title: Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency.
abstract: Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems.
authors.affiliation: Harvard Reproductive Endocrine Sciences Center & Reproductive Endocrine Unit of the Department of Medicine, and Medicine.
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Balasubramanian
authors.affiliation: Harvard Reproductive Endocrine Sciences Center & Reproductive Endocrine Unit of the Department of Medicine, and Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul 138-736, Korea;
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Center for Human Disease Modeling, Department of Cell Biology and Pediatrics, Duke University, Durham, NC 27710;
authors.forename: Ludmila
authors.initials: L
authors.lastname: Francescatto
authors.affiliation: Center for Human Disease Modeling, Department of Cell Biology and Pediatrics, Duke University, Durham, NC 27710;
authors.forename: Jason
authors.initials: J
authors.lastname: Willer
authors.affiliation: Harvard Reproductive Endocrine Sciences Center & Reproductive Endocrine Unit of the Department of Medicine, and.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Horton
authors.affiliation: Department of Otolaryngology, Massachusetts Eye & Ear Infirmary, Boston, MA 02114; Otology and Laryngology, and.
authors.forename: Eleni P
authors.initials: EP
authors.lastname: Asimacopoulos
authors.affiliation: Department of Otolaryngology, Massachusetts Eye & Ear Infirmary, Boston, MA 02114; Otology and Laryngology, and.
authors.forename: Konstantina M
authors.initials: KM
authors.lastname: Stankovic
authors.affiliation: Harvard Reproductive Endocrine Sciences Center & Reproductive Endocrine Unit of the Department of Medicine, and.
authors.forename: Lacey
authors.initials: L
authors.lastname: Plummer
authors.affiliation: Harvard Reproductive Endocrine Sciences Center & Reproductive Endocrine Unit of the Department of Medicine, and.
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Buck
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne NE1 3BZ, United Kingdom;
authors.forename: Richard
authors.initials: R
authors.lastname: Quinton
authors.affiliation: Department of Pediatrics, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN 46202;
authors.forename: Todd D
authors.initials: TD
authors.lastname: Nebesio
authors.affiliation: Institute of Maternal and Child Research, University of Chile, Casilla 226-3, Santiago, Chile; and.
authors.forename: Veronica
authors.initials: V
authors.lastname: Mericq
authors.affiliation: Institute of Maternal and Child Research, University of Chile, Casilla 226-3, Santiago, Chile; and.
authors.forename: Paulina M
authors.identifier: http://orcid.org/0000-0001-8725-6348
authors.initials: PM
authors.lastname: Merino
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Meyer
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia.
authors.forename: Dorota
authors.initials: D
authors.lastname: Monies
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114; Departments of Genetics, Harvard Medical School, Boston, MA 20115;
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh 11211, Saudi Arabia.
authors.forename: Nada
authors.initials: N
authors.lastname: Al Tassan
authors.affiliation: Center for Human Disease Modeling, Department of Cell Biology and Pediatrics, Duke University, Durham, NC 27710;
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: Harvard Reproductive Endocrine Sciences Center & Reproductive Endocrine Unit of the Department of Medicine, and Medicine, wcrowley@partners.org.
authors.forename: William F
authors.initials: WF
authors.lastname: Crowley
mesh_terms: D000818:Animals; D001483:Base Sequence; D058747:CHARGE Syndrome / Q000235:genetics / Q000473:pathology; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D003677:Deficiency Diseases / Q000235:genetics*; D055785:Gene Knockdown Techniques; D007987:Gonadotropin-Releasing Hormone / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D017436:Kallmann Syndrome / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010037:Otolithic Membrane / Q000473:pathology; D010641:Phenotype; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D015027:Zebrafish / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D007987:Gonadotropin-Releasing Hormone; D004265:DNA Helicases; C491434:CHD7 protein, human
keywords: CHARGE syndrome; CHD7; Kallmann syndrome; idiopathic hypogonadotropic hypogondism; missense mutations