Dataset Information

A Clinical and Molecular Genetic Study of 50 Families with Autosomal Recessive Parkinsonism Revealed Known and Novel Gene Mutations.

ABSTRACT: In this study, the role of known Parkinson's disease (PD) genes was examined in families with autosomal recessive (AR) parkinsonism to assist with the differential diagnosis of PD. Some families without mutations in known genes were also subject to whole genome sequencing with the objective to identify novel parkinsonism-related genes. Families were selected from 4000 clinical files of patients with PD or parkinsonism. AR inheritance pattern, consanguinity, and a minimum of two affected individuals per family were used as inclusion criteria. For disease gene/mutation identification, multiplex ligation-dependent probe amplification, quantitative PCR, linkage, and Sanger and whole genome sequencing assays were carried out. A total of 116 patients (50 families) were examined. Fifty-four patients (46.55%; 22 families) were found to carry pathogenic mutations in known genes while a novel gene, not previously associated with parkinsonism, was found mutated in a single family (2 patients). Pathogenic mutations, including missense, nonsense, frameshift, and exon rearrangements, were found in Parkin, PINK1, DJ-1, SYNJ1, and VAC14 genes. In conclusion, variable phenotypic expressivity was seen across all families.

SUBMITTER: Taghavi S

PROVIDER: S-EPMC5683945 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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A Clinical and Molecular Genetic Study of 50 Families with Autosomal Recessive Parkinsonism Revealed Known and Novel Gene Mutations.

Taghavi Shaghayegh S Chaouni Rita R Tafakhori Abbas A Azcona Luis J LJ Firouzabadi Saghar Ghasemi SG Omrani Mir Davood MD Jamshidi Javad J Emamalizadeh Babak B Shahidi Gholam Ali GA Ahmadi Mona M Habibi Seyed Amir Hassan SAH Ahmadifard Azadeh A Fazeli Atena A Motallebi Marzieh M Petramfar Peyman P Askarpour Saeed S Askarpour Shiva S Shahmohammadibeni Hossein Ali HA Shahmohammadibeni Neda N Eftekhari Hajar H Shafiei Zarneh Amir Ehtesham AE Mohammadihosseinabad Saeed S Khorrami Mehdi M Najmi Safa S Chitsaz Ahmad A Shokraeian Parasto P Ehsanbakhsh Hossein H Rezaeidian Jalal J Ebrahimi Rad Reza R Madadi Faranak F Andarva Monavvar M Alehabib Elham E Atakhorrami Minoo M Mortazavi Seyed Erfan SE Azimzadeh Zahra Z Bayat Mahdis M Besharati Amir Mohammad AM Harati-Ghavi Mohammad Ali MA Omidvari Samareh S Dehghani-Tafti Zahra Z Mohammadi Faraz F Mohammad Hossein Pour Banafsheh B Noorollahi Moghaddam Hamid H Esmaili Shandiz Ehsan E Habibi Arman A Taherian-Esfahani Zahra Z Darvish Hossein H Paisán-Ruiz Coro C

Molecular neurobiology 20170513 4

In this study, the role of known Parkinson's disease (PD) genes was examined in families with autosomal recessive (AR) parkinsonism to assist with the differential diagnosis of PD. Some families without mutations in known genes were also subject to whole genome sequencing with the objective to identify novel parkinsonism-related genes. Families were selected from 4000 clinical files of patients with PD or parkinsonism. AR inheritance pattern, consanguinity, and a minimum of two affected individu ...[more]

PMID: 28502045

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Project description:The frequency of inherited bilateral autosomal recessive non-syndromic hearing loss (ARNSHL) in Pakistan is 1.6/1000 individuals. More than 50% of the families carry mutations in GJB2 while mutations in MYO15A account for about 5% of recessive deafness. In the present study a cohort of 30 ARNSHL families was initially screened for mutations in GJB2 and MYO15A. Homozygosity mapping was performed by employing whole genome single nucleotide polymorphism (SNP) genotyping in the families that did not carry mutations in GJB2 or MYO15A. Mutation analysis was performed for the known ARNSHL genes present in the homozygous regions to determine the causative mutations. This allowed the identification of a causative mutation in all the 30 families including 9 novel mutations, which were identified in 9 different families (GJB2 (c.598G>A, p.Gly200Arg); MYO15A (c.9948G>A, p.Gln3316Gln; c.3866+1G>A; c.8767C>T, p.Arg2923* and c.8222T>C, p.Phe2741Ser), TMC1 (c.362+18A>G), BSND (c.97G>C, p.Val33Leu), TMPRSS3 (c.726C>G, p.Cys242Trp) and MSRB3 (c.20T>G, p.Leu7Arg)). Furthermore, 12 recurrent mutations were detected in 21 other families. The 21 identified mutations included 10 (48%) missense changes, 4 (19%) nonsense mutations, 3 (14%) intronic mutations, 2 (9%) splice site mutations and 2 (9%) frameshift mutations. GJB2 accounted for 53% of the families, while mutations in MYO15A were the second most frequent (13%) cause of ARNSHL in these 30 families. The identification of novel as well as recurrent mutations in the present study increases the spectrum of mutations in known deafness genes which could lead to the identification of novel founder mutations and population specific mutated deafness genes causative of ARNSHL. These results provide detailed genetic information that has potential diagnostic implication in the establishment of cost-efficient allele-specific analysis of frequently occurring variants in combination with other reported mutations in Pakistani populations.

Dataset Information

A Clinical and Molecular Genetic Study of 50 Families with Autosomal Recessive Parkinsonism Revealed Known and Novel Gene Mutations.

Publications

A Clinical and Molecular Genetic Study of 50 Families with Autosomal Recessive Parkinsonism Revealed Known and Novel Gene Mutations.

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