Two novel CHD7 variants in patients with typical and mild features of CHARGE syndrome co-occurring with esophageal atresia

Abstract

CHARGE syndrome ( C oloboma, H eart defect, A tresia of the choanae, growth R etardation, G enital abnormalities, E ar anomalies/deafness) is a rare genetic autosomal dominant disease with a prevalence of 1/10,000 live births. It is associated with pathogenic variants in the chromodomain-helicase-DNA-binding protein 7 ( CHD7 ) gene. Although CHARGE syndrome is known to be associated with esophageal atresia (EA) and tracheoesophageal fistulas in 15–20% of cases, there are only a few clinical and molecular case descriptions of CHARGE syndrome in the context of EA. We present two individuals with novel CHD7 variants with variable clinical expression of CHARGE syndrome co-occurring with EA. Individual 1 had typical CHARGE syndrome, and a rare type D EA that required direct anastomosis repair. Genetic testing revealed a likely pathogenic essential splice site variant, c.4644+1G > T. Individual 2 had a mild CHARGE phenotype and a type A EA that required complex repair via the Foker process. The described expression of previously unreported typical CHD7 variants expands the current knowledge of CHARGE syndrome co-occurring with EA that could help with future patient care and genetic counseling. We hope that the description of the previously unreported variant of uncertain significance with a mild CHARGE phenotype will assist future classification efforts of this variant. • Novel report of two variants in CHD7 gene with wide clinical symptom variability. • Two clinical cases of CHARGE syndrome co-occurring with esophageal atresia. • Call to attention for genetic studies in infants born with esophageal atresia. • Call for innovations to public database of locus specific CHD7 variants.