Recessive mosaicism in ABCA12 causes blaschkoid congenital ichthyosiform erythroderma

Abstract

Summary We report the unique case of a 3‐year‐old girl who presented with linear erythematosquamous lesions following the lines of Blaschko, suggestive of genetic mosaicism in the skin. Single‐candidate gene analyses were performed on DNA from blood, excluding Conradi–Hünermann–Happle syndrome, erythrokeratodermia variabilis and a mosaic presentation of pityriasis rubra pilaris. With whole‐exome sequencing (WES) on DNA from the patient's blood, a heterozygous missense mutation in exon 25 of the ABCA12 gene was detected. By manually scrutinizing the WES data, another low‐percentage pathogenic frameshift mutation was found in the adjacent exon 26 of the same gene. This frameshift mutation was confirmed with Sanger sequencing in DNA isolated from a lesional skin biopsy. A subsequent cloning experiment was performed to prove that the patient is compound heterozygous for both mutations in the affected skin, explaining the blaschkoid ichthyosiform erythrodermic phenotype. The patient's phenotype was elucidated by the combination of a germline mutation and an acquired postzygotic mutation in ABCA12, resulting in the diagnosis of a mosaic manifestation of autosomal recessive congenital ichthyosis. Postzygotic compound allelic loss in autosomal recessive disorders is extremely rare and will not appear as the typical phenotype of the known germline mutation‐associated disease. This is the first report of a proven biallelic mosaic presentation of an autosomal recessive genodermatosis, and we propose the term ‘recessive mosaicism’ for this kind of manifestation. What's already know about this topic? Specific mutations in the ABCA12 lipid transporter are known to cause different phenotypes like harlequin ichthyosis, congenital ichthyosiform erythroderma and lamellar ichthyosis. In mosaicism, two or more cell populations that are genetically different arise postzygotically in the developing embryo. In the skin, mosaicism can present itself in different patterns of affected skin, often caused by a dominant genetic mutation. What does this study add? We report a unique patient with blaschkoid congenital ichthyosiform erythroderma due to biallelic mutations, one inherited germline missense mutation and the other a postzygotic frameshift mutation in the ABCA12 gene. This study describes the diagnostic approach and applied research that can be used if one encounters a similar diagnostic dilemma with manifestations suspected for genetic mosaicism. We propose the term ‘recessive mosaicism’ for this kind of mosaic presentation of an autosomal recessive genodermatosis.

Clinical and genetic investigation of ichthyosis in familial and sporadic cases in south of Tunisia: genotype–phenotype correlation

“…As clearly observed, no pathogenic variations in SPINK5 gene, neither in genes involved in erythrokeratoderma variabilis (EKV) were found in ILC patients (data not shown), confirming then different etiologies. Recently, Leersum et al [ 39 ] also reported a novel clinical phenotype of ichthyosis in a 3-year-old girl presenting a linear erythematosquamous lesions following the lines of Blaschko caused by ABCA12 mosaicism. This particular form of ichthyosis was explained by the combination of a germline mutation and an acquired postzygotic mutation in this gene.…”

Patients with keratinization disorders due to ABCA12 variants showing pityriasis rubra pilaris phenotypes

“…10 As we were unable to analyze the DNA samples from the epidermis in this study, we are unable to completely exclude the possibility of revertant mosaicism in keratinocytes within unaffected areas in the present cases. van Leersum et al 4 reported a patient with blaschkoid CIE due to biallelic pathogenic variants, one being an inherited germline missense variant and the other being a postzygotic frameshift variant in ABCA12. However, the hyperkeratotic areas in the present cases did not follow the Blaschko lines.…”

“…3 Moreover, pathogenic variants in ABCA12 are known to cause a localized nevoid form of CIE due to recessive mosaicism. 4 ABCA12 belongs to the large superfamily of adenosine triphosphate-binding cassette (ABC) transporter genes. ABC transporters bind ATP for the transport of various molecules across the limiting membrane.…”

Revertant Mosaicism in Genodermatoses: Natural Gene Therapy Right before Your Eyes

“…Remarkably, while there is a large number of autosomal recessive genodermatoses and there are millions of carriers of the gene variants in the associated genes, segmental type 1 mosaicism for such recessive genodermatoses is only rarely reported. One of the few examples is a case of blaschkoid congenital ichthyosiform erythroderma due to somatic mosaicism for a second ABCA12 variant [ 21 ]. While this has not been thoroughly investigated, this lack of observations may reflect that, for many disorders, cells lacking the protein encoded by the gene involved have a developmental disadvantage.…”