Genotype and Cardiac Rhabdomyoma Phenotype Analyses in Tuberous Sclerosis Complex Diseases

Cardiac rhabdomyomas (CRs) are one of the typical phenotypes of tuberous sclerosis complex (TSC) diseases. Patients with CR could present various phenotypes and different severities. TSC1 and TSC2 are candidate genes for TSC. The genotype and phenotype relationship of the CR phenotype in TSC is unknown.

TSC1 and TSC2 pathogenic and likely pathogenic variants from the HGMD, ClinVar, and LOVD databases were identified (last date: 2024.12.01). After critical exclusion criteria and pathogenicity reanalyses, statistical analyses were performed for enrichment evaluation.

In this study, 1250 variants of TSC1 were finally included, and 26 variants (20.8%) were reported to cause the CR phenotype. In Exon 15, 5.1% of them were CR-related (p < 0.001), and 7.1% of them were enriched in Exon 18 (p = 0.008). After adjusting by the Benjamini-Hochberg FDR method, the FDR-adjusted p values were still significant for Exon 15 (p = 0.006) and Exon 18 (p = 0.028). Considering the size of each exon, there is no significant enrichment by Poisson model analysis. We included 2690 variants of TSC2; 117 variants (4.3%) were reported to cause the CR phenotype. In Exon 41, 12% of variants were CR-related (p = 0.003). The FDR-adjusted p value was not significant for Exon 41 (p = 0.11). Considering the size of each exon, in Poisson model analysis, there are significant enrichments detected in Exon 37 (IRR = 2.72 [1.42, 5.19], p = 0.003), Exon 38 (IRR = 3.26 [1.65, 6.44], p = 0.001), and Exon 41 (IRR = 5.79 [3.11, 10.77], p < 0.001). After adjusting by the Benjamini-Hochberg FDR method, significant differences remained in these three exons.

CR phenotypes demonstrated partial enrichment in specific exons, highlighting the importance of exon-level interpretation during genetic counseling.