Zhu Linyan, Zhou Rui, Zhang Lianxiao, Chen Mei, Zhang Shengmin, Huang Xiaxi, Shi Yubo, Ding Huiqing
Department of Obstetrics and Gynaecology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China.
Department of Ultrasound, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China.
Front Pediatr. 2024 Dec 19;12:1505924. doi: 10.3389/fped.2024.1505924. eCollection 2024.
Autosomal 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 gene. Milder forms like LI and CIE usually involve at least one non-truncating variant.
Whole-exome sequencing (WES) was performed on fetal and parental DNA, and gene variants were validated by Sanger sequencing. The functional effect of the novel variant c.7104 + 6T > A was evaluated using an minigene system, with splicing analysis conducted via PCR and Sanger sequencing.
A 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.
In conclusion, this study identified a novel genetic variant, c.7104 + 6T > A in , as the cause of ARCI in a fetus, thereby enriched the known mutation spectrum.
常染色体隐性先天性鱼鳞病（ARCI）是一组遗传性皮肤病，其特征为角质化异常，会导致严重的健康问题并降低生活质量。ARCI包括丑角样鱼鳞病（HI）、先天性鱼鳞病样红皮病（CIE）和板层状鱼鳞病（LI）。虽然所有ARCI基因都与LI和CIE相关，但HI特别与该基因中的严重突变有关。LI和CIE等较轻的形式通常涉及至少一个非截短变异。
对胎儿和父母的DNA进行全外显子组测序（WES），并通过桑格测序验证基因变异。使用一个微型基因系统评估新变异c.7104 + 6T > A的功能效应，通过聚合酶链反应（PCR）和桑格测序进行剪接分析。
在胎儿中鉴定出ABCA12基因的复合杂合变异，包括c.5784G > A（p.W1928*）和c.7104 + 6T > A，分别遗传自父亲和母亲。根据美国医学遗传学与基因组学学会（ACMG）的指南，c.7104 + 6T > A变异被分类为意义未明的变异（VUS）。计算预测表明该变异影响剪接。一项微型基因检测进一步证实，ABCA12基因中的c.7104 + 6T > A变异导致两种异常的mRNA剪接：一个69个碱基对的缺失（c.7036_7104del，p.Val2346_Glu2368del）和外显子47的跳跃，这两种情况都会导致提前终止密码子和截短蛋白。
总之，本研究鉴定出一个新的基因变异，即ABCA12基因中的c.7104 + 6T > A，作为一名胎儿患ARCI的病因，从而丰富了已知的ABCA12基因突变谱。
