Autosomal Recessive Congenital Ichthyosis (ARCI) via the CYP4F22 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: CYP4F22, ABCA12, TGM1, ALOXE3, ALOX12B, NIPAL4, and PNPLA1. CYP4F22 mutations cause autosomal recessive congenital ichthyosis type 5 (OMIM#604777). The CYP4F22 protein (cytochrome P450, family 4, subfamily F, polypeptide 22) belongs to the cytochrome P450 enzyme superfamily which is involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. The CYP4F22 protein plays a role in the 12(R)-lipoxygenase pathway in arachidonic acid metabolism in the epidermis. To date, about 10 distinct mutations have been documented in HGMD (Human Gene Mutation Database). Causative mutations include missense (6/9), nonsense (1/9), small deletion (1/9) and large deletion (1/9) (Lefèvre et al. Hum Mol Genet 15(5):767-776, 2006).

One study identified 7 different homozygous CYP4F22 mutations in 12 consanguineous families from Mediterranean countries. CYP4F22 mutations account for ~8% of ARCI. Only one large deletion in CYP4F22 was reported (Lefèvre et al. Hum Mol Genet 15(5):767-776, 2006; Richard and Bale., GeneReviews, 2012; Human Gene Mutation Database).

To date, only 9 distinct mutations have been documented in CYP4F22 (Human Gene Mutation Database). Causative mutations include missense (6/9), nonsense (1/9), small deletion (1/9) and large deletion (1/9) (Lefèvre et al. Hum Mol Genet15(5):767-776, 2006).

This test provides full coverage of all coding exons of the CYP4F22 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).