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This summary integrates evidence from case reports, multi‑patient studies, and functional assessment models demonstrating that alterations in MYL4 are associated with atrial fibrillation (PMID:27066836, PMID:27742809). In a familial case report, a heterozygous missense mutation, c.31G>A (p.Glu11Lys), was identified that cosegregated with early‐onset atrial fibrillation, conduction disease, and atrial myopathy with complete penetrance, supporting a strong role for MYL4 in disease pathogenesis (PMID:27066836).
A multi‑patient study further extended these findings by reporting a rare frameshift deletion in MYL4, observed in eight homozygous individuals with early‑onset atrial fibrillation, pacemaker implantation due to sick sinus syndrome, and ischemic stroke (PMID:27742809). This study provided compelling genetic evidence that loss‑of‑function mutations in MYL4 under an autosomal recessive inheritance pattern result in a complete penetrance of the early‐onset phenotype.
Functional studies using genetically engineered rat models recapitulated the human phenotype. In these models, both knock‑in of the c.31G>A (p.Glu11Lys) mutation and complete knockout of MYL4 led to disruption of sarcomeric integrity, atrial enlargement, and electrical disturbances, which collectively support a mechanism of haploinsufficiency and structural dysfunction underlying atrial fibrillation (PMID:29080865).
The convergence of multiple independent lines of genetic evidence—including detailed segregation analyses in affected families (PMID:27066836) and robust population‐based findings of recessive founder alleles (PMID:27742809)—with consistent functional validation strongly supports the role of MYL4 in atrial fibrillation.
While some reports documented heterozygous mutations leading to a dominant presentation, the preponderance of evidence favors a recessive model in which biallelic loss‑of‑function variants yield a consistent and severe phenotype. This duality highlights potential allelic heterogeneity that may guide personalized therapeutic management in affected individuals.
In conclusion, the integration of clinical, genetic, and experimental data firmly establishes a strong gene‑disease association between MYL4 and atrial fibrillation. This evidence not only reinforces diagnostic decision‑making but also underpins the potential for targeted interventions and future research into disease mechanisms.
Key Take‑home: Pathogenic variants in MYL4, whether through missense or loss‑of‑function mechanisms, consistently disrupt atrial structure and function, making MYL4 a critical gene in the pathogenesis and clinical management of atrial fibrillation.
Gene–Disease AssociationStrongMultiple independent studies demonstrate that both heterozygous and homozygous MYL4 variants are linked to atrial fibrillation, including segregation in familial cases (PMID:27066836) and identification of eight homozygous carriers with early‑onset disease (PMID:27742809), complemented by functional assay concordance (PMID:29080865). Genetic EvidenceStrongCase reports and multi‑patient studies have identified pathogenic variants in MYL4, including the c.31G>A (p.Glu11Lys) missense change and a frameshift deletion, which demonstrate consistent genotype‐phenotype correlations and have been observed in both familial and population‐based analyses. Functional EvidenceStrongFunctional studies in genetically engineered rat models recapitulated key aspects of the human atrial fibrillation phenotype, including disruption of sarcomeric architecture, atrial enlargement, and electrophysiological abnormalities, thereby validating the mechanistic impact of MYL4 mutations. |