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Transient bullous dermolysis of the newborn (TBDN) is a self-improving, subepidermal blistering disorder evident at birth or shortly thereafter, with skin fragility that markedly diminishes over the first months to years of life. Electron microscopy reveals abnormalities in anchoring fibril formation below the lamina densa, and immunofluorescence staining demonstrates intracellular accumulation of type VII collagen in keratinocytes (PMID:9406826). Clinically, TBDN features tense, flaccid, or herpetiform bullae primarily on acral sites, often sparing mucosae, and heals without scarring.
Genetic analyses have identified both dominant and recessive COL7A1 variants in TBDN. A G>C transversion at the −1 position of intron 35 abolishes the exon 36 3′-splice acceptor, predicting in-frame exon skipping and segregating in three generations of an autosomal dominant pedigree (PMID:9406826). Separate reports describe a compound heterozygote for a dominant glycine substitution (c.6751G>C (p.Gly2251Arg)) and a recessive glycine variant (c.4556G>A (p.Gly1519Asp)) in a single patient (PMID:9856844), an autosomal dominant p.Gly2025Asp variant with nail dystrophy in a father and self-resolving skin symptoms in the proband (PMID:38415502), and five additional unrelated patients from Southeast Asia with heterozygous glycine substitutions (e.g., c.4705G>A (p.Gly1569Arg), c.5108G>A (p.Gly1703Glu)) (PMID:33258232). In total, eight probands have been described across four studies.
Inheritance is predominantly autosomal dominant with variable expressivity; segregation of the intron 35 splice defect through two additional affected relatives supports familial transmission (PMID:9406826). A single case of compound heterozygosity illustrates that recessive alleles may modify disease severity when combined with dominant glycine substitutions.
The variant spectrum in TBDN comprises one canonical splice-site mutation and multiple glycine missense substitutions within the triple-helical domain of type VII collagen, underscoring the critical role of glycine residues in collagen stability. No founder alleles have been identified, and carrier frequencies are currently unknown.
Functional assays demonstrate that mutant COL7A1 transcripts yield truncated or misfolded proteins that accumulate intracellularly, with diminished secretion of functional collagen VII and severely hypoplastic anchoring fibrils on electron microscopy (PMID:9406826; PMID:9856844). These findings support a dominant-negative mechanism whereby aberrant collagen VII impairs fibril assembly.
Overall, the evidence for COL7A1 in TBDN meets a Strong ClinGen classification based on multiple unrelated probands (n=8), segregation in a multigenerational family, and concordant functional data. Genetic evidence is Strong given the diversity of pathogenic variant classes and familial transmission, while functional evidence is Moderate given robust in vitro and ultrastructural assays. No credible conflicting reports have emerged. COL7A1 testing should be considered in newborns with transient bullae, informing prognosis, genetic counseling, and potential enrollment in emerging RNA- or gene-based therapies.
Gene–Disease AssociationStrongEight probands across four studies, including multigenerational segregation and consistent functional defects Genetic EvidenceStrongMultiple unrelated AD and AR cases, familial segregation, variant diversity exceeding ClinGen genetic cap Functional EvidenceModerateIn vitro immunofluorescence, electron microscopy, and transcript analyses demonstrate dominant-negative collagen VII retention |