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A Novel Pathogenic Variant in the Fzd6 Gene Causes Recessive Nail Dysplasia in a Large Iranian Kindred Publisher Pubmed



Mohammadiasl J1 ; Pourreza MR2 ; Mohammadi A2 ; Eskandari A2 ; Mozafarjalali S3 ; Tabatabaiefar MA2, 4
Authors
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Authors Affiliations
  1. 1. Department of Medical Genetics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
  2. 2. Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
  3. 3. Department of Obstetrics and Gynecology, Arash Hospital, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran

Source: Journal of Dermatological Science Published:2017


Abstract

Background 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. Objective A large multiplex family with NDNC was referred for genetic counselling. Thorough genetic evaluation was performed. Methods 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. Results A homozygous 1 bp 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. Conclusions 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. © 2017 Japanese Society for Investigative Dermatology
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