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TAF6 has been recently implicated in Cornelia de Lange syndrome (CdLS) through studies identifying homozygous missense mutations in families from two distinct world populations (PMID:25574841). These findings support an autosomal recessive inheritance pattern for TAF6-related CdLS-like features. The reported cases document mutations in TAF6 that appear to segregate with the phenotype, warranting further evaluation for clinical diagnostic decision‑making and potential commercial genetic testing.
The genetic evidence is supported by the identification of at least one unique variant, c.212T>C (p.Ile71Thr), observed in affected individuals. Although the number of probands is limited, the segregation of recessive variants in these families along with consistent phenotypic features such as facial dysmorphism and hirsutism (PMID:25574841) provides a compelling signal for disease causation.
Phenotypically, patients present with abnormalities of the face and hirsutism, key features observed in CdLS. These clinical characteristics, when combined with the observed genetic alterations, allow clinicians to refine differential diagnoses and inform cascade testing in affected families.
Functional studies further strengthen the association by demonstrating that mutations in TAF6 disrupt critical transcriptional activation functions. In particular, experimental work has revealed that alterations in the histone-fold and HEAT repeat domains of TAF6 impair proper TFIID complex assembly and promoter occupancy (PMID:29485702), reinforcing the pathogenic mechanism at the molecular level.
To date, there is no substantial conflicting evidence undermining this gene‑disease relationship. While the current number of documented families is modest, the combination of genetic and functional data provides a coherent narrative that links TAF6 dysfunction to the clinical manifestations of CdLS.
Key take‑home: The integration of segregation data, a validated variant c.212T>C (p.Ile71Thr), and functional disruption of TAF6 in transcriptional regulation underscores its clinical utility in the diagnostic evaluation of CdLS, supporting its role in precision medicine.
Gene–Disease AssociationModerateHomozygous TAF6 mutations have been reported in families from two distinct populations with CdLS‑like phenotypes, although the number of probands is limited (PMID:25574841). Genetic EvidenceModerateAt least one unique missense variant, c.212T>C (p.Ile71Thr), segregates in an autosomal recessive manner in affected individuals, supporting its role in CdLS (PMID:25574841). Functional EvidenceModerateExperimental studies demonstrate that mutations in TAF6 disrupt transcriptional activation through impaired TFIID complex function, in line with the observed clinical phenotype (PMID:29485702). |