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

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. Key words: Disorders of sex development; CHD7 variants; Genital abnormalities