Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
This summary details the association between FKBP14 and Ehlers-Danlos syndrome, a connective tissue disorder characterized by features such as progressive kyphoscoliosis, myopathy, hearing impairment, and, in select cases, vascular complications (PMID:24677762). Multiple independent studies have identified biallelic loss‑of‑function mutations in FKBP14 underlying this autosomal recessive disorder, with patients presenting a consistent constellation of clinical features that support its clinical validity.
In a seminal report, four children and one adult were described with FKBP14‑related Ehlers-Danlos syndrome, including one case that expanded the phenotype by demonstrating severe vascular complications (PMID:24677762). Additional studies have corroborated these findings in independent cohorts, with one multi‑patient investigation reporting a cohort of approximately 40 affected individuals with recurrent homozygous or compound heterozygous mutations in FKBP14 (PMID:22265013).
The genetic evidence is robust; multiple families have been identified that segregate pathogenic variants, notably the recurrent frameshift mutation c.362dup (p.Glu122ArgfsTer7), which has been detected in several unrelated probands. The cumulative evidence from variant spectra—including frameshift, splice, and nonsense alterations—supports the strong genetic basis for the disorder (PMID:24677762, PMID:22265013).
Segregation analysis in familial studies further reinforces the autosomal recessive inheritance pattern, with affected individuals consistently harboring biallelic mutations. Although detailed counts of segregating affected relatives are not uniformly reported, the recurrent identification of the same mutation on shared haplotypes suggests a founder effect or risk allele in certain populations.
Functional studies have provided critical experimental evidence supporting a pathogenic mechanism involving loss of FKBP14 function. Investigations into fibroblast biology have shown that deficiency of FKBP14 leads to endoplasmic reticulum dysregulation and abnormal collagen folding, which in turn explains the extracellular matrix defects observed in patients (PMID:22265013, PMID:22989269).
While one study noted vascular complications in a family member without confirmed biallelic status, the overall body of evidence shows minimal conflicting data. Integrating both genetic and experimental findings underscores the strong clinical validity of the FKBP14–Ehlers‑Danlos syndrome association, rendering it a valuable diagnostic target and a model for precision medicine in connective tissue disorders.
Key take‑home: The comprehensive genetic and functional evidence establishes FKBP14 as a critical gene in the etiology of autosomal recessive Ehlers‑Danlos syndrome, with significant implications for molecular diagnostics and patient management.
Gene–Disease AssociationStrongMultiple independent studies have reported biallelic FKBP14 mutations in patients with Ehlers-Danlos syndrome, including at least 40 affected individuals overall (PMID:22265013, PMID:24677762), with supportive segregation and a recurrent pathogenic frameshift variant. Genetic EvidenceStrongRecurrent identification of the frameshift mutation c.362dup (p.Glu122ArgfsTer7) across unrelated probands and families, alongside a spectrum of loss‑of‑function variants, underpins the genetic association and autosomal recessive inheritance. Functional EvidenceModerateExperimental studies in patient-derived fibroblasts demonstrate that the loss of FKBP14 disrupts ER integrity and collagen folding, supporting the pathogenic mechanism even though detailed functional quantitation remains limited. |