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Variant analysis of the chromodomain helicase DNA-binding protein 7 in pediatric disorders of sex development.

ABSTRACT: Importance:This study investigated the role of the chromodomain helicase DNA-binding protein 7 (CHD7) in disorders of sex development (DSD). Objective:We aimed to present the potential pathogenicity of CHD7 variants in pediatric patients with DSD. Methods:Choosing cases with CHD7 variants from DSD patients in Beijing Children's Hospital to assess for the study. Prediction software tools were used to predict variant pathogenicity in these subjects. Results:Among the 113 DSD patients, 22 cases had CHD7 variants. Twenty-four different CHD7 variants were identified in the 22 DSD patients. Prediction software combined with ClinVar database information and their clinical manifestations revealed that, of the 18 patients with 46, XY DSD, two had CHARGE syndrome and two had Kallmann syndrome. Seven of the variants were highly categorized as "likely to be pathogenic" and seven as "suspected to be pathogenic". Of the four patients with 46, XX DSD, three had ovotesticular DSD (c.305A>G, c.2788G>A, and c.3098G>A) and one had testicular DSD (c.2831G>A). Interpretation:A high frequency of CHD7 variants was found in the DSD patients, especially those with 46, XY DSD. Thus, the detection of a pathogenic CHD7 variant could suggest a diagnosis of hypogonadotropic hypogonadism for 46, XY DSD patients, but pre-pubescent patients should be reassessed in adolescence to confirm this diagnosis. This study also suggests that DNA sequencing could help to identify pre-pubescent DSD patients. Further data are required to determine the connection between CHD7 variants and sex-reversal in patients with 46, XX DSD, and the accumulation of these data is essential and necessary for DSD research.

SUBMITTER: Zhang B

PROVIDER: S-EPMC7331373 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Variant analysis of the chromodomain helicase DNA-binding protein 7 in pediatric disorders of sex development.

Zhang Beibei B Song Yanning Y Li Wei W Gong Chunxiu C

Pediatric investigation 20190322 1

<h4>Importance</h4>This study investigated the role of the chromodomain helicase DNA-binding protein 7 (<i>CHD7</i>) in disorders of sex development (DSD).<h4>Objective</h4>We aimed to present the potential pathogenicity of <i>CHD7</i> variants in pediatric patients with DSD.<h4>Methods</h4>Choosing cases with <i>CHD7</i> variants from DSD patients in Beijing Children's Hospital to assess for the study. Prediction software tools were used to predict variant pathogenicity in these subjects.<h4>Re ...[more]

PMID: 32851286

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Project description:Chromodomain-helicase-DNA-binding protein 4 (CHD4) is an epigenetic regulator identified as an oncogenic element that may provide a novel therapeutic target for the treatment of breast cancer (BC). CHD4-the core component of the nucleosome remodeling and deacetylase (NuRD) complex-may be mutated in patients with this disease. However, information on CHD4 mutants that might allow their use as biomarkers of therapeutic success and prognosis is lacking. The present work examines mutations in CHD4 reported in patients with breast cancer and included in public databases and attempts to identify their roles in its development. The databases revealed 81 point mutations across different types of breast cancer (19 of which also appeared in endometrial, intestinal, nervous system, kidney, and lymphoid organ cancers). 71.6% of the detected mutations were missense mutations, 13.6% were silent, and 6.2% nonsense. Over 50% affected conserved residues of the ATPase motor (ATPase and helicase domains), and domains of unknown function in the C-terminal region. Thirty one mutations were classified in the databases as either 'deleterious', 'probably/possibly damaging' or as 'high/medium pathogenic'; another five nonsense and one splice-site variant were predicted to produce potentially harmful truncated proteins. Eight of the 81 mutations were categorized as putative driver mutations and have been found in other cancer types. Some mutations seem to influence ATPase and DNA translocation activities (R1162W), while others may alter protein stability (R877Q/H, R975H) or disrupt DNA binding and protein activity (R572*, X34_splice) suggesting CHD4 function may be affected. In vivo tumorigenecity studies in endometrial cancer have revealed R975H and R1162W as mutations that lead to CHD4 loss-of-function. Our study provides insight into the molecular mechanism whereby CHD4, and some of its mutants could play a role in breast cancer and suggest important implications for the biological comprehension and prognosis of breast cancer, identifying CHD4 as a novel therapeutic target for BC patients.

Dataset Information

Variant analysis of the chromodomain helicase DNA-binding protein 7 in pediatric disorders of sex development.

Publications

Variant analysis of the chromodomain helicase DNA-binding protein 7 in pediatric disorders of sex development.

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