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

Sun, Bang; Wang, Xi; Mao, Jiangfeng; Zhao, Zhiyuan; Nie, Min; Wu, Xueyan

doi:10.3389/fgene.2021.770680

Cited by 4 publications

(8 citation statements)

References 32 publications

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“…KS patients are more likely to have abnormal olfactory function, but it is also common for patients with abnormal olfactory bulb to have normal olfactory function. In this study cohort, most male patients had reproductive system abnormalities with a high incidence, such as micropenis (92.3%), cryptorchidism (41.7%), penis retraction (7.7%), and scrotal division (7.7%), which were consistent with literature reports [ 16 – 19 ]. These findings suggest the possibility and necessity of early diagnosis of IHH.…”

Section: Resultssupporting

confidence: 90%

“…In addition, KS5 and nIHH8 also have pronunciation defects, which may also be related to CHD7 gene, and more sample studies are needed. However, the variants assessed as P or LP (4/5, 80%) were more common to have extragonadal manifestations than the single-gene variants assessed as US (0/2, 0%), which was consistent with the report by Sun et al [16]. nIHH1 detected 3 gene variants, and on the condition that the pathogenicity of each variant (including the CHD7 variant classified as US) was not clear, the link between gene and phenotype does not allow the possibility of a linear correlation.…”

Section: Molecular Genetic Analysissupporting

confidence: 90%

“…CHD7 c.409T>G(p.S137A) in the ClinVar database was also reported to be benign or likely benign, with no specific disease description. Other studies reported c.2182G>A(p.D728N) of CHD7 in IHH or CHARGE syndrome [ 16 – 18 ], c.1369A>G(p.T457A) of SEMA3A [ 19 ], and c.749G>A(p.R250H) of CHD7 in abnormal sexual development [ 20 ]. At the same time, no focal duplication of ANOS1 gene has been reported, and only multiple abnormal patients with multiple gene duplication have been reported [ 21 ].…”

Section: Resultsmentioning

confidence: 99%

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The Clinical and Genetic Characteristics in Children with Idiopathic Hypogonadotropin Hypogonadism

Zhang

Yang

Zou

2022

Journal of Oncology

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Background. Idiopathic hypogonadotropin hypogonadism (IHH) is caused by hypothalamic-pituitary-gonadal axis dysfunction. This is divided into Kallmann syndrome which has an impaired sense of smell and hypogonadotropin hypogonadism with normal olfactory (nIHH sense. Approximately 60% of patients are associated with Kallmann syndrome, whereas there are approximately 40% with hypogonadotropin hypogonadism (nIHH). This disease is associated with various variants in genes along with different phenotypic characteristics, and even those gene variations could also lead to the cancer formation in patients. So, current study has been designed to investigate and to better understand the characteristics of various IHH-associated genes and the correlation between IHH genes and phenotype. Methods. The cohort included 14 children with IHH (6 patients of KS and 8 patients of IHH), including 13 boys and 1 girl. Exclusion criteria are as follows: diagnosis of secondary hypogonadotropin hypogonadism due to tumor, trauma, drugs, or other systemic diseases. Clinical data and genetic results were analyzed. Results. Almost all male patients showed micropenis (12/13, 92.3%), and few of them had cryptorchidism (5/13, 41.7%). A total of 6 genes, CHD7, PROKR2, ANOS1, FGFR1, SEMA3A, and NDNF, were detected. CHD7 was the most common (11/17, 64.7%), and the main mutation type was missense mutation (14/16, 87.5%). Six reported variants and 10 new variants (5 genes, including entire ANSO1 duplicates) were found. Neonatal variation was detected in 3 patients with IHH. Eight patients inherited the variation from their father, while five patients inherited it from their mother. One patient had both FGFR1 and SEMA3A gene variants, while the other had two different CHD7 gene variants and entire ANSO1 repeats. According to ACMG criteria, 4 variants were pathogenic (P), 2 were possibly pathogenic (LP), and 8 had uncertain significance (US). In patients with P or LP (5/6, 83.3%), we found that extragonadal symptoms were more common. Conclusions. It was concluded that variations in the studied genes could lead to the IHH. Ten new variants have been reported which may lead to different symptoms of IHH. For CHD7 variants, the rare sequencing variants (RSVs) of P or LP showed commonly associated with CHARGE syndrome. Findings of the current study may help for the better diagnosis and treatment of IHH.

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Section: Resultssupporting

confidence: 90%

Section: Molecular Genetic Analysissupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

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The Clinical and Genetic Characteristics in Children with Idiopathic Hypogonadotropin Hypogonadism

Zhang

Yang

Zou

2022

Journal of Oncology

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“…This missense change has been observed in two individuals with Kallman syndrome. 12 , 13 We present the cited cases in a table together with the data of our patients (Table 2 ).…”

Section: Discussionmentioning

confidence: 99%

A clinical case of identical twins with hypogonadotropic hypogonadism, primary empty sella syndrome and identified rare CHD7 gene variant

Petrov

Babadzhanova

Orbetzova

et al. 2023

Clinical Case Reports

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Empty sella syndrome is a complex syndrome with a diverse clinical presentation. The combination with functional hypogonadotropic hypogonadism is a real challenge for the clinician. Mutations in the CHD7 gene could be a possible, yet unproven, cause of "empty sella" syndrome. Patients with hypogonadotropic hypogonadism should be examined for possible CHD7 mutations, even if they do not have any CHARGE syndrome characteristics.

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“…In addition, CHD7 mutations in CHARGE syndrome are typically truncating and can lead to serious genetic dysfunction, whereas mutations in isolated HH with or without minor CHARGE features are predominantly of the missense type that has less impact on gene function compared with truncating mutation [ 15 , 16 ]. Furthermore, following the classification of missense mutations in patients with isolated HH based on ACMG guidelines, minor CHARGE features have been reported to be more commonly present in patients with pathogenic or likely pathogenic mutations than in those with uncertain significance mutations [ 20 ]. These pieces of evidence suggest that isolated HH harboring CHD7 mutations is a mild form of CHARGE syndrome.…”

Section: Discussionmentioning

confidence: 99%

Combined pituitary hormone deficiency harboring CHD7 gene missense mutation without CHARGE syndrome: a case report

et al. 2023

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Background Heterozygous loss-of-function mutations in the chromodomain helicase DNA-binding protein 7 (CHD7) gene cause CHARGE syndrome characterized by various congenital anomalies. A majority of patients with CHARGE syndrome present with congenital hypogonadotropic hypogonadism (HH), and combined pituitary hormone deficiency (CPHD) can also be present. Whereas CHD7 mutations have been identified in some patients with isolated HH without a diagnosis of CHARGE syndrome, it remains unclear whether CHD7 mutations can be identified in patients with CPHD who do not fulfill the criteria for CHARGE syndrome. Case presentation A 33-year-old woman was admitted to our hospital. She had primary amenorrhea and was at Tanner stage 2 for both pubic hair and breast development. She was diagnosed with CPHD (HH, growth hormone deficiency, and central hypothyroidism), and a heterozygous rare missense mutation (c.6745G > A, p.Asp2249Asn) in the CHD7 gene was identified. Our conservation analysis and numerous in silico analyses suggested that this mutation had pathogenic potential. She had mild intellectual disability, a minor feature of CHARGE syndrome, but did not fulfill the criteria for CHARGE syndrome. Conclusions We report a rare case of CPHD harboring CHD7 mutation without CHARGE syndrome. This case provides valuable insights into phenotypes caused by CHD7 mutations. CHD7 mutations can have a continuous phenotypic spectrum depending on the severity of hypopituitarism and CHARGE features. Therefore, we would like to propose a novel concept of CHD7-associated syndrome.

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

Cited by 4 publications

References 32 publications

The Clinical and Genetic Characteristics in Children with Idiopathic Hypogonadotropin Hypogonadism

The Clinical and Genetic Characteristics in Children with Idiopathic Hypogonadotropin Hypogonadism

A clinical case of identical twins with hypogonadotropic hypogonadism, primary empty sella syndrome and identified rare CHD7 gene variant

Combined pituitary hormone deficiency harboring CHD7 gene missense mutation without CHARGE syndrome: a case report

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