Congenital Ichthyosis and Related Disorders Panel

Congenital ichthyosis is a highly heterogeneous skin scaling disorder caused by abnormal skin keratinization. Autosomal recessive congenital ichthyosis (ARCI) includes harlequin ichthyosis, congenital ichthyrosis erythroderma and lamellar ichthyosis (Oji et al. 2010). The major clinical features are: congenital collodion membrane, ectropion, eclabium, alopecia, palmar-plantar hyperkeratosis, and hypohidrosis. Harlequin ichthyosis 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 are prominent erythroderma and white scales. Some patients have less severe congenital collodion membrane. Lamellar ichthyosis is characterized by brown dark, coarse scales with very mild erythema, alopecia and often includes congenital collodion membrane.

Autosomal recessive ichthyosis are caused by pathogenic variants in the TGM1, ALOXE3, ALOX12B, ABCA12, CYP4F22, CLDN1, NIPAL4, PNPLA1, CERS3, LIPN, POMP, SLC27A4, and ST14 genes.

Pathogenic variants in the ABHD5 gene cause autosomal recessive Chanarin-Dorfman syndrome which is characterized by congenital ichthyosis, hepatosplenomegaly, vacuolated granulocytes and myopathy (Samuelov et al. 2011). Pathogenic variants in the AP1S1 gene are associated with MEDNIK, which is characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma (Montpetit et al. 2008).

Autosomal dominant ichthyosis and related conditions are caused by pathogenic variants in the KRT1, KRT2, KRT9 and KRT10 genes. KRT1 is involved in autosomal dominant Epidermolytic hyperkeratosis, KRT2 is involved in autosomal dominant Ichthyosis bullosa of Siemens, KRT9 is involved in autosomal dominant Palmoplantar keratoderma, epidermolytic, and KRT10 is involved in Ichthyosis, cyclic, with epidermolytic hyperkeratosis.

KRT1 and KRT10 are also involved in autosomal recessive Epidermolytic hyperkeratosis.

~80% of Autosomal Recessive Congenital Ichthyosis (ARCI) patients have pathogenic variants in TGM1, ALOXE3, ALOX12B, ABCA12, NIPAL4, CYP4F22 and PNPLA1 (Fischer 2009; Richard and Bale 2014). In a recently study, 84% of the 113 patients with clinical diagnosed autosomal recessive ichthyosis were found to have bi-allelic pathogenic variants in one of these genes TGM1, ABCA12, ALOXE3, ALOX12B, NIPAL4, CYP4F22, PNPLA1, CERS3, SLC27A4 and ABHD5 (Pigg et al. 2016).

Pathogenic variants in TGM1 are responsible for 38~50% of ARCI cases; ALOX12B, ALOXE3, ABCA12 and CYP4F22 account for about 5 - 10% of ARCI cases each; and pathogenic variants in PNPLA1and NIPAL4 each account for only a small portion of ARCI cases. In addition, ABCA12 is the major gene for Harlequin ichthyosis and TGM1 is the major gene for Lamellar ichthyosis (Fischer 2009; Richard and Bale 2014).

KRT1 and KRT10 pathogenic variants were identified in 9 and 19 of 28 unrelated epidermolytic ichthyosis patients (Arin et al. 2011). KRT2 pathogenic variants were identified in 4 out of 26 families with keratinopathic ichthyoses (Hotz et al. 2016).

To date, only a few large deletions/duplications have been documented in the TGM1, ALOXE3, ABCA12, CYP4F22, ABHD5, KRT1, KRT10, and CERS3 genes (Pigg et al. 2016; Ullah et al. 2016; Lefèvre et al. 2006; Scott et al. 2013; Samuelov et al. 2011; Takeichi et al. 2016; Lamb et al. 2014; Radner et al. 2013; Human Gene Mutation Database). No large deletions/insertions in the ALOX12B, AP1S1, CLDN1, LIPN, NIPAL4, PNPLA1, POMP, SLC27A4, ST14, KRT2, and KRT9 genes have been reported.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).