PDF(Pubmed)
Abstract：
BACKGROUND: Ichthyosis 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).
METHODS: A 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.
RESULTS: Compound 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.
CONCLUSIONS: The 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.
METHODS: A 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.
RESULTS: Compound 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.
CONCLUSIONS: The 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.
摘要：
背景:鱼鳞病是一种常见的角化性皮肤病,病因和遗传异质性。有四种类型的非综合征遗传性鱼鳞病，其中常染色体隐性遗传性先天性鱼鳞病（ARCI）是一组异质性的隐性孟德尔疾病。具有不同表型的ARCI和ABCA12致病性变异已被证明会导致复杂的ARCI表型，包括丑角鱼鳞病（HI），层状鱼鳞病（LI）和先天性鱼鳞病样红皮病（CIE）。
方法：一名散发性男性患者，临床诊断为CIE，参加了这项研究。将外显子组测序与Sanger测序相结合以确认诊断并鉴定致病变体。使用多个软件程序进行了计算机预测，和鉴定的变体使用ACMG指南进行解释.对所有文献报道的ABCA12变体进行了综述，以探索基因型-表型相关性。
结果：复合杂合ABCA12变体[c.53811G>A和c.5485G>C（p。Asp1829His)](NM_173076)被鉴定。在公共数据库中未检测到这两种变体。c.5381+1G>A预测会影响ABCA12mRNA剪接，Asp1829在各种物种中高度保守。计算机模拟分析表明,这两种变体负责患者的表型。基因型-表型相关性分析显示ABCA12中的双等位基因截短变体和/或外显子/氨基酸缺失是HI的最常见原因。双等位基因错义变体在LI和CIE中最常见。
结论：复合杂合ABCA12变异体可导致患者出现E表型。ABCA12致病变种的谱被拓宽。基因型-表型相关性分析提供了详细的证据，可用于未来的产前诊断，并可以告知ABCA12相关ARCI患者需要遗传咨询。
方法：一名散发性男性患者，临床诊断为CIE，参加了这项研究。将外显子组测序与Sanger测序相结合以确认诊断并鉴定致病变体。使用多个软件程序进行了计算机预测，和鉴定的变体使用ACMG指南进行解释.对所有文献报道的ABCA12变体进行了综述，以探索基因型-表型相关性。
结果：复合杂合ABCA12变体[c.53811G>A和c.5485G>C（p。Asp1829His)](NM_173076)被鉴定。在公共数据库中未检测到这两种变体。c.5381+1G>A预测会影响ABCA12mRNA剪接，Asp1829在各种物种中高度保守。计算机模拟分析表明,这两种变体负责患者的表型。基因型-表型相关性分析显示ABCA12中的双等位基因截短变体和/或外显子/氨基酸缺失是HI的最常见原因。双等位基因错义变体在LI和CIE中最常见。
结论：复合杂合ABCA12变异体可导致患者出现E表型。ABCA12致病变种的谱被拓宽。基因型-表型相关性分析提供了详细的证据，可用于未来的产前诊断，并可以告知ABCA12相关ARCI患者需要遗传咨询。
