Table 1.

Summary of Molecular Genetic Testing Used in Autosomal Recessive Congenital Ichthyosis

Gene 1 / Locus NameProportion of ARCI Attributed to Mutation of This GeneTest Method
TGM138%-55% (~90% of LI) 2, 3Sequence analysis 4, 5
Deletion/duplication analysis 6, 7
ALOX12B6.8%-12% 3, 8Sequence analysis 4
Deletion/duplication analysis 6, 7
ALOXE34%-6.8% 3, 8Sequence analysis 4
Deletion/duplication analysis 6, 7
ABCA125% (>93% of harlequin ichthyosis) 9Sequence analysis 4
Deletion/duplication analysis 6, 9
NIPAL4 (ICHTHYIN)A few percent of patients 10, 11Sequence analysis 4
Deletion/duplication analysis 6, 7
CYP4F228% 12Sequence analysis 4
Deletion/duplication analysis 6
PNPLA1Rare 13Sequence analysis 4
Deletion/duplication analysis 6, 7
LIPNRare, up to 5% 14Sequence analysis 4
CERS3Rare 15Sequence analysis 4
UnknownSee footnote 16NA

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.


Pathogenic variants have been also described in “bathing suit ichthyosis,” a rare clinical variant of ARCI.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Of individuals with the LI phenotype, at least 90% have pathogenic variants in both TGM1 alleles [Huber et al 1995, Russell et al 1995]. The founder splice-site variant c.877-2 A>G accounts for 34% of mutated TGM1 alleles [Herman et al 2009]; and missense variants in arginine codons account for 41% [Farasat et al 2009].


Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


No exon or whole-gene deletions or duplications of TGM1, ALOX12B, ALOXE3, NIPAL4, or PNPLA1 have been reported to cause ARCI.


Pathogenic variants have been also described in a rare clinical variant of ARCI, "self-improving collodion baby/ichthyosis" [Raghunath et al 2003, Vahlquist et al 2010].


Pathogenic variants in ABCA12 have been found in virtually all children with harlequin ichthyosis of diverse ethnic backgrounds [Akiyama et al 2005, Kelsell et al 2005, Thomas et al 2006]. Most are nonsense changes and small insertions/deletions resulting in premature termination of protein translation; splice site defects are less common. Partial-gene deletions spanning from one to 35 exons have been observed and require deletion/duplication analysis to detect. Note: While pathogenic variants in ABCA12 account for most cases of harlequin ichthyosis, ABCA12 pathogenic variants have also been reported in ten families with LI (most from northern Africa) [Lefèvre et al 2003] and in eight families with CIE [Akiyama 2010]. See also Parmentier et al [1996], Parmentier et al [1999].


Pathogenic variants have also been described in a rare clinical variant of ARCI, “acral self-improving collodion baby" [Mazereeuw-Hautier et al 2009].


There is a higher prevalence of NIPAL4 pathogenic variants in Sweden and Norway, where they account for approximately 89% of TGM1-negative cases with erythrodermic ARCI without collodion presentation [Dahlqvist et al 2007]. The two common pathogenic missense variants in this cohort are p.Ala176Asp and p.Gly230Arg [Dahlqvist et al 2007], while p.Ala176Asp also accounted for half the mutant alleles in families from Colombia, Turkey, and Algeria in another study [Lefèvre et al 2004]. See also Fischer [2009].


One study reports homozygous CYP4F22 pathogenic variants in 12 consanguineous families from Algeria, France, Italy, and Lebanon, including a large deletion spanning ten exons [Lefèvre et al 2006]. See also Fischer [2009].


Two consanguineous families from northern Africa [Grall et al 2012] and one patient from Galicia [Fachal et al 2014]


One study reports a homozygous 2-bp deletion in LIPN in a large consanguineous family with childhood-onset ARCI [Israeli et al 2011]. Biallelic LIPN pathogenic variants accounted for ARCI in 1/20 Israeli families (5%) tested [Israeli et al 2013].


Three consanguineous Tunisian families with congenital ichthyosis, eye, heart, and skeletal anomalies due to a contiguous gene deletion encompassing ADAMTS17, CERS3, and FLJ42289 were reported. Weill-Marchesani syndrome-like extracutaneous features were attributed to deletion of ADAMTS17, while deletion of CERS3 was associated with congenital ichthyosis [Radner et al 2013]. This causal relationship was confirmed when a homozygous splice donor site and missense variant in CERS3 were identified in two additional families with ARCI without extracutaneous findings [Radner et al 2013, Eckl et al 2013].


Further heterogeneity is suggested by the fact that some affected families do not have pathogenic variants in any of the nine known genes and their phenotype does not map to the other known genes [Krebsová et al 2001]. Pathogenic variants have not been identified in any of the following situations: (1) linkage to two other loci on the same chromosome (chromosome 19) has been suggested [Fischer et al 2000, Virolainen et al 2000]; (2) homozygosity mapping in two consanguineous families identified a region on chromosome 12 [Mizrachi-Koren et al 2005], and (3) linkage to a locus on 15q26.3 has been suggested in an aboriginal family from Taiwan [Wu & Lee 2011], which is possibly identical to the location of CERS3.

From: Autosomal Recessive Congenital Ichthyosis

Cover of GeneReviews®
GeneReviews® [Internet].
Pagon RA, Adam MP, Ardinger HH, et al., editors.
Seattle (WA): University of Washington, Seattle; 1993-2016.
Copyright © 1993-2016, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.