Early results of sarcomeric gene screening from the Egyptian National BA-HCM Program

Abstract

The present study comprised sarcomeric genotyping of the three most commonly involved sarcomeric genes: MYBPC3, MYH7, and TNNT2 in 192 unrelated Egyptian hypertrophic cardiomyopathy (HCM) index patients. Mutations were detected in 40 % of cases. Presence of positive family history was significantly (p=0.002) associated with a higher genetic positive yield (49/78, 62.8 %). The majority of the detected mutations in the three sarcomeric genes were novel (40/62, 65 %) and mostly private (47/62, 77 %). Single nucleotide substitution was the most frequently detected mutation type (51/62, 82 %). Over three quarters of these substitutions (21/27, 78 %) involved CpG dinucleotide sites and resulted from C>T or G>A transition in the three analyzed genes, highlighting the significance of CpG high mutability within the sarcomeric genes examined. This study could aid in global comparative studies in different ethnic populations and constitutes an important step in the evolution of the integrated clinical, translational, and basic science HCM program.

Fig. 1

Multidisciplinary approach involving genetics and cardiology in management of HCM patients and their families in BA HCM program

Fig. 2

Strategy of genetic analysis in BA HCM study through initial screening with DHPLC (WAVE™ Transgenomics) followed by bidirectional automated sequencing of variant profile

Fig. 3

Bidirectional automated sequencing of MYBPC3 exon7 and MYH7 exon35 and flanking intronic sequences in index patient PU1 and screening of an affected brother (PU1′a) showing cosegregation of MYBPC3 intron 7 substitution mutation: c.821 + 3G > T with potential splice effect as predicted by in silico tools and not MYH7 missense variant (Arg1662His) indicating likely pathogenicity of the MYBPC3 intronic variant

Fig. 4

Univariate analysis of clinical parameters as predictors of positive sarcomeric genetic yield in Egyptian HCM patients using chi-square test (MedCalc-version 12.2.1) *Statistically significant association at p value <0.05