ABCA12 mutations in patients with autosomal recessive congenital ichthyosis: evidence of a founder effect in the Spanish population and phenotype-genotype implications

Esperón-Moldes, Uxia; Ginarte, Manuel; Rodríguez-Pazos, L.; Fachal, Laura; Pozo, T. Zamorano; Aguilar, Jesús Luelmo; González, J. del Boz; Santiago, Ana Martín; Vega, Ana

doi:10.1016/j.jdermsci.2018.05.012

Cited by 5 publications

(9 citation statements)

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“…Exceptions are two LI cases (patients 57 and 64) who harbor nonsense and frameshift variants. Interestingly these two patients did not show a more severe phenotype compared to other LI patients who carried missense mutations in both alleles (Akiyama et al, ; Bučková et al, ; Chao, Aleshin, Goldstein, Worswick, & Hogeling, ; Esperón‐Moldes et al, ; Fukuda et al, ; Hellström‐Pigg et al, ; Israeli et al, ; Lefèvre et al, ; Loo et al, ; Murase et al, ; Natsuga et al, ; Nawaz et al, ; Numata et al, ; Sakai et al, ; Scott et al, ; Shimizu et al, ; Sitek et al, ; Thomas et al, ; Wada et al, ; Wakil et al, ). The majority of the genotype‐phenotype associations found in these patients are in accordance with the correlations previously established by Akiyama, with some few exceptions as previously stated (Akiyama, ).…”

Section: Discussionmentioning

confidence: 89%

“…2007; Diociaiuti et al, 2016;Hellström-Pigg et al, 2016;Kelsell et al, 2005;Loo, Batilando, Tan, & Koh, 2018;Scott et al, 2013;Takeichi, Sugiura, Matsuda, Kono, & Akiyama, 2013;Thomas et al, 2006;Tourette et al, 2012;Umemoto et al, 2011) all these patients were diagnosed with HI at birth (with exception of patient 13 of whom there was not available phenotypic information). However, there are still few data of patients carrying a combination of splice-site and missense variants; from the eight patients reported to date, four showed CIE (patients 3, 15, 19, 26) (Bochner et al, 2017;Esperón-Moldes et al, 2018;Fukuda et al, 2012), and one presented HI (patient-16) (Hellström-Pigg et al, 2016). We also identified a total of sixty-three ABCA12 missense carrier patients.…”

Section: Of 15mentioning

confidence: 89%

“…Ten out of the 30 patients were compound heterozygous carriers of one ABCA12 splice‐site variant affecting the consensus splice‐site and a second truncating variant including eight nonsense (patients 1, 4, 8, 9, 13, 17, 22, and 30) and two frameshift (patients 5 and 23); (Akiyama et al, ; Diociaiuti et al, ; Hellström‐Pigg et al, ; Kelsell et al, ; Loo, Batilando, Tan, & Koh, ; Scott et al, ; Takeichi, Sugiura, Matsuda, Kono, & Akiyama, ; Thomas et al, ; Tourette et al, ; Umemoto et al, ) all these patients were diagnosed with HI at birth (with exception of patient 13 of whom there was not available phenotypic information). However, there are still few data of patients carrying a combination of splice‐site and missense variants; from the eight patients reported to date, four showed CIE (patients 3, 15, 19, 26) (Bochner et al, ; Esperón‐Moldes et al, ; Fukuda et al, ), and one presented HI (patient‐16) (Hellström‐Pigg et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Seven are homozygous carriers, and from these, those with pathogenic variants affecting the consensus splice-sites and its surroundings, are classified as HI (patients 7, 11, 12, 18, 25, and 27) (Akiyama et al, 2005;Goldsmith et al, 2013;Hellström-Pigg et al, 2016;Kelsell et al, 2005;Sheth, Bhavsar, Patel, Joshi, & Sheth, 2018;Thomas et al, 2008). Only two HI patients were compound heterozygous carriers of two different splice-site variants (patients 24 and 28) (Esperón-Moldes et al, 2018;Washio et al, 2017). Interestingly, the homozygous carrier of the synonymous variant c.3456G>A, p.(Ser1152=) (patient 10), located in the middle of the exon 24, shows a CIE phenotype.…”

Section: Discussionmentioning

confidence: 99%

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A novel ABCA12 pathologic variant identified in an Ecuadorian harlequin ichthyosis patient: A step forward in genotype‐phenotype correlations

Montalván-Suárez

Esperón-Moldes

Rodríguez-Pazos

et al. 2019

Molec Gen & Gen Med

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Background Autosomal recessive congenital ichthyoses (ARCI) have been associated with different phenotypes including: harlequin ichthyosis (HI), congenital ichthyosiform erythroderma (CIE), and lamellar ichthyosis (LI). While pathogenic variants in all ARCI genes are associated with LI and CIE phenotypes, the unique gene associated with HI is ABCA12 . In HI, the most severe ARCI form, pathogenic variants in both ABCA12 gene alleles usually have a severe impact on protein function. The presence of at least one non‐truncating variant frequently causes a less severe congenital ichthyosis phenotype (LI and CIE). Methods We report the case of a 4‐year‐old Ecuadorian boy with a severe skin disease. Genetic diagnosis was performed by NGS. In silico predictions were performed using Alamut software v2.11. A review of the literature was carried out to identify all patients carrying ABCA12 splice‐site and missense variants, and to explore their genotype‐phenotype correlations. Results Genetic testing revealed a nonsense substitution, p.(Arg2204*), and a new missense variant, p.(Val1927Leu), in the ABCA12 gene. After performing in silico analysis and a comprehensive review of the literature, we conclude that p.(Val1927Leu) affects a well conserved residue which could either disturb the protein function or alter the splicing process, both alternatives could explain the severe phenotype of our patient. Conclusion This case expands the spectrum of ABCA12 reported disease‐causing variants which is important to unravel genotype‐phenotype correlations and highlights the importance of missense variants in the development of HI.

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Section: Discussionmentioning

confidence: 89%

Section: Of 15mentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A novel ABCA12 pathologic variant identified in an Ecuadorian harlequin ichthyosis patient: A step forward in genotype‐phenotype correlations

Montalván-Suárez

Esperón-Moldes

Rodríguez-Pazos

et al. 2019

Molec Gen & Gen Med

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“…Akiyama 9 suggested that at least one missense mutation in transmembrane domains might underlie the CIE phenotype in Japan. In Spain, two unrelated patients with CIE demonstrated homozygous p.Asn1380Ser mutations, and a founder effect was reported 13 …”

Section: Discussionmentioning

confidence: 99%

Congenital ichthyosiform erythroderma with a novel variant inABCA12in a Chinese patient

Yang

Zhan

et al. 2020

Pediatric Investigation

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Introduction Congenital ichthyosiform erythroderma (CIE ) is characterized by fine, whitish scales on a background of erythematous skin over the whole body; it is reportedly caused by mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, and TGM1 genes. Case presentation A 15‐month‐old girl presented with CIE associated with compound heterozygous ABCA12 mutations, a known missense mutation c.4139A>G (p.Asn1380Ser) from her father, and a novel missense mutation c.4300A>G (p.Thr1434Ala) from her mother. Conclusion This is the first report to indicate that compound heterozygous missense mutations in the first ATP‐binding cassette of ABCA12 could contribute to the onset of CIE.

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Novel CYP4F22 mutations associated with autosomal recessive congenital ichthyosis (ARCI). Study of the CYP4F22 c.1303C>T founder mutation

et al. 2020

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Mutations in CYP4F22 cause autosomal recessive congenital ichthyosis (ARCI). However, less than 10% of all ARCI patients carry a mutation in CYP4F22. In order to identify the molecular basis of ARCI among our patients (a cohort of ninety-two Spanish individuals) we performed a mutational analysis using direct Sanger sequencing in combination with a multigene targeted NGS panel. From these, eight ARCI families (three of them with Moroccan origin) were found to carry five different CYP4F22 mutations, of which two were novel. Computational analysis showed that the mutations found were present in highly conserved residues of the protein and may affect its structure and function. Seven of the eight families were carriers of a highly recurrent CYP4F22 variant, c.1303C>T; p.(His435Tyr). A 12Mb haplotype was reconstructed in all c.1303C>T carriers by genotyping ten microsatellite markers flanking the CYP4F22 gene. A prevalent 2.52Mb haplotype was observed among Spanish carrier patients suggesting a recent common ancestor. A smaller core haplotype of 1.2Mb was shared by Spanish and Moroccan families. Different approaches were applied to estimate the time to the most recent common ancestor (TMRCA) of carrier patients with Spanish origin. The age of the mutation was calculated by using DMLE and BDMC2. The algorithms estimated that the c.1303C>T variant arose approximately 2925 to 4925 years ago, while Spanish carrier families derived from a common ancestor who lived in the XIII century. The present study reports five CYP4F22 mutations, two of them novel, increasing the number of CYP4F22 mutations currently listed. Additionally, our results suggest that the recurrent c.1303C>T change has a founder effect in Spanish population and c.1303C>T carrier families originated from a single ancestor with probable African ancestry.

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ABCA12 mutations in patients with autosomal recessive congenital ichthyosis: evidence of a founder effect in the Spanish population and phenotype-genotype implications

Cited by 5 publications

References 9 publications

A novel ABCA12 pathologic variant identified in an Ecuadorian harlequin ichthyosis patient: A step forward in genotype‐phenotype correlations

A novel ABCA12 pathologic variant identified in an Ecuadorian harlequin ichthyosis patient: A step forward in genotype‐phenotype correlations

Congenital ichthyosiform erythroderma with a novel variant inABCA12in a Chinese patient

Novel CYP4F22 mutations associated with autosomal recessive congenital ichthyosis (ARCI). Study of the CYP4F22 c.1303C>T founder mutation

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