Expanding the phenotype associated with SMARCC2 variants: a fetus with tetralogy of Fallot.

Background: Coffin-Siris syndrome-8 (CSS8) is a rare autosomal dominant disorder caused by variants in SMARCC2, a core subunit of the chromatin-remodeling complex BRG1-associated factor (BAF). The clinical characteristics of this disorder have not been entirely determined because of the rarity of clinical reports. The BAF complex plays a crucial role in embryogenesis and cardiac development, and pathogenic variants in genes encoding the components of the BAF complex have been associated with congenital heart disease (CHD). However, variants in SMARCC2 have not been reported in patients with CHD.

Case Presentation: A 28-year-old primigravida was referred at 24 weeks gestation for prenatal echocardiography. The echocardiographic findings were consistent with a prenatal ultrasound diagnosis of tetralogy of Fallot (TOF). After detailed counseling, the couple decided to terminate the pregnancy and undergo genetic testing. A trio (fetus and the parents) whole-exome sequencing (WES) and copy number variation sequencing (CNV-seq) were performed. CNV-seq identified no chromosomal abnormalities. WES analysis revealed a pathogenic, de novo heterozygous frameshift variant in SMARCC2 (NM_003075.5: c.3561del, p.Leu1188fs). The genetic diagnosis of CSS8 was considered given the identification of the SMARCC2 pathogenic variant.

Conclusions: We report the first prenatal case with the SMARCC2 variant. The presence of CHD further broadens the phenotypic spectrum of SMARCC2-related disease.