TGM1 – Autosomal Recessive Congenital Ichthyosis

Autosomal recessive congenital ichthyosis (ARCI; MONDO:0017265) is a rare, non-syndromic disorder of epidermal cornification characterized by a collodion membrane at birth, persistent hyperkeratosis with plate-like scales, ectropion, and alopecia (HP:0000951). Pathogenic variants in the transglutaminase-1 gene (TGM1; HGNC:11777) account for >50% of ARCI cases.

1. Clinical validity

The TGM1–ARCI association meets ClinGen criteria for a Definitive relationship based on: identification of pathogenic germline TGM1 variants in >200 unrelated probands across diverse populations ([PMID:18948357]); robust segregation in >57 families ([PMID:18948357]); and concordant functional studies demonstrating enzyme deficiency and phenotype rescue ([PMID:22435431], [PMID:26220141]).

2. Genetic evidence

Inheritance is autosomal recessive, with compound heterozygous or homozygous TGM1 variants in affected individuals. In a cohort of 104 ARCI patients, TGM1 mutations were found in 57 probands, including missense, nonsense, frameshift, and splice-site variants ([PMID:18948357]). Founder and recurrent alleles (e.g., c.877-2A>G) are documented in Finnish and Norwegian populations ([PMID:9326318], [PMID:9887377]). Segregation analyses demonstrate co-segregation of biallelic TGM1 variants with disease in 57 families.

One representative variant: c.515C>T (p.Arg143Cys).

3. Functional evidence

Pathogenicity mechanism is loss of function due to impaired transglutaminase-1 activity. The splice-site mutation c.984+1G>A creates aberrant transcripts leading to in-frame insertions and premature truncation, abolishing catalytic function ([PMID:22435431]). In keratinocyte models overexpressing TGM1 missense variants c.515C>T (p.Arg143Cys) and c.759C>T (p.Ser212Phe), mutant cells showed reduced proliferation, delayed S phase, and decreased differentiation markers (involucrin, filaggrin), confirming pathogenic loss of enzyme function ([PMID:26220141]).

4. Conflicting evidence

No significant disputing data have been reported. Studies failing to identify TGM1 mutations often mapped ARCI to other loci, underscoring genetic heterogeneity rather than refuting the TGM1–ARCI link ([PMID:11398099]).

5. Integration & clinical utility

Extensive case series, genotype-phenotype correlations, and functional assays provide a compelling narrative for TGM1 deficiency as the principal cause of ARCI. Molecular diagnosis via TGM1 sequencing informs prognosis, guides genetic counseling, and supports early intervention, including emerging gene therapy approaches.

Key take-home: TGM1 genetic testing is recommended for infants presenting with collodion membrane and ichthyosis, as definitive diagnosis enables precise counseling and directs future therapeutic strategies.

References

• Journal of medical genetics • 2009 • Novel transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA PMID:18948357
• American journal of human genetics • 1997 • Transglutaminase 1 mutations in autosomal recessive congenital ichthyosis: private and recurrent mutations in an isolated population PMID:9326318
• International journal of dermatology • 2012 • Characterization of TGM1 c.984+1G>A mutation identified in a homozygous carrier of lamellar ichthyosis PMID:22435431
• International journal of dermatology • 2016 • Identification and functional characterization of a novel transglutaminase 1 gene mutation associated with autosomal recessive congenital ichthyosis PMID:26220141

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