Abstract:

Objective To summarize the clinical features and genetic characteristics of children with CHARGE syndrome caused by CHD7 gene variants, thereby enriching the mutation spectrum of the CHD7 gene. Methods We retrospectively analyzed clinical and genetic data from 13 patients diagnosed with CHARGE syndrome due to confirmed CHD7 gene variants between January 2018 and December 2024 at our hospital, using whole-exome sequencing and Sanger sequencing for validation, and performed pathogenicity analysis. Results Among the 13 patients, 9 were male and 4 female, with an age at initial diagnosis ranging from 1 day to 12 years. Nine presented in the neonatal period due to respiratory distress and swallowing/feeding difficulties, while four were referred for developmental delay and genital abnormalities. The most common clinical phenotypes included growth and developmental delay (13/13), swallowing/feeding difficulties (12/13), ear malformations (11/13), cardiac defects (10/13), cranial nerve dysfunction (10/13), and genital anomalies (9/13). All 13 patients carried CHD7 gene variants, including six frameshift mutations, four nonsense mutations, and three missense mutations. Three novel variants c.2630_2631dup (p.Asn878Leufs*11), c.2233_2235delinsAATA (p.Val745Asnfs*17), and c.2824A>G (p.Thr942Ala) (NM_017780) had not been previously reported. Family-based testing revealed that 12 variants were de novo, while one (c.2824A>G) was inherited from a clinically unaffected mother. ACMG classification indicated that c.2630_2631dup and c.2233_2235delinsAATA were pathogenic (PVS1+PS2+PM2_Supporting), c.2824A>G was classified as a variant of uncertain significance (PM2_Supporting+PP4), and the rest were previously reported pathogenic or likely pathogenic variants. Conclusions CHARGE syndrome presents with a broad range of clinical phenotypes, often manifesting initially in newborns with respiratory and feeding difficulties. This study identified three novel CHD7 gene variants, expanding the known mutation spectrum. Children presenting with multiple malformations and growth/developmental delays should be evaluated for this condition, and genetic testing should be initiated early.

Key words: CHARGE syndrome, whole-exome sequencing, CHD7 gene, child