Indian Wellderly exomes underscore NRAP roles in elderly hypertrophic cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is a genetic disorder that affects people of all ages, with the elderly population being inadequately studied. It is primarily caused by gene variants that encode proteins involved in the structure and function of the heart muscle. The identification of genes associated with elderly HCM requires ethnic-specific genomic sequences from Wellderly individuals. Currently, no Indian Wellderly dataset is available. To address this, we collected and sequenced the Indian Wellderly population. We built a novel Indian database of healthy aging nucleotide sequences (named i-DHANS) and is newly accessible at IndiCardiome. Utilizing this database and Indian HCM cohort, we identified nebulin-related anchoring protein (NRAP) as a gene associated with elderly HCM. NRAP is crucial for the assembly of myofibrils and transmission of force from the sarcomere to the extracellular matrix. Our functional analysis showed that the identified NRAP variant had significantly reduced interactions with its interacting partners, such as Kelch-like protein 41 (KLHL41) and -actinin, implying a loss of function. In summary, our findings indicate that NRAP is a new elderly cardiomyopathy gene, and our Indian Wellderly database is a valuable resource for identifying ethnic-specific genes for various diseases.