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This summary reviews the association between the DZIP1 gene and mitral valve prolapse. The evidence is derived primarily from a detailed case report demonstrating that defects in primary cilia function contribute to mitral valve pathology. The study identified a deleterious missense variant, c.72C>A (p.Ser24Arg), that segregated in a large family with autosomal dominant transmission of the disease. Affected individuals in this family presented with key cardiac symptoms including sudden cardiac death, arrhythmia, and congestive heart failure (PMID:31118289).
Genetic evidence supporting the association comes from rigorous familial segregation analysis. The presence of the c.72C>A (p.Ser24Arg) variant in affected family members, along with evidence that this variant disrupts normal protein function, is consistent with the reported autosomal dominant mode of inheritance. Although the multi‐patient study did not report additional DZIP1 variants, DZIP1 remains one of the four known causative genes included in the broader evaluation of mitral valve prolapse (PMID:32277046).
The autosomal dominant inheritance pattern is further strengthened by segregation data, with multiple affected relatives observed within the family. Such segregation, even when derived from a single large pedigree, provides important insight into the gene‐disease mechanism and supports its clinical relevance. The study’s findings highlight not only the presence of the variant but also its co‐segregation with disease phenotypes among several family members (PMID:31118289).
Functional evidence plays a pivotal role in establishing causality by linking the genetic alteration to a disruption in biological processes. In this instance, a mutant mouse model harboring the c.72C>A (p.Ser24Arg) variant demonstrated impaired ciliogenesis and abnormal extracellular matrix deposition during cardiac development, which recapitulated the clinical features of mitral valve prolapse. These experimental findings lend robust support to the pathogenic role of the DZIP1 variant (PMID:31118289).
Integration of the genetic and functional data reveals a cohesive narrative in which the c.72C>A (p.Ser24Arg) mutation in DZIP1 is strongly associated with mitral valve prolapse. A combination of familial segregation, autosomal dominant transmission, and definitive animal model studies collectively supports the gene–disease association. Additionally, the inclusion of DZIP1 among the limited list of known causative genes further underscores its clinical significance for diagnostic testing and potential therapeutic strategies.
Key take‑home sentence: The integration of segregation data and experimental validation confirms that the DZIP1 mutation is a strong diagnostic marker for mitral valve prolapse, underscoring its utility in clinical and commercial genetic testing.
Gene–Disease AssociationStrongA large family demonstrating autosomal dominant segregation of the c.72C>A (p.Ser24Arg) variant combined with supportive functional data from mouse models confirms the strong association between DZIP1 and mitral valve prolapse (PMID:31118289). Genetic EvidenceModerateThe identification of a deleterious missense variant in a segregating family, in addition to its acknowledgement as a known causative gene for MVP, provides moderate genetic evidence (PMID:31118289). Functional EvidenceStrongExperimental assessments in a mouse model recapitulated the MVP phenotype via impaired ciliogenesis and altered ECM deposition, strongly supporting the pathogenic role of the DZIP1 variant (PMID:31118289). |