A Molecular Screening Test for Usher Syndrome

Abstract

Purpose: : Usher syndrome (US) is the main cause of combined deaf/blindness in the world. Early diagnosis of Usher syndrome promises benefits for early rehabilitation, education and family planning, and provides the basis for natural history studies. However, current approaches for screening children are expensive and have limited sensitivity. An inexpensive DNA based screening to detect US in high risk children is urgently needed.

Methods: : The screening test was developed using the Applied Biosystems SNPlex^TM platform and is directed against 95 recurring mutations observed in the Usher genes. Specificity of the test was determined using controls with the known mutations. Sensitivity was determined in 250 subjects across three phenotypic groups: hearing impaired with RP, ARRP alone, and hearing loss alone.

Results: : Specificity was determined to be 93%. The sensitivity was 98%. The theoretical detection rate was estimated to be 52% but the observed detection rate was 42%. The detection rate varied depending upon the phenotype of the subject referred for testing.

Conclusions: : Newborn hearing screening programs now routinely identify very young children at high risk for US. The integration of US testing and tests for other genetic causes of hearing loss into newborn hearing screening programs has great potential to benefit Usher patients and their families. However, a major obstacle to US screening has been cost. This DNA screening test effectively addresses that issue. Other costs associated with screening will need to be also considered: positive results require follow up to confirm the existence and phase of mutations by conventional DNA sequencing; clinical testing of retinal function is required to confirm the diagnosis at the phenotypic level. This tiered approach reduces the cost of screening to a manageable level making possible large scale screening projects to detect US children at the earliest stages of their RP. In addition to providing useful information to caregivers and educators of the deaf and hard of hearing, screening programs could provide subjects suitable for natural history studies to identify differences in the early development of RP on a genotype specific basis.

Keywords: gene screening • clinical (human) or epidemiologic studies: systems/equipment/techniques • retina