Mutations In Cohort Research Articles

Prevalence of myocilin gene mutations in a novel UK cohort of POAG patients

To identify the prevalence of myocilin gene mutations in a UK glaucoma cohort. Primary open-angle (POAG) and normal tension glaucoma patients were recruited from the Southampton University Hospital Trust Eye Clinic and satellite regional glaucoma clinics. Phenotype data relating to disease history and other potential risk factors were recorded and blood samples collected for each consenting participant. Point mutation analysis of the myocilin gene was carried out using six overlapping PCR fragments covering the entire coding sequence of the gene. A total of 316 POAG samples were examined of which 7 (2.2 %) tested positive for disease-causing mutations in this gene. One of these seven non-synonymous mutations represented a previously unreported amino-acid substitution of cysteine for arginine at codon 296 (p.R296C) of the myocilin protein. This study identifies a 2.2% prevalence of myocilin mutations in a cohort of ethnically homogenous glaucoma patients selected from a UK ophthalmic clinic. A novel myocilin mutation is also described. This study identifies that myocilin genetic screening is feasible in NHS glaucoma clinics for genetic counselling and cascade testing of relatives of patients affected by myocilin glaucoma.

The Need for Appropriate Genotyping Strategies for Glucocerebrosidase Mutations in Cohorts With Parkinson Disease

The article by Tan et al1 reporting mutations in the glucocerebrosidase gene (GBA) in Chinese patients with Parkinson disease (PD) is the third recent article in series of patients of Chinese ancestry.1–3 These studies are important because they support the previously described association of GBA mutations and par-kinsonism in white and Ashkenazi Jewish PD cohorts4,5 in a population that is clearly of non–Ashkenazi Jewish ancestry. Tan and colleagues chose to screen for only 2 GBA mutations, L444P and N370S. While both of these mutations are relatively common in white and Ashkenazi Jewish populations, the N370S mutation has not been reported in Asian patients with Gaucher disease.6 Thus, the frequency of GBA mutations reported in this article, 2.4%, is likely to be a vast underestimate. In a larger cohort, Wu et al2 screened 518 Taiwanese patients with PD for 2 GBA mutations, L444P and R120W. They identified L444P in 15 patients (2.9%) and in 4 of 339 control subjects (1.2%), with the L444P mutation being part of a recombinant allele, RecNciI, in 2 patients and 2 control subjects. One patient had an R120W mutation. We have sequenced GBA in 184 Chinese subjects with PD from Taiwan (92 of these were described previously3) and identified 7 different mutations in a total of 10 subjects (5.4%) (Table). Four L444P alleles (2.2%) and no N370S alleles were found. Only 1 mutation, V460M, was identified among 92 Taiwanese control samples (1.1%).3 Thus, while the article by Tan and colleagues probably accurately reflects the frequency of L444P among Chinese subjects with PD, our sequencing study indicates that by merely screening for this mutation, at least half of the mutant alleles may be missed in this population. Although direct sequencing is a more labor-intensive means to identify mutant alleles, we feel that it is essential in order to identify the true mutation frequency in a non–Ashkenazi Jewish cohort. Table Glucocerebrosidase Gene Mutations Identified in 184 Taiwanese Patients With Parkinson Disease

Postmortem molecular analysis of KCNQ1 and SCN5A genes in sudden unexplained death in young Australians

The cause of sudden death in young people remains unknown in up to 50% of postmortem cases. Mutations in the ion channel genes are known to cause primary arrhythmogenic disorders such as long QT and Brugada syndromes, which can present with sudden cardiac death and a negative autopsy. In this study, 59 sudden unexplained deaths occurring in Australians aged ≤ 35 years with a negative autopsy, from 1994–2002, were studied. Genomic DNA was extracted from paraffin-embedded tissues. Genetic analysis of the KCNQ1 and SCN5A genes was performed using denaturing high-performance liquid chromatography and direct DNA sequencing. Nine DNA sequence variants were identified in the KCNQ1 gene and 9 sequence variants were identified in the SCN5A gene. In total, 23 out of 59 cases were found to have at least one DNA variant in KCNQ1 or SCN5A, of which one, H558R in the SCN5A gene, caused an amino acid substitution. None of the DNA variants were determined to be disease causing as they were also identified in control populations. In conclusion, no disease-causing mutations were found in the KCNQ1 or SCN5A genes in this cohort. A more selective screening approach, including only individuals with a clinical or family history of arrhythmogenic disorders, may yield greater success in identifying disease-causing mutations in cohorts of young individuals who have died suddenly.

Racial differences in the incidence of BRCA1 and BRCA2 mutations in a cohort of early onset breast cancer patients: African American compared to white women

Purpose: To evaluate the frequency and distribution of BRCA1 and BRCA2 mutations in a cohort of young women with breast cancer and to compare the distribution of mutations as a...