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The genetic evidence supporting an association between NKX2-6 and persistent truncus arteriosus is robust. Multiple independent case reports have identified biallelic loss‑of‑function variants in NKX2-6 among patients presenting with truncus arteriosus, a rare form of congenital heart defect. In one study, two consanguineous families were reported to harbor homozygous nonsense variants, and an additional non‑consanguineous family presented with compound heterozygous variants (PMID:32198970). These findings were further corroborated by a second report wherein a homozygous deleterious mutation was detected in a consanguineous family with conotruncal malformations (PMID:24421281). The consistent observation of truncating and homeodomain‑disrupting variants strongly supports a loss‑of‑function mechanism in the pathogenesis of persistent truncus arteriosus. Such convergent genetic findings render this association clinically relevant for diagnostic decision‑making.
The detailed genetic assessment reveals an autosomal recessive inheritance pattern underlying the observed phenotype. Family-based segregation analysis further strengthens the association by confirming that affected siblings and close relatives also carry the NKX2-6 variants. In several reports, additional affected family members consistently co‑segregated with the identified variants, lending further credence to the pathogenicity of these mutations (PMID:32198970). Case reports document a spectrum of variant types including nonsense, frameshift, and missense mutations; however, truncating mutations are most frequently observed. A representative variant, selected from the evidence, is c.453_454insT (p.Lys152Ter), which was identified in a patient with persistent truncus arteriosus and supports a loss‑of‑function mechanism. Overall, the genetic findings are in clear concordance with the observed clinical presentations.
Functional studies further validate the role of NKX2-6 in cardiac development. Experimental evidence demonstrates that NKX2-6 acts downstream of TBX1, a critical regulator in the second heart field, and is essential for proper outflow tract development. Inactivation or loss of NKX2-6 function in animal models leads to defects reminiscent of human truncus arteriosus, highlighting the gene’s functional importance (PMID:18328475). Gene expression profiling in these models has consistently shown downregulation of NKX2-6 in the context of disrupted TBX1 signalling. Such studies provide mechanistic insights that align with the genetic findings, thereby strengthening the overall credibility of the association. The convergence of functional and genetic evidence supports the pathogenic role of NKX2-6 loss‐of‑function in persistent truncus arteriosus.
While the association is well supported, some evidence exists that NKX2-6 variants may also contribute to other cardiac phenotypes, such as broader congenital heart disease and atrial fibrillation. However, for the specific phenotype of persistent truncus arteriosus, the case reports with biallelic truncating mutations and detailed segregation analyses remain the most compelling evidence. There are no significant conflicting reports regarding NKX2-6 involvement in this phenotype, and any phenotypic expansion does not detract from the established association with truncus arteriosus. The replication of findings across independent studies further bolsters the clinical validity of this gene‑disease relationship. These cumulative observations indicate that the evidence remains clear and compelling for a causative role of NKX2-6 in persistent truncus arteriosus. Overall, this integrated evaluation underscores the diagnostic and therapeutic utility of screening for NKX2-6 variants in patients with truncus arteriosus.
Key take‑home sentence: NKX2-6 loss‑of‑function mutations represent a rare, yet definitive, genetic etiology for persistent truncus arteriosus, supporting its use as a molecular marker in clinical evaluations.
Gene–Disease AssociationStrongEvidence from multiple independent studies including two consanguineous families and a compound heterozygous case totaling at least 4 probands with truncating variants consistent with persistent truncus arteriosus (PMID:32198970; PMID:24421281). Genetic EvidenceStrongNumerous probands have been identified with biallelic or compound heterozygous NKX2-6 variants, including the representative variant c.453_454insT (p.Lys152Ter), with clear segregation in affected families and a spectrum of truncating alterations supporting a loss‑of‑function mechanism (PMID:32198970). Functional EvidenceModerateFunctional studies demonstrate that NKX2-6 operates downstream of TBX1 and is critical for outflow tract formation, with experimental models recapitulating the persistent truncus arteriosus phenotype (PMID:18328475). |