Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
J Dermatol Sci. 2017 Oct;88(1):134-138. doi: 10.1016/j.jdermsci.2017.04.017. Epub 2017 May 13.
Nail disorder nonsyndromic congenital (NDNC) is a very rare clinically and genetically heterogeneous disease inherited both in recessive or dominant modes. FZD6 is a component of Wnt-FZD signaling pathway in which recessive loss-of-function variants in the corresponding genes could lead to nail anomalies.
A large multiplex family with NDNC was referred for genetic counselling. Thorough genetic evaluation was performed.
PCR-Sanger sequencing was carried out for the coding exons and exon-intron boundaries of the FZD6 gene. Co-segregation analysis, in silico evaluation and computational protein modeling was accomplished.
A homozygous 1bp deletion variant, c.1859delC (p.Ser620Cysfs*75), leading to a truncating protein was found in the patient. Parents were heterozygous for the variant. The variant was found to be co-segreagting with the phenotype in the family. Computational analysis and protein modeling revealed its pathogenic consequence by disturbing the cytoplasmic domain structure and signaling through loss of phosphorylation residues. The variant met the criteria of being pathogenic according to the ACMG guideline.
This is the first report of the genetic diagnosis of NDNC in Iran. We also report a novel pathogenic variant. The study of the FZD6 gene is recommended as the first step in the diagnostic routing of the autosomal recessive NDNC patients with enlarged nails.
指甲发育不良非综合征性先天性（NDNC）是一种非常罕见的临床和遗传异质性疾病，以隐性或显性模式遗传。FZD6 是 Wnt-FZD 信号通路的一个组成部分，相应基因中的隐性失功能变异可导致指甲异常。
一个患有 NDNC 的大型多重家族被转介进行遗传咨询。进行了彻底的遗传评估。
对 FZD6 基因的编码外显子和外显子-内含子边界进行了 PCR-Sanger 测序。完成了共分离分析、计算机预测评估和计算蛋白质建模。
在患者中发现了一个纯合的 1bp 缺失变异，c.1859delC（p.Ser620Cysfs*75），导致截断蛋白。父母为该变异的杂合子。该变异与家系中的表型共分离。计算分析和蛋白质建模表明，由于磷酸化残基丢失，其通过干扰细胞质结构和信号传导而导致致病性。该变异符合 ACMG 指南的致病性标准。
这是伊朗首例 NDNC 的基因诊断报告。我们还报告了一个新的致病性变异。建议对具有大指甲的常染色体隐性 NDNC 患者进行 FZD6 基因研究作为诊断途径的第一步。
