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Novel Transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the United States
  1. Sharifeh Farasat (farasats{at}cc.nih.gov)
  1. NIH, United States
    1. Ming-Hui Wei (weim{at}mail.nih.gov)
    1. NIH, United States
      1. David J Liewehr (liewehrd{at}mail.nih.gov)
      1. NCI, United States
        1. Matthew Herman (hermanm{at}mail.nih.gov)
        1. NIH, United States
          1. Seth M Steinberg (steinbergs{at}mail.nih.gov)
          1. NCI, United States
            1. Sherri Bale (sherribale{at}genedx.com)
            1. Gene Dx, United States
              1. Philip Fleckman (fleck{at}u.washington.edu)
              1. University of Washington, United States
                1. Jorge Toro (toroj{at}mail.nih.gov)
                1. NIH, United States

                  Abstract

                  Autosomal recessive congenital ichthyosis (ARCI) is a rare hereditary disorder of cornification. Mutations in the transglutaminase-1 (TGM1) gene, which encodes for the epidermal enzyme transglutaminase-1 (TGase-1), are one of the causes of ARCI. We characterized the TGM1 mutation spectrum, and investigated genotype-phenotype correlations in 104 patients with ARCI ascertained through the National Registry for Ichthyosis and Related Disorders in the United States. Germline mutations in TGM1 were identified in 55% (57/104) of ARCI patients. Arginine residues in TGase-1 were mutated in 39% (22/57) of patients overall and 54% (20/37) of those with missense mutations. Fifty-five percent (12/22) of missense mutations were within CpG dinucleotides and 92% (11/12) of these mutations were C-> T or G->A transitions. Our genotype-phenotype investigation found that ARCI patients with TGM1 mutations were significantly associated with presence of collodion membrane at birth (p=0.006), ectropion (p=0.001), plate-like scales (p=0.005), and alopecia (p=0.001). Patients with at least one mutation predicted to truncate TGase-1 were more likely to encounter worst hypohidrosis (p=0.001) and worst overheating (p=0.0007) at onset of symptoms compared with those with exclusively TGM1 missense mutations. We developed a logistic model that predicted that individuals with collodion membrane, alopecia, and/or eye problems are about four times more likely to have TGM1 mutations than patients without these findings. In conclusion, this is the largest molecular and genetic investigation of ARCI patients to date. It expands the TGM1 mutation spectrum and shows that despite genetic and phenotypic heterogeneity in ARCI, TGM1 is the main causative gene for this disorder.

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