nios e Gen\u00e9tica Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de S\u00e3o Paulo (FMUSP), S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca H V","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Unidade de Endocrinologia do Desenvolvimento, Laborat\u00f3rio de Horm\u00f4nios e Gen\u00e9tica Molecular LIM42, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de S\u00e3o Paulo (FMUSP), S\u00e3o Paulo, Brazil"},{"name":"Universidade de S\u00e3o Paulo, Zebrafish Facility, S\u00e3o Paulo, S\u00e3o Paulo, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora 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