A novel variant c.7104 + 6T > A of ABCA12 linked to autosomal recessive congenital ichthyosis verified by minigene splicing assay
BackgroundAutosomal recessive congenital ichthyosis (ARCI) is a group of genetic skin disorders characterized by abnormal keratinization, leading to significant health issues and reduced quality of life. ARCI encompasses harlequin ichthyosis (HI), congenital ichthyosiform erythroderma (CIE), and lam...
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Frontiers Media S.A.
2024-12-01
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| Series: | Frontiers in Pediatrics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fped.2024.1505924/full |
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| author | Linyan Zhu Rui Zhou Lianxiao Zhang Mei Chen Shengmin Zhang Xiaxi Huang Yubo Shi Huiqing Ding |
| author_facet | Linyan Zhu Rui Zhou Lianxiao Zhang Mei Chen Shengmin Zhang Xiaxi Huang Yubo Shi Huiqing Ding |
| author_sort | Linyan Zhu |
| collection | DOAJ |
| description | BackgroundAutosomal recessive congenital ichthyosis (ARCI) is a group of genetic skin disorders characterized by abnormal keratinization, leading to significant health issues and reduced quality of life. ARCI encompasses harlequin ichthyosis (HI), congenital ichthyosiform erythroderma (CIE), and lamellar ichthyosis (LI). While all ARCI genes are linked to LI and CIE, HI is specifically associated with severe mutations in the ABCA12 gene. Milder forms like LI and CIE usually involve at least one non-truncating ABCA12 variant.MethodsWhole-exome sequencing (WES) was performed on fetal and parental DNA, and ABCA12 gene variants were validated by Sanger sequencing. The functional effect of the novel variant c.7104 + 6T > A was evaluated using an in vitro minigene system, with splicing analysis conducted via PCR and Sanger sequencing.ResultsA compound heterozygous variation in the ABCA12 gene, comprising c.5784G > A (p.W1928*) and c.7104 + 6T > A, was identified in the fetus, inherited from the father and mother, respectively. According to ACMG guidelines, the c.7104 + 6T > A variant is classified as a Variant of Uncertain Significance (VUS). Computational predictions suggested that this variant affects splicing. A minigene assay further confirmed that the c.7104 + 6T > A variant in ABCA12 leads to two types of aberrant mRNA splicing: a 69-base pair deletion (c.7036_7104del, p.Val2346_Glu2368del) and skipping of Exon 47, both of which result in a premature stop codon and a truncated protein.ConclusionIn conclusion, this study identified a novel genetic variant, c.7104 + 6T > A in ABCA12, as the cause of ARCI in a fetus, thereby enriched the known ABCA12 mutation spectrum. |
| format | Article |
| id | doaj-art-597a5df968c24bafb7c335303f25b42d |
| institution | Kabale University |
| issn | 2296-2360 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pediatrics |
| spelling | doaj-art-597a5df968c24bafb7c335303f25b42d2024-12-19T04:20:49ZengFrontiers Media S.A.Frontiers in Pediatrics2296-23602024-12-011210.3389/fped.2024.15059241505924A novel variant c.7104 + 6T > A of ABCA12 linked to autosomal recessive congenital ichthyosis verified by minigene splicing assayLinyan Zhu0Rui Zhou1Lianxiao Zhang2Mei Chen3Shengmin Zhang4Xiaxi Huang5Yubo Shi6Huiqing Ding7Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, ChinaDepartment of Obstetrics and Gynaecology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, ChinaDepartment of Obstetrics and Gynaecology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, ChinaDepartment of Ultrasound, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, ChinaDepartment of Ultrasound, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, ChinaDepartment of Obstetrics and Gynaecology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, ChinaDepartment of Obstetrics and Gynaecology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, ChinaDepartment of Obstetrics and Gynaecology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, ChinaBackgroundAutosomal recessive congenital ichthyosis (ARCI) is a group of genetic skin disorders characterized by abnormal keratinization, leading to significant health issues and reduced quality of life. ARCI encompasses harlequin ichthyosis (HI), congenital ichthyosiform erythroderma (CIE), and lamellar ichthyosis (LI). While all ARCI genes are linked to LI and CIE, HI is specifically associated with severe mutations in the ABCA12 gene. Milder forms like LI and CIE usually involve at least one non-truncating ABCA12 variant.MethodsWhole-exome sequencing (WES) was performed on fetal and parental DNA, and ABCA12 gene variants were validated by Sanger sequencing. The functional effect of the novel variant c.7104 + 6T > A was evaluated using an in vitro minigene system, with splicing analysis conducted via PCR and Sanger sequencing.ResultsA compound heterozygous variation in the ABCA12 gene, comprising c.5784G > A (p.W1928*) and c.7104 + 6T > A, was identified in the fetus, inherited from the father and mother, respectively. According to ACMG guidelines, the c.7104 + 6T > A variant is classified as a Variant of Uncertain Significance (VUS). Computational predictions suggested that this variant affects splicing. A minigene assay further confirmed that the c.7104 + 6T > A variant in ABCA12 leads to two types of aberrant mRNA splicing: a 69-base pair deletion (c.7036_7104del, p.Val2346_Glu2368del) and skipping of Exon 47, both of which result in a premature stop codon and a truncated protein.ConclusionIn conclusion, this study identified a novel genetic variant, c.7104 + 6T > A in ABCA12, as the cause of ARCI in a fetus, thereby enriched the known ABCA12 mutation spectrum.https://www.frontiersin.org/articles/10.3389/fped.2024.1505924/fullautosomal recessive congenital ichthyosis (ARCI)ABCA12 genevariantminigene assaymRNA splicing |
| spellingShingle | Linyan Zhu Rui Zhou Lianxiao Zhang Mei Chen Shengmin Zhang Xiaxi Huang Yubo Shi Huiqing Ding A novel variant c.7104 + 6T > A of ABCA12 linked to autosomal recessive congenital ichthyosis verified by minigene splicing assay Frontiers in Pediatrics autosomal recessive congenital ichthyosis (ARCI) ABCA12 gene variant minigene assay mRNA splicing |
| title | A novel variant c.7104 + 6T > A of ABCA12 linked to autosomal recessive congenital ichthyosis verified by minigene splicing assay |
| title_full | A novel variant c.7104 + 6T > A of ABCA12 linked to autosomal recessive congenital ichthyosis verified by minigene splicing assay |
| title_fullStr | A novel variant c.7104 + 6T > A of ABCA12 linked to autosomal recessive congenital ichthyosis verified by minigene splicing assay |
| title_full_unstemmed | A novel variant c.7104 + 6T > A of ABCA12 linked to autosomal recessive congenital ichthyosis verified by minigene splicing assay |
| title_short | A novel variant c.7104 + 6T > A of ABCA12 linked to autosomal recessive congenital ichthyosis verified by minigene splicing assay |
| title_sort | novel variant c 7104 6t a of abca12 linked to autosomal recessive congenital ichthyosis verified by minigene splicing assay |
| topic | autosomal recessive congenital ichthyosis (ARCI) ABCA12 gene variant minigene assay mRNA splicing |
| url | https://www.frontiersin.org/articles/10.3389/fped.2024.1505924/full |
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