Abstract：
BACKGROUND: Most cases of hereditary ichthyoses present with generalized scaling and skin dryness. However, in some cases skin involvement is restricted to particular body regions as in acral lamellar ichthyosis.
OBJECTIVE: We report on the genetic basis of acral ichthyosis in two families presenting with a similar phenotype.
METHODS: Genetic testing was performed by targeted next generation sequencing and whole-exome sequencing. For identity-by-descent analysis, the parents were genotyped and data analysis was performed with the Chromosome Analysis Suite Software. RT-PCR with RNA extracted from skin samples was used to analyse the effect of variants on splicing.
RESULTS: Genetic testing identified a few heterozygous variants, but only the variant in KRT2 c.1912 T > C, p.Phe638Leu segregated with the disease and remained the strongest candidate. Pairwise identity-by-descent analysis revealed no indication of family relationship. Phenylalanine 638 is the second last amino acid upstream of the termination codon in the tail of K2, and substitution to leucine is predicted as probably damaging. Assessment of the variant is difficult, in part due to the lack of crystal structures of this region.
CONCLUSIONS: Altogether, we show that a type of autosomal dominant acral ichthyosis is most probably caused by an amino acid substitution in the C-terminus of keratin 2.
OBJECTIVE: We report on the genetic basis of acral ichthyosis in two families presenting with a similar phenotype.
METHODS: Genetic testing was performed by targeted next generation sequencing and whole-exome sequencing. For identity-by-descent analysis, the parents were genotyped and data analysis was performed with the Chromosome Analysis Suite Software. RT-PCR with RNA extracted from skin samples was used to analyse the effect of variants on splicing.
RESULTS: Genetic testing identified a few heterozygous variants, but only the variant in KRT2 c.1912 T > C, p.Phe638Leu segregated with the disease and remained the strongest candidate. Pairwise identity-by-descent analysis revealed no indication of family relationship. Phenylalanine 638 is the second last amino acid upstream of the termination codon in the tail of K2, and substitution to leucine is predicted as probably damaging. Assessment of the variant is difficult, in part due to the lack of crystal structures of this region.
CONCLUSIONS: Altogether, we show that a type of autosomal dominant acral ichthyosis is most probably caused by an amino acid substitution in the C-terminus of keratin 2.
摘要：
背景：大多数遗传性鱼鳞病病例表现为全身性鳞屑和皮肤干燥。然而,在某些情况下，皮肤受累仅限于特定的身体区域，如肢层状鱼鳞病。
目的：我们报道了表现相似表型的两个家系中的肢端鱼鳞病的遗传基础。
方法：通过靶向下一代测序和全外显子组测序进行基因检测。对于按血统的身份分析，对父母进行基因分型,并使用染色体分析套件软件进行数据分析.使用从皮肤样品提取的RNA的RT-PCR来分析变体对剪接的影响。
结果：基因检测发现了一些杂合变异，但只有KRT2c.1912T>C中的变体，p.Phe638Leu与该疾病分离，并且仍然是最强的候选者。按血统成对身份分析显示没有家庭关系的迹象。苯丙氨酸638是K2尾部终止密码子上游的倒数第二个氨基酸,并且预测到亮氨酸的取代可能是有害的。对变体的评估是困难的，部分原因是该区域缺乏晶体结构。
结论：总而言之，我们表明，一种常染色体显性端性鱼鳞病很可能是由角蛋白2C末端的氨基酸取代引起的。
目的：我们报道了表现相似表型的两个家系中的肢端鱼鳞病的遗传基础。
方法：通过靶向下一代测序和全外显子组测序进行基因检测。对于按血统的身份分析，对父母进行基因分型,并使用染色体分析套件软件进行数据分析.使用从皮肤样品提取的RNA的RT-PCR来分析变体对剪接的影响。
结果：基因检测发现了一些杂合变异，但只有KRT2c.1912T>C中的变体，p.Phe638Leu与该疾病分离，并且仍然是最强的候选者。按血统成对身份分析显示没有家庭关系的迹象。苯丙氨酸638是K2尾部终止密码子上游的倒数第二个氨基酸,并且预测到亮氨酸的取代可能是有害的。对变体的评估是困难的，部分原因是该区域缺乏晶体结构。
结论：总而言之，我们表明，一种常染色体显性端性鱼鳞病很可能是由角蛋白2C末端的氨基酸取代引起的。
