A novel homozygous frame-shift mutation in the SLC29A3 gene: a new case report and review of literature.

BACKGROUND: The SLC29A3 gene, encoding a nucleoside transporter protein, is found in intracellular membranes. Based on the literatures, mutations in this gene cause a wide range of clinical manifestations including H syndrome, pigmented hypertrichosis with insulin dependent diabetes, Faisalabad histiocytosis, and dysosteosclerosis. However, all these disorders with their different names and terminologies are actually the same entity termed H syndrome. CASE PRESENTATION: We report four GJB2 and GJB6 negative deaf patients from two Iranian related families who present the associated symptoms of SLC29A3-disorder. Whole Exome Sequencing (WES) using Next Generation Illumina Sequencing was used to enrich all exons of protein-coding genes as well as some other important genomic regions in one of studied patients. A novel homozygous frame-shift mutation c.307-308delTT (p.Phe103fs) in exon 3 of SLC29A3 gene was identified in a 35 years old man with profound hearing loss, camptodactyly, rheumatoid arthritis and delayed puberty without any skin changes, short stature and insulin dependent diabetes mellitus. The mutation found was also confirmed by Sanger sequencing in other studied patients and their healthy parents. In compared to proband, however the clinical manifestations of these patients were different, indicating variable expressivity of mutant SLC29A3 gene as well as possible involvement of other modifier genes. CONCLUSION: The present study uncovered a rare novel homozygous frame-shift mutation c.307-308delTT in SLC29A3 gene of four related patients with various manifestation of SLC29A3-disorder. Such studies can help to conduct genetic counseling and subsequently, prenatal diagnosis more accurately for individuals at the high risk of these types of genetic disorders.

Next-generation sequencing approach to molecular diagnosis of Iranian patients with Duchenne/Becker muscular dystrophy: Several novel variants identified.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) constitute the second most prevalent muscular dystrophy, with large deletions or duplications accounting for 66% of cases. No effective treatment exists for DMD/BMD. At present, genetic diagnosis serves as the foundation for gene therapy treatments. In this study, a comprehensive molecular investigation was conducted. The subjects diagnosed with DMD/BMD were initially examined using multiplex ligation-dependent probe amplification (MLPA) technology. The negative MLPA results were analyzed further using next-generation sequencing (NGS) technology. The MLPA detected 201 deletions (65.9%) and 20 duplications (6.6%) along the dystrophin gene among the 305 Iranian patients examined. The deletion of exon 52 in the amenable skipping subgroup was associated with an earlier onset age and a more severe phenotype. Twenty-one of the small mutations found in 58 MLPA-negative patients were novel. The most prevalent variants were nonsense variants (46.5%), frameshift variants (31%), splicing variants (6.9%), missense variants (10.4%), and synonymous mutations (5.1%). Our results demonstrate that MLPA and NGS can be effective diagnostic tools for very young patients with a single exon deletion.

A novel recessive PDZD7 bi-allelic mutation in an Iranian family with non-syndromic hearing loss.

BACKGROUND: Autosomal recessive non-syndromic hearing loss (ARNSHL) is genetically and phenotypically heterogeneous with over 110 genes causally implicated in syndromic and non-syndromic hearing loss. Here, we investigate the genetic etiology of deafness in two GJB2 and GJB6 negative patients presenting with pre-lingual, progressive, severe hearing loss. METHODS: Targeted exome sequencing (TES) using Next Generation Illumina Sequencing was used to analyze the exonic and some other important genomic regions of 154 genes in the proband. Subsequently, the mutation found was confirmed by Sanger sequencing in other affected sibling and healthy family members. The possible impact of the reported mutation on the corresponding protein was also evaluated by using bioinformatics tools. Moreover, the affected patients underwent audiological and ophthalmic evaluations. RESULTS: TES identified a novel homozygous missense mutation c.251T>C (p.I84T) in exon 3 of PDZD7 gene. In addition, segregation and phenotype-genotype correlation analysis as well as in-silico evaluations confirmed the autosomal recessive inheritance pattern and disease-causing nature of mutation found. CONCLUSIONS: In overall, our finding could expand the pathogenic mutations spectrum and strengthens the clinical importance of the PDZD7 gene in ARNSHL patients. It can also aid to conduct genetic counseling, prenatal diagnosis and clinical management of these types of genetic disorders.