Autosomal Recessive Congenital Ichthyosis (ARCI) via the ABCA12 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: ABCA12, TGM1, ALOXE3, ALOX12B, NIPAL4, CYP4F22 and PNPLA1. ABCA12 mutations cause recessive Harlequin ichthyosis (OMIM#242500) and autosomal recessive congenital ichthyosis type 4A (OMIM#601277). ABCA12 (ATP-binding cassette, sub-family A (ABC1), member 12) belongs to the superfamily of ATP-binding cassette (ABC) transporters which transport various lipids across extra- and intracellular membranes. ABCA12 mutations are mainly associated with Harlequin ichthyosis. To date, about 80 distinct causative mutations have been documented in HGMD (Human Gene Mutation Database). Mutations include missense (~30%), nonsense (30%), splicing mutations (12%), small deletions (~18%), small duplications (~4%). Four large deletions within ABCA12 and one case of paternal uniparental isodisomy have been documented. Homozygous and compound heterozygous truncating mutations lead to the Harlequin ichthyosis, while missense mutations are more associated with the severe type of lamellar ichthyosis (Lefévre et al., Hum Mol Genet 12(18):2369-2378, 2003; Castiglia et al. Clin Genet 76(4):392-397, 2009; Akiyama et al. Hum Mutat 31(10):1090-1096, 2010; Richard and Bale. GeneReviews, 2012). 

ABCA12 is the major gene for Harlequin ichthyosis (Lefévre et al. Hum Mol Genet 12(18):2369-2378, 2003; Thomas et al. J Invest Dermatol 126(11):2408-2413, 2006). ABCA12 mutations account for ~5% of ARCI and 95% of Harlequin ichthyosis (Richard and Bale. GeneReviews, 2012).

Four large deletions within ABCA12 and one case of paternal uniparental isodisomy have been documented (Lefévre et al. Hum Mol Genet 12(18):2369-2378, 2003; Castiglia et al. Clin Genet 76(4):392-397, 2009).

This test provides full coverage of all coding exons of the ABCA12 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).