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 prepubescent 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.

The Clinical and Genetic Characteristics in Children with Idiopathic Hypogonadotropin Hypogonadism

“…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][17][18][19]. These findings suggest the possibility and necessity of early diagnosis of IHH.…”

“…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 ].…”