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Dilated cardiomyopathy (DCM) is characterized by ventricular dilation and systolic dysfunction, affecting approximately 1 in 250 individuals. Genetic factors contribute to 20–35% of pediatric DCM cases, with over 30 genes implicated in its pathogenesis. The ankyrin repeat domain 1 gene, ANKRD1, encodes cardiac ankyrin repeat protein (CARP), a key component of the titin-N2A mechanosensory complex. CARP functions as a transcriptional co-repressor and stress-responsive myofibrillar protein in cardiomyocytes. Emerging studies have identified ANKRD1 variants in both familial and sporadic DCM, suggesting a direct role in disease etiology.
In a cohort of 231 independent DCM cases, targeted sequencing of ANKRD1 revealed five heterozygous missense variants absent in 400 controls, including two pedigrees with co-segregation under an autosomal dominant model (PMID:19525294). A separate analysis of 208 DCM probands uncovered three additional heterozygous missense variants in four unrelated patients (PMID:19608030). A clinical case report described an infant with DCM harboring an ANKRD1 variant (PMID:34852870). In total, at least 10 unrelated probands carry rare, conserved ANKRD1 missense changes, with familial clustering in two pedigrees and no reported loss-of-function alleles.
Reported pathogenic ANKRD1 alleles are exclusively missense and cluster within CARP functional domains. Variants include c.196C>G (p.Arg66Gly), c.197G>A (p.Arg66Gln), c.313C>T (p.Pro105Ser), c.319G>T (p.Val107Leu), c.347C>T (p.Thr116Met), c.523G>A (p.Ala175Thr), c.552G>T (p.Met184Ile), and c.827C>T (p.Ala276Val). These substitutions affect residues critical for CARP interaction with titin and myopalladin. The cumulative prevalence of ANKRD1 variants in DCM cohorts is approximately 2%. None of these variants recur as founder alleles, and they are absent or extremely rare in population databases, underscoring their likely pathogenicity.
Functional assays demonstrate concordant effects of ANKRD1 variants on CARP activity. Neonatal rat cardiomyocytes expressing Thr116Met, Arg66Gln, Arg66Gly, Ala276Val, and Ala175Thr variants exhibited decreased transcriptional repression and enhanced phenylephrine-induced hypertrophy (PMID:19525294). Yeast two-hybrid and stretch-induced gene expression studies showed that Pro105Ser and Val107Leu mutations disrupt CARP binding to Talin 1 and FHL2, leading to altered mechanotransduction (PMID:19608030). Mutant CARP variants did not mislocalize but significantly dysregulated stretch-responsive transcriptional programs, indicating a dominant-negative or loss-of-function effect.
The mechanistic basis of ANKRD1-associated DCM likely involves perturbation of the titin-N2A mechanosensor and downstream gene regulation. CARP variants compromise repressor function, triggering maladaptive gene expression and sarcomere disorganization. Disruption of CARP–titin and CARP–myopalladin interactions impairs stretch-based signaling, promoting ventricular dilation. Patient-derived iPSC models further show that ANKRD1 knockout can ameliorate dilated phenotypes in vitro, reinforcing causality. These findings align with a haploinsufficiency or dominant-negative mechanism affecting cardiomyocyte stress responses.
Integration of genetic and experimental data supports an autosomal dominant association between ANKRD1 and Dilated cardiomyopathy. The identification of eight distinct missense variants in 10 probands, two segregating families, and consistent functional disruption fulfills ClinGen criteria for a moderate level of evidence. Additional large pedigrees and in vivo models will help define variant-specific penetrance. Nonetheless, ANKRD1 should be included in DCM gene panels to enhance molecular diagnosis and guide family screening. Key take-home: ANKRD1 missense variants provide clinically actionable diagnoses in up to 2% of DCM cases.
Gene–Disease AssociationModerate10 unrelated probands, two familial segregations, consistent functional data Genetic EvidenceModerateIdentification of eight missense variants in 10 probands with autosomal dominant inheritance across three cohorts Functional EvidenceModerateCell-based reporter and interaction assays show loss of CARP repressor activity and disrupted protein binding |