PDigenic Mutations in Junctional Epidermolysis Bullosa in An Iranian Family.

In this study, we describe one Iranian patient who was diagnosed with Epidermolysis Bullosa (EB) because of mutations in three candidate genes, including 3 mutations. Two missense mutations in the LAMA3 (D3134H) and LAMB3 (Y339H) genes and also, a synonymous mutation in the ITGB4 (H422H) gene were identified that leads to the Junctional-EBHerlitz (JEB-Herlitz) clinical phenotype. The patient had a heterozygous LAMA3 mutation combined with a heterozygous mutation in LAMB3. Our results propose that these mutations produce novel protein-coding transcripts which explain the JEB-Herlitz phenotype in the patient. Interestingly, this is the first report indicating that a digenic inheritance in the LAMA3 and LAMB3 which is responsible for JEB-Herlitz. Also, this is the first digenic inheritance recognized in the JEB-Herlitz family. This study provides a new way to clarify the molecular mechanisms of LAMA3 and LAMB3 genes in JEB-Herlitz.

Identification of A Novel Missense Mutation in The Norrie Disease Gene: The First Molecular Genetic Analysis and Prenatal Diagnosis of Norrie Disease in An Iranian Family.

Norrie disease (ND) is a rare X-linked recessive disorder, which is characterized by congenital blindness and, in several cases, accompanied with mental retardation and deafness. ND is caused by mutations in NDP, located on the proximal short arm of the X chromosome (Xp11.3). The disease has been observed in many ethnic groups worldwide, however, no such case has been reported from Iran. In this study, we present the molecular analysis of two patients with ND and the subsequent prenatal diagnosis. Screening of NDP identified a hemizygous missense mutation (p.Ser133Cys) in the affected male siblings of the family. The mother was the carrier for the mutation (p.Ser133Cys). In a subsequent chorionic amniotic pregnancy, we carried out prenatal diagnosis by sequencing NDP in the chorionic villi sample at 11 weeks of gestation. The fetus was carrying the mutation and thus unaffected. This is the first mutation report and prenatal diagnosis of an Iranian family with ND, and highlights the importance of prenatal diagnostic screening of this congenital disorder and relevant genetic counseling.

Identification of Novel PTPRQ and MYO1A Mutations in An Iranian Pedigree with Autosomal Recessive Hearing Loss.

Autosomal recessive non-syndromic hearing loss (ARNSHL) is defined as a genetically heterogeneous disorder. The aim of the present study was to screen for pathogenic variants in an Iranian pedigree with ARNSHL. Next-generation targeted sequencing of 127 deafness genes in the proband detected two novel variants, a homozygous missense variant in PTPRQ (c.2599 T>C, p.Ser867Pro and a heterozygous missense variant in MYO1A (c.2804 T>C, p.Ile935Thr), both of which were absent in unaffected sibs and two hundred unaffected controls. Our results suggest that the homozygous PTPRQ variant maybe the pathogenic variant for ARNSHL due to the recessive nature of the disorder. Nevertheless, the heterozygous MYO1A may also be involved in this disorder due to the multigenic pattern of ARNSHL. Our data extend the mutation spectrum of PTPRQ and MYO1A, and have important implications for genetic counseling in unaffected sibs of this family. In addition, PTPRQ and MYO1A pathogenic variants have not to date been reported in the Iranian population.

Next-generation sequencing identifies three novel missense variants in ILDR1 and MYO6 genes in an Iranian family with hearing loss with review of the literature.

OBJECTIVES: Hearing impairment is the most common sensorineural disorder and is genetically heterogeneous. Identification of the pathogenic mutations underlying hearing impairment is difficult, since causative mutations in 127 different genes have so far been reported. METHODS: In this study, we performed Next-generation sequencing (NGS) in 2 individuals from a consanguineous family with hearing loss. RESULTS: Three novel mutations in known deafness genes were identified in the family; MYO6-p.R928C and -p.D1223N in heterozygous state and ILDR1-p.Y143C in homozygous state. Sanger sequencing confirmed co-segregation of the three mutations with deafness in the family. The identified mutation in ILDR1 gene is located in the immunoglobulin-type domain of the ILDR1 protein and the detected mutations in MY06 are located in the tail domain of the MYO6 protein. The mutations are predicted to be pathogenic by SIFT, PolyPhen and Mutation Taster. CONCLUSIONS: Our results suggest that either the homozygous ILDR1-p.Y143C mutation might be the pathogenic variant for ARNSHL or heterozygous MYO6- p.R928C, -p.D1223N might be involved in these patient's disorder due to compound heterozygousity. To our knowledge, this is the first ILDR1 and MYO6 mutations recognized in the southwest Iran. Our data expands the spectrum of mutations in ILDR1 and MYO6 genes.

Identification of a novel missence mutation in FGFR3 gene in an Iranian family with LADD syndrome by Next-Generation Sequencing.

Lacrimo-auriculo-dento-digital syndrome (LADD) is a multiple congenital anomaly and a genetically heterogeneous disorder. The aim of this study was to identify the pathogenic gene in an Iranian family with LADD syndrome and review the literature on reported mutations that involved in pathogenesis of LADD syndrome. One novel variant, c.1882 G > A, in fibroblast growth factor receptor 3 (FGFR3) was identified by next generation sequencing and Sanger sequencing. The heterozygous FGFR3 c.1882 G > A variant results in substitution of aspartic acid with asparagine at amino acid 628 (p.D628N) and co-segregated with the phenotype in the LADD family. Our findings suggest that the heterozygous FGFR3 c.1882 G > A variant might be the pathogenic mutation, because this amino acid is conserved in several species. Our data extend the mutation spectrum of the FGFR3 gene and have important implications for genetic counseling for the families. This is the second report of FGFR3 involvement in syndromic deafness in humans, and confirms the gene's positive role in inner ear development. In addition, this is the first FGFR3 mutation recognized in the Iranian LADD family.

Next-Generation Sequencing Reveals One Novel Missense Mutation in COL1A2 Gene in an Iranian Family with Osteogenesis imperfecta

BAckground: Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disorder characterized by bone loss and bone fragility. The aim of this study was to investigate the variants of three genes involved in the pathogenesis of OI. Methods: Molecular genetic analyses were performed for COL1A1, COL1A2, and CRTAP genes in an Iranian family with OI. The DNA samples were analyzed by next-generation sequencing (NGS) gene panel and Sanger sequencing. Results: Five different variants were identified in COL1A1 and COL1A2, including two variants in COL1A1 and three variants in COL1A2. Among the five causative COL1A1 and COL1A2 variants, one novel variants, c.1081 G>A, was found in COL1A2, which was identified in two siblings. Conclusion: Our finding extends the variant spectrum of the COL1A2 gene and has important implications for genetic counseling of families. The NGS is a powerful molecular diagnostic strategy for OI, a heterogeneous disorder.