Autosomal Recessive Congenital Ichthyosis (ARCI) via the ALOX12B 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: ALOX12B, CYP4F22, ABCA12, TGM1, ALOXE3, NIPAL4, and PNPLA1. ALOX12B mutations cause autosomal recessive congenital ichthyosis type 2 (OMIM# 242100). ALOX12B (12R-lipoxygenase) encoded by ALOX12B (OMIM#603741) belongs to the arachidonate lipoxygenases family. This enzyme family plays a key role in the biosynthesis of hydroxy derivatives of arachidonic acid. ALOX12B catalyzes the conversion of arachidonic acid to 12R-hydroxyeicosatetraenoic acid during formation of the epidermal lipid barrier. To date, about 40 distinct mutations have been documented in HGMD (Human Gene Mutation Database). Causative mutations are mainly missense (77%), other reported mutations include one nonsense, two splicing site, 4 small deletions and two small insertions. No large deletion/insertions have been reported (Jobard et al. Hum Mol Genet 11(1):107-113, 2002 ; Eckl et al. Hum Mutat 26(4):351-361, 2005).

ALOX12B mutations account for ~10% of ARCI (Eckl et al. J Invest Dermatol 129(6):1421-1428, 2009; Richard and Bale. GeneReviews, 2012).

To date, no large deletion/insertions have been reported in ALOX12B (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the ALOX12B 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).