Comprehensive Screening of Causative Genes for Sporadic or Non-Mendelian Patients With Retinitis Pigmentosa

Abstract

Purpose: : More than half of the retinitis pigmentosa (RP) cases are genetically simplex or multiplex. To date, 37 causative genes of RP have been identified; however, the elucidation of gene defects in simplex or multiplex RP patients/families remains problematic. The aim of our study was to identify the genetic causes of RP in patients with unknown or non-Mendelian inheritance.

Methods: : Since 2003, 52 simplex (sporadic) RP patients, 151 patients from 141 multiplex (non-Mendelian inheritance) RP families, 6 sporadic patients with retinal degeneration were studied. A total of 108 exons of 30 RP-causing genes that harbored the reported mutations were screened by an efficient denaturing high-performance liquid chromatography (dHPLC)-based assay. Aberrant fragments were subsequently analyzed by automatic sequencing.

Results: : Twenty-six mutations, including 2 frameshift mutations, one single amino acid deletion, and 23 missense mutations, were identified in 28 probands (14.07%). Eighteen mutations have not been reported to date. Three pairs of combined mutations in different genes were identified in 2 sporadic cases and 1 multiplex family, indicating the possibility of novel digenic patterns.

Conclusions: : We elucidated the mutation spectrum in Japanese RP patients and demonstrated the validity of the mutation detection system using dHPLC-sequencing for genetic diagnosis in RP patients independent of familial incidence, which may provide a model strategy for identifying genetic causes in other diseases linked to a wide range of genes.

Keywords: gene screening • mutations • retinal degenerations: hereditary