Autosomal Recessive Congenital Ichthyosis (ARCI) via the NIPAL4 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: NIPAL4, PNPLA1, ABCA12, TGM1, ALOXE3, ALOX12B, and CYP4F22. NIPAL4 mutations mainly cause autosomal recessive congenital ichthyosis type 6 (OMIM#612281), which is characterized by prominent erythroderma and white, superficial scales. The NIPAL4 protein coded by the NIPAL4 gene (OMIM#609383) is a component in the granular layer of the epidermis and functions as a magnesium transporter and may also serve as an endogenous lipid mediator for trioxilins A3 and B3 in the hepoxilin pathway. To date, only 10 causative mutations have been reported: 7 missense, 1 nonsense, and two splicing site mutations (Lefèvre et al. Hum Mol Genet 13(20):2473-2482. 2004; Richard and Bale. GeneReviews, 2012; Scott et al. J Invest Dermatol 133(2):573-576. 2013).

NIPAL4 mutations account for only a small portion of ARCI cases overall (Richard and Bale. GeneReviews, 2012). Mutations in NIPAL4 were found in 16 of 18 (89%) families with the specific abnormal epidermal ultrastructures diagnosed by electron microscopy (Dahlqvist et al. J Med Genet 44(10):615-620, 2007).

No large deletions or duplications have been reported in NIPAL4 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the NIPAL4 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).