Coffin-Siris syndrome and cancer susceptibility

Abstract

Coffin-Siris syndrome (CSS) is a rare neurodevelopmental disorder that is associated with multiple congenital anomalies and caused by de novo monoallelic germline pathogenic variants in BAF-complex genes. Despite their function as tumor suppressors, the cancer risk in patients with CSS remains unclear. We analyzed cancer sequencing data sets, conducted a comprehensive literature review of patients with CSS diagnosed with malignancies, and examined a cohort of 376 CSS registry patients to estimate cancer frequency. A review of the literature identified several reports of patients with CSS diagnosed with a malignancy, with ARID1A being the most frequent causative gene and associated with hepatoblastoma in 3 cases. Although no cases of malignancy were reported among the patients in the CSS registry, only 26 patients with ARID1A-CSS were available for analysis. Combining these patients with all cases reported in the literature led to the estimate of hepatoblastoma prevalence in ARID1A-CSS of 3.6% (95% CI 0.79%-10.4%). Our findings suggest the hepatoblastoma risk among patients with ARID1A-CSS may exceed the established 1% risk threshold and therefore warrant surveillance. There remains insufficient evidence to support any other CSS gene-cancer association, emphasizing the need for further systematic study.

Keywords: ARID1A; ARID1B; BAF-complex; Cancer susceptibility; Coffin-Siris syndrome.

Figure 1

Forest plot representing the prevalence of hepatoblastoma in patients with ARID1A-CSS and ARID1B-CSS among all reported cases who survived the perinatal period, inclusive of those in our CSS registry. The solid circle with a horizontal bar represents the point prevalence and 95% CI, calculated using the modified Wald method. Surveillance screening thresholds of 1% and 5% are depicted for reference.