Genomic rearrangements of the PRPF31 gene account for 2.5% of autosomal dominant retinitis pigmentosa.

PURPOSE: To determine whether genomic rearrangements in the PRPF31 (RP11) gene are a frequent cause of autosomal dominant retinitis pigmentosa (adRP) in a cohort of patients with adRP. METHODS: In a cohort of 200 families with adRP, disease-causing mutations have previously been identified in 107 families. To determine the cause of disease in the remaining families, linkage testing was performed with markers for 13 known adRP loci. In a large American family, evidence was found of linkage to the PRPF31 gene, although DNA sequencing revealed no mutations. SNP testing throughout the genomic region was used to determine whether any part of the gene was deleted. Aberrant segregation of a SNP near exon 1 was observed, leading to the testing of additional SNPs in the region. After identifying an insertion-deletion mutation, the remaining 92 families were screened for genomic rearrangements in PRPF31 with multiplex ligation-dependent probe amplification (MLPA). RESULTS: Five unique rearrangements were identified in the 93 families tested. In the large family used for linkage exclusion testing, an insertion-deletion was found that disrupts exon 1. The other four mutations identified in the cohort were deletions, ranging from 5 kb to greater than 45 kb. Two of the large deletions encompass all PRPF31 as well as several adjacent genes. The two smaller deletions involve either 5 or 10 completely deleted exons. CONCLUSIONS: In an earlier long-term study of 200 families with adRP, disease-causing mutations were identified in 53% of the families. Mutation-testing by sequencing missed large-scale genomic rearrangements such as insertions or deletions. MLPA was used to identify genomic rearrangements in PRPF31 in five families, suggesting a frequency of approximately 2.5%. Mutations in PRPF31 now account for 8% of this adRP cohort.

Lack of an association between the angiotensin-converting enzyme insertion/deletion polymorphism and intracranial aneurysms in a Caucasian population in the United States.

OBJECT: The identification of polymorphisms associated with an increase in the risk of developing disease is integral to the development of genetic biomarkers to identify individuals at risk. Based on reports indicating a role for angiotensin-converting enzyme (ACE) in the pathogenesis of intracranial aneurysms (IAs) as well as hypertension, an independent risk factor for IAs, the authors investigated the association between an insertion/deletion (I/D) polymorphism in the ACE gene and IAs in a Caucasian population in the US. METHODS: The patient population consisted of 162 randomly selected Caucasian patients who underwent surgical repair of an IA at Memorial-Hermann Hospital (Houston, TX) and had no family history of the disease. The ACE I/D polymorphism was typed using polymerase chain reaction amplification of genomic DNA, and allele and genotype frequencies were compared between the patients with IAs and 143 healthy Caucasian volunteers (control group) by performing logistic regression and chi-square tests. The ACE I/D allele frequencies did not differ significantly between the patient and control populations. There were similar allele and genotype frequencies in male and female study participants in both patient and control populations. The authors found no evidence of an association between the allelic or genotypic distribution of the ACE I/D polymorphism and aneurysmal subarachnoid hemorrhage or unruptured IAs. CONCLUSIONS: Contrary to findings in two European Caucasian populations (one British and one Polish), this polymorphism did not contribute to the risk of developing IAs in a Caucasian population in the US.