Mutational Spectrum of the ABCA12 Gene and Genotype–Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis

Hotz, Alrun; Köpp, Julia; Bourrat, E.; Oji, Vinzenz; Süßmuth, Kira; Komlósi, Katalin; Bouadjar, B.; Tantcheva‐Poór, Iliana; Pigg, Maritta; Betz, Regina C.; Giehl, Kathrin; Schedel, Fiona; Weibel, Lisa; Schulz, Stefan; Stölzl, Dora; Tadini, Gianluca; Demiral, Emine; Berggård, Karin; Zimmer, Andreas; Alter, Svenja; Fischer, Judith

doi:10.3390/genes14030717

Cited by 7 publications

(9 citation statements)

References 26 publications

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“…The authors speculated that the detected mutations c.4412A>G, p.(His1471Arg) and c.4601C>T, p.(Thr1534Met) do not completely abolish ABCA12 activity, which could lead to an intermediate phenotype resembling EKVP. However, both mutations have already been described in two patients with ARCI in Hotz et al [ 20 ]: the mutation c.4412A>G was detected compound heterozygous with a second pathogenic variant in patient P34; the variant c.4601C>T was found in a homozygous state in patient P5 in this publication. Neither patient showed any features of EKV.…”

Section: Discussionmentioning

confidence: 50%

“…Molecular genetic analysis revealed two heterozygous mutations in ABCA12 (transcript ENST00000272895.7, NCBI reference sequence NM_173076.2, GRCh37.p13), including the splice-site mutation c.6962+1G>A, p.?. The mutation on the other allele, c.4139A>G, p.(Asn1380Ser), is the most frequent mutation in ABCA12 [ 20 ]. Her brother, P2, was similar affected since birth.…”

Section: Resultsmentioning

confidence: 99%

“…For missense mutations, the location within the protein is important. Pathogenic missense mutations are located primarily in transmembrane and ATP-binding cassette domains [ 20 , 24 ]. Mutation-specific phenotypes have been described, for example, in the TGM1 gene: Raghunath et al [ 25 ] described a particular mutation leading to a self-healing collodion baby.…”

Section: Discussionmentioning

confidence: 99%

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Erythrokeratodermia Variabilis-like Phenotype in Patients Carrying ABCA12 Mutations

Hotz,

Fölster-Holst,

Oji

et al. 2024

Genes

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Erythrokeratodermia variabilis (EKV) is a rare genodermatosis characterized by well-demarcated erythematous patches and hyperkeratotic plaques. EKV is most often transmitted in an autosomal dominant manner. Until recently, only mutations in connexins such as GJB3 (connexin 31), GJB4 (connexin 30.3), and occasionally GJA1 (connexin 43) were known to cause EKV. In recent years, mutations in other genes have been described as rare causes of EKV, including the genes KDSR, KRT83, and TRPM4. Features of the EKV phenotype can also appear with other genodermatoses: for example, in Netherton syndrome, which hampers correct diagnosis. However, in autosomal recessive congenital ichthyosis (ARCI), an EKV phenotype has rarely been described. Here, we report on seven patients who clinically show a clear EKV phenotype, but in whom molecular genetic analysis revealed biallelic mutations in ABCA12, which is why the patients are classified in the ARCI group. Our study indicates that ARCI should be considered as a differential diagnosis in EKV.

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Section: Discussionmentioning

confidence: 50%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Erythrokeratodermia Variabilis-like Phenotype in Patients Carrying ABCA12 Mutations

Hotz,

Fölster-Holst,

Oji

et al. 2024

Genes

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“…Phenotypic overlap occurs sometimes. It has been shown that ABCA12 variants correlate with phenotypic severity (Akiyama, 2010 ; Hotz et al., 2023 ; Loo et al., 2018 ; Montalvan‐Suarez et al., 2019 ; Umemoto et al., 2011 ). Current studies generally support that most biallelic truncation variants and/or exon/amino acid deletions lead to HI.…”

Section: Discussionmentioning

confidence: 99%

Compound heterozygous ABCA12 variants identified in a Chinese patient with congenital ichthyosiform erythroderma: Advancing genotype–phenotype correlations and literature review

Liu,

Guo,

Zhang

et al. 2024

Molec Gen & Gen Med

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BackgroundIchthyosis is a common keratotic skin disease with high clinical, etiological and genetic heterogeneity. There are four types of non‐syndromic hereditary ichthyoses, among which autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of recessive Mendelian disorders. ARCI present with different phenotypes and ABCA12 pathogenic variants have been shown to cause complex ARCI phenotypes, including harlequin ichthyosis (HI), lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE).MethodsA sporadic male patient, clinically diagnosed with CIE, was enrolled in this study. Exome sequencing was combined with Sanger sequencing to confirm the diagnosis and identify the pathogenic variants. In silico predictions were made using multiple software programs, and the identified variants were interpreted using the ACMG guidelines. A review of all literature reported ABCA12 variants was performed to explore genotype–phenotype correlations.ResultsCompound heterozygous ABCA12 variants [c.5381+1G>A and c.5485G>C (p.Asp1829His)] (NM_173076) were identified. The two variants were not detected in the public database. c.5381+1G>A is predicted to affect ABCA12 mRNA splicing and Asp1829 is highly conserved among various species. In silico analysis suggested that these two variants were responsible for the phenotype of the patient. Genotype–phenotype correlation analysis showed that biallelic truncation variants and/or exon/amino acid deletions in ABCA12 are the most common causes of HI. Biallelic missense variants are most common in LI and CIE.ConclusionsThe compound heterozygous ABCA12 variants caused the CIE phenotype observed in the patient. The spectrum of ABCA12 pathogenic variants were broaden. Genotype–phenotype correlation analysis provided detailed evidence which can be used in future prenatal diagnosis and can inform the need for genetic counselling for patients with ABCA12‐related ARCIs.

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“…These phenotypic differences occur depending on the type of ABCA12 mutation. Truncating variants on both alleles of ABCA12 tend to lead to HI, and the combination of two missense variants mainly leads to CIE or LI 12,13 . Thus, there are genotype–phenotype correlations.…”

Section: Introductionmentioning

confidence: 99%

Updated mutational spectrum and genotype–phenotype correlations in ichthyosis patients with ABCA12 pathogenic variants

Noda,

Takeichi,

Tanahashi

et al. 2024

Experimental Dermatology

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Autosomal recessive congenital ichthyoses (ARCI) is a genetically heterogeneous condition that can be caused by pathogenic variants in at least 12 genes, including ABCA12. ARCI mainly consists of congenital ichthyosiform erythroderma (CIE), lamellar ichthyosis (LI) and harlequin ichthyosis (HI). The objective was to determine previously unreported pathogenic variants in ABCA12 and to update genotype–phenotype correlations for patients with pathogenic ABCA12 variants. Pathogenic variants in ABCA12 were detected using Sanger sequencing or a combination of Sanger sequencing and whole‐exome sequencing. To verify the pathogenicity of a previously unreported large deletion and intron variant, cDNA analysis was performed using total RNA extracted from hair roots. Genetic analyses were performed on the patients with CIE, LI, HI and non‐congenital ichthyosis with unusual phenotypes (NIUP), and 11 previously unreported ABCA12 variants were identified. Sequencing of cDNA confirmed the aberrant splicing of the variant ABCA12 in the patients with the previously unreported large deletion and intron variant. Our findings expand the phenotype spectrum of ichthyosis patients with ABCA12 pathogenic variants. The present missense variants in ABCA12 are considered to be heterogenous in pathogenicity, and they lead to varying disease severities in patients with ARCI and non‐congenital ichthyosis with unusual phenotypes (NIUP).

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Mutational Spectrum of the ABCA12 Gene and Genotype–Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis

Cited by 7 publications

References 26 publications

Erythrokeratodermia Variabilis-like Phenotype in Patients Carrying ABCA12 Mutations

Erythrokeratodermia Variabilis-like Phenotype in Patients Carrying ABCA12 Mutations

Compound heterozygous ABCA12 variants identified in a Chinese patient with congenital ichthyosiform erythroderma: Advancing genotype–phenotype correlations and literature review

Updated mutational spectrum and genotype–phenotype correlations in ichthyosis patients with ABCA12 pathogenic variants

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