High frequency of CHD7 mutations in congenital hypogonadotropic hypogonadism

Gonçalves, Catarina I.; Patriarca, Filipa M.; Aragüés, José Maria; Carvalho, Davide; Fonseca, Fernando; Martins, Sofia; Marques, Olinda; Pereira, Bernardo Dias; Martinez-de-Oliveira, José; Lemos, Manuel C.

doi:10.1038/s41598-018-38178-y

Cited by 18 publications

(15 citation statements)

References 35 publications

(44 reference statements)

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“…Thus, the triple correlation among CHD7 , CHH, and CHARGE started to gain importance. Our CHD7 detection rate was consistent with that reported in previous four studies, which explored CHD7 variants in CHH patients, with detection rates of 16% (18/116) ( Xu et al, 2018 ), 16% (8/50) ( Gonçalves et al, 2019 ), 10.2% (18/177) ( Li et al, 2020 ), and 6% (6/101) 9 .…”

Section: Discussionsupporting

confidence: 91%

Classification of CHD7 Rare Variants in Chinese Congenital Hypogonadotropic Hypogonadism Patients and Analysis of Their Clinical Characteristics

et al. 2022

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Purpose:CHD7 rare variants can cause congenital hypogonadotropic hypogonadism (CHH) and CHARGE syndrome. We aimed to summarize the genotype and phenotype characteristics of CHH patients with CHD7 rare variants.Methods: Rare sequencing variants (RSVs) were detected by Sanger sequencing in a series of 327 CHH patients and were interpreted and grouped according to the American College of Medical Genetics and Genomics (ACMG) guideline. Detailed phenotyping and genotype-phenotype correlation were analyzed.Results: The RSV detection rate was 11.01% (36/327) in the CHH patients. We identified 30 RSVs and 19 of them were novel. Following ACMG criteria, three variants were pathogenic (P), 4 were likely pathogenic (LP), 3 were of uncertain significance with paradoxical evidence (US1), and 20 were of uncertain significance without enough evidence (US2). All patients (4/4, 100%) with P or LP variants manifested extragonadal symptoms.Conclusion: Addition of 19 novel CHD7 variants expanded the spectrum of variants, and pathogenic or likely pathogenic RSVs were more likely to cause syndromic CHH. For CHH patients carrying CHD7 RSVs, detailed genotyping and phenotyping can facilitate clinical diagnosis and therapy.

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Section: Discussionsupporting

confidence: 91%

Classification of CHD7 Rare Variants in Chinese Congenital Hypogonadotropic Hypogonadism Patients and Analysis of Their Clinical Characteristics

et al. 2022

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“…Genetic analysis of CHD7 contributes to the diagnosis of CHARGE syndrome and has expanded the phenotypic spectrum of CHD7 variants in individuals with lacking the full clinical features of CHARGE syndrome. CHD7 variants have been identified in normosmic isolated hypogonadotropic hypogonadism (nIHH), Kallmann syndrome (KS), self-limited delayed puberty, as well as CHARGE syndrome ( 3 , 4 , 5 , 6 , 7 ).…”

Section: Introductionmentioning

confidence: 99%

Phenotypic spectrum of patients with mutations in CHD7: clinical implications of endocrinological findings

Kim

Choi

Hwang

et al. 2022

Endocrine Connections

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Objective: Heterozygous CHD7 mutations cause a broad spectrum of clinical phenotypes ranging from typical CHARGE syndrome to self-limited delayed puberty. This study aimed to investigate the clinical characteristics of endocrine dysfunction in patients with CHD7 mutations. Methods: The clinical features and endocrine findings from 30 patients with CHD7 variants were retrospectively reviewed. A diagnosis of CHARGE syndrome was based on the Verloes diagnostic criteria. Results: Seventeen patients fulfilled the criteria for typical CHARGE syndrome, one patient for partial/incomplete CHARGE, and the remaining 11 patients had atypical CHARGE syndrome. One patient was diagnosed with Kallmann syndrome and unilateral deafness. The most frequently observed features were inner ear anomalies (80.0%), intellectual disability (76.7%), and external ear anomalies (73.3%). The mean height and weight SDSs at diagnosis were -2.6 ± 1.3 and -2.2 ± 1.8, respectively. Short stature was apparent in 18 patients (60%), and one patient was diagnosed with growth hormone deficiency. Seventeen males showed genital hypoplasia, including micropenis, cryptorchidism, or both. Seven patients after pubertal age had hypogonadotropic hypogonadism with hyposmia/anosmia and olfactory bulb hypoplasia. Truncating CHD7 mutations were the most common (n = 22), followed by missense variants (n = 3), splice-site variants (n = 2), and large deletion (n = 2). Conclusions: A diverse phenotypic spectrum was observed in patients with CHD7 variants, and endocrine defects such as short stature and delayed puberty occurred in most patients. Endocrine evaluation, especially for growth and pubertal impairment, should be performed during diagnosis and follow-up to improve the patient’s quality of life.

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“…CHD7 belongs to the CHD (Chromodomain Helicase DNAbinding) family of enzymes and heterozygous mutations of CHD7 account for ∼70% of CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth/development, Genital abnormalities, and Ear anomalies) syndrome cases (4)(5)(6)(7)(8)(9)(10)(11)(12). In addition, CHD7 mutations also have been identified in idiopathic hypogonadotropic hypogonadism (IHH), Kallmann syndrome (KS), autism spectrum disorders (ASD), DiGeorge syndrome, and nonsyndromic patients with congenital heart defects (13)(14)(15)(16)(17)(18).…”

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confidence: 99%

CHD7 regulates cardiovascular development through ATP-dependent and -independent activities

Yan

Thienthanasit

Chen

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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CHD7 encodes an ATP-dependent chromatin remodeling factor. Mutation of this gene causes multiple developmental disorders, including CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth/development, Genital abnormalities, and Ear anomalies) syndrome, in which conotruncal anomalies are the most prevalent form of heart defects. How CHD7 regulates conotruncal development remains unclear. In this study, we establish that deletion of Chd7 in neural crest cells (NCCs) causes severe conotruncal defects and perinatal lethality, thus providing mouse genetic evidence demonstrating that CHD7 cell-autonomously regulates cardiac NCC development, thereby clarifying a long-standing controversy in the literature. Using transcriptomic analyses, we show that CHD7 fine-tunes the expression of a gene network that is critical for cardiac NCC development. To gain further molecular insights into gene regulation by CHD7, we performed a protein–protein interaction screen by incubating recombinant CHD7 on a protein array. We find that CHD7 directly interacts with several developmental disorder-mutated proteins including WDR5, a core component of H3K4 methyltransferase complexes. This direct interaction suggested that CHD7 may recruit histone-modifying enzymes to target loci independently of its remodeling functions. We therefore generated a mouse model that harbors an ATPase-deficient allele and demonstrates that mutant CHD7 retains the ability to recruit H3K4 methyltransferase activity to its targets. Thus, our data uncover that CHD7 regulates cardiovascular development through ATP-dependent and -independent activities, shedding light on the etiology of CHD7-related congenital disorders. Importantly, our data also imply that patients carrying a premature stop codon versus missense mutations will likely display different molecular alterations; these patients might therefore require personalized therapeutic interventions.

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High frequency of CHD7 mutations in congenital hypogonadotropic hypogonadism

Cited by 18 publications

References 35 publications

Classification of CHD7 Rare Variants in Chinese Congenital Hypogonadotropic Hypogonadism Patients and Analysis of Their Clinical Characteristics

Classification of CHD7 Rare Variants in Chinese Congenital Hypogonadotropic Hypogonadism Patients and Analysis of Their Clinical Characteristics

Phenotypic spectrum of patients with mutations in CHD7: clinical implications of endocrinological findings

CHD7 regulates cardiovascular development through ATP-dependent and -independent activities

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