Autosomal Recessive Congenital Ichthyosis (ARCI) via the TGM1 Gene

Autosomal recessive congenital ichthyosis (ARCI) is a highly heterogeneous skin scaling disorder caused by abnormal skin keratinization. ARCI includes harlequin ichthyosis, congenital ichthyrosis erythroderma and lamellar ichthyosis (Oji et al. J Am Acad Dermatol 63(4):607-641, 2010). The major clinical features are: congenital collodion membrane, ectropion, eclabium, alopecia, palmar-plantar hyperkeratosis, and hypohidrosis. Harlequin ichthyosis (OMIM#242500) is the severe form of ARCI. The infants are born covered with armor like thick scales separated with deep fissures. Patients may have bilateral ectropion and eclabium. Limb movement may be restricted by the thick scales which can lead to digital necrosis. Some patients may die at birth or shortly after birth due to sepsis, dehydration, and impaired thermoregulation. The main features of congenital ichthyosis erythroderma (OMIM#242100) are prominent erythroderma and white scales. Some patients have less severe congenital collodion membrane. Lamellar ichthyosis (OMIM#242300) is characterized by brown dark, coarse scales with very mild erythema, alopecia and often includes congenital collodion membrane.

ARCI is caused by mutations in at least the following seven genes: TGM1, ALOXE3, ALOX12B, ABCA12, NIPAL4, CYP4F22 and PNPLA1. Transglutaminase-1, a catalytic membrane-bound enzyme encoded by TGM1 (OMIM# 190195) plays a key role in the formation of the cornified cell envelope in the epidermis of the skin. The enzyme catalyzes the ankylglutamine formation which leads to crosslinking of proteins and the conjugation of polyamines to proteins during skin formation. Cornified cells are the most insoluble component of the epidermis and function as the skin’s physical barrier. Mutations in TGM1 explain about 50% of ARCI and around 90% of lamellar ichthyrosis. To date, about 140 distinct causative mutations have been documented in HGMD (Human Gene Mutation Database). Mutations include missense (~60%), nonsense (15%), splicing mutations (7%) and small insertions/deletions (~11%). No large deletions/insertions involving TGM1 have been documented. The c.877-2A>G mutation was seen in about 30% of North American and Norwegian ARCI patients (Farasat et al. J Med Genet 46(2):103-111, 2009; Herman et al. Human Mutation 30(4): 537–547, 2009; and Richard and Bale. GeneReviews, 2012).

TGM1 mutations were identified in 115 out of 234 ARCI patients (Herman et al. Human Mutation 30(4): 537–547, 2009). Mutations in TGM1 explain ~90% of lamellar ichthyosis (Richard and Bale. GeneReview, 2012).

No gross deletions/duplications have been reported to date in TGM1 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the TGM1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.