ArticleProceedings of the National Academy of Sciences of the United States of America2014
Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 77 citations in OpenAlex.
- Genetics of Idiopathic Hypogonadotropic HypogonadismJournal of clinical research in pediatric endocrinology · 2026Review
- Synthesizing the latest guideline-based recommendations for the management of female hypogonadism.Archives of endocrinology and metabolism · 2025Review
- De novo CHD7 variant in a CHARGE syndrome preterm infant initially diagnosed as idiopathic hypogonadotropic hypogonadism: a case report and literature review.BMC pediatrics · 2025Review
- [Expert consensus on auditory intervention and language rehabilitation of CHARGE syndrome].Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery · 2025Article
- Application and insights of targeted next-generation sequencing in a large cohort of 46,XY disorders of sex development in Chinese.Biology of sex differences · 2024Article
- Review
- Article
- Illuminating the terminal nerve: Uncovering the link between GnRH-1 neuron and olfactory development.The Journal of comparative neurology · 2024Article
- Variety of genetic defects in GnRH and hypothalamic-pituitary signaling and development in normosmic patients with IHH.Frontiers in endocrinology · 2024Article
- Transcriptional and spatiotemporal regulation of the dauer program.Transcription · 2023Review
- A clinical case of identical twins with hypogonadotropic hypogonadism, primary empty sella syndrome and identified rareClinical case reports · 2023Article
- Combined pituitary hormone deficiency harboring CHD7 gene missense mutation without CHARGE syndrome: a case report.BMC endocrine disorders · 2023Article
- Expanding the reproductive organ phenotype of CHD7-spectrum disorder.American journal of medical genetics. Part A · 2023Article
- Genetic Analysis of Patients with Congenital Hypogonadotropic Hypogonadism: A Case Series.International journal of molecular sciences · 2023Article
- Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms.JCI insight · 2023Article
- Prevalence and Phenotypic Effects of Copy Number Variants in Isolated Hypogonadotropic Hypogonadism.The Journal of clinical endocrinology and metabolism · 2022Article
- The CHARGE syndrome ortholog CHD-7 regulates TGF-β pathways inProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Phenotypic spectrum of patients with mutations in CHD7: clinical implications of endocrinological findings.Endocrine connections · 2022Article
- HERVH-derived lncRNAs negatively regulate chromatin targeting and remodeling mediated by CHD7.Life science alliance · 2022Article
- Craniofacial and cardiac defects inFrontiers in cell and developmental biology · 2022Article
Corrections and comments
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Authors and funding
19 authors at 8 institutions in 5 countries.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.