Founder effect of a pathogenic TNNT2 variant in the northwest of Spain responsible for a non-severe phenotype of hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder, with a prevalence between 1/250-500 individuals. The yield of genetic testing for this condition stands at 40%. The most prevalent genes are MYBPC3 and MYH7, with small contributions of other genes, such as TNNT2, TNNI3, TPM1, MYL2 or FHOD3. At our center, we have identified a recurrent variant in TNNT2, p.Asn271Ile, associated with HCM. Most probands came from the northwest of Spain (Galicia), which suggested that they may share a common origin. Purpose We aimed to determine whether carriers of the p.Asn271Ile variant in TNNT2 share a common haplotype, in order to estimate the age of the mutation and describe the associated phenotype. Methods We analyzed probands who had TNNT2 sequenced by NGS at our center. Enrichment of the variant was observed in the HCM cohort. Eight highly polymorphic microsatellite markers flanking the variant in 18 Galician HCM probands were also analyzed, compromising a region of approximately 7,300 kb. Custom PCR assays were designed, and fragment length analysis was performed by capillary electrophoresis. Results TNNT2 p.Asn271Ile was identified in 49/28,802 probands (0.17%). The variant was significantly enriched in HCM probands (47/11,870; 0.39%) compared to internal non-HCM controls (2/14,804; 0.02%), with an OR=29.3 (IC95%=7.1-120.7). The analysis revealed that the 18 HCM Galician probands shared a common haplotype of 500 kb, estimating that p.Asn271Ile has arisen approximately 26.5 generations ago (650 years). Regarding genotype-phenotype correlation, our data (more than 180 carriers from 64 families) shows a relatively benign behavior, with an advance mean age at diagnosis [(49.8 (±17.7)], non-severe left ventricular hypertrophy [15.3 (±5.3)], and a lower rate of major events among carriers of p.Asn271Ile in TNNT2, compared to both other genetic variants in TNNT2 and the main genetic cause of HCM (i.e., null variants in MYBPC3) (p=0.0001 for both comparisons). The prevalence of left ventricular systolic dysfunction and left ventricular tract obstruction was also smaller than that described for other sarcomeric genes (3.54% and 12%, respectively). Conclusions A founder effect of the pathogenic variant p.Asn271Ile has been demonstrated, with the variant arising approximately 650 years ago. The clinical behavior in carriers of this cohort showed to be relatively benign compared to the behavior of other genetic variants in this gene and null variants in MYBPC3.