Title : Genetic landscape of restrictive cardiomyopathy: A study of 40 cases from North India
Abstract:
Background and Aim
Restrictive cardiomyopathy is one of the rarest types of cardiomyopathy with a prevalence of 1: 1500-2000 in USA. Clincioradiologicaly, it is characterized by normal ventricles, dilated atrial chambers with diastolic dysfunction. Many secondary etiological factors can cause RCM however idiopathic RCM is mostly genetic in etiology. Identification of specific mutation is important to known the diagnosis, clinical severity, familial penetrance and prognosis. Present study highlights the complete genetic profile of RCM patients.
Methods
40 RCM patients along with their first-degree family members were enrolled in the study after written informed consent. Detailed clinical evaluation, ECG and Echocardiography screening and/or cardiac MRI was performed in the proband to identify the RCM phenotype. Endomyocardial biopsy was performed to see any identifiable cause. For molecular study 5 ml peripheral blood in EDTA vial is collected. DNA isolation, purification and quantification was performed. Whole exome sequencing was performed in Illumina Novaseq 6000 platform. Identified mutation was further confirmed by sanger sequencing. Mutation-specific primer design and Sanger sequencing were used to confirm variants and perform family screening. In silico analysis was used to make the predictions.
Results and Conclusion
The mean age of onset was 27.8 yrs. (Range 4 to 70 years). 58.1 % of patients were male. Most of the patients belong to NYHA class III. 13.9 % were familial whereas 86.1 % were sporadic. The mean ejection fraction was 48.5%. Whole exome sequencing revealed 28 variants identified in TNNI3, TTN, TPL1, ANK2, COL4A3, MYH7, MYH6, ANKRD1, FLNC, CRELD1, genes. Common variants were observed in the FLNC gene followed by TNNI3 and MYH7 genes whereas in Western literature TNNI3 and TNNT2 genes were most commonly involved. Out of these 28 different variants 7 were predicted to be pathogenic/likely pathogenic by FATHMM, Mutation Taster, SIFT and Polyphen and the rest were predicted to be variants of unknown significance (VOUS). 3 cases underwent heart transplantation and 12 cases died because of the disease severity during follow-up. Each identified variant was tested in the first degree family members along with Echocardiographic screening. Early stage disease was identified in 5 individuals who are kept under close observation follow up and health education.
Further detailed molecular research is necessary to determine the pathogenicity of VUS variants.
