Deafness in both ears and progressive loss of vision due to retinitis pigmentosa are the indicators of Usher syndrome, a genetic dual deficit disorder. There are three clinical subtypes of Usher syndrome, the most severe of which is Usher type 1 (USH1). This syndrome involves deafness at birth, progressive blindness and balance problems. In 1861, a physician working in Berlin described the clinical features of Usher syndrome in Jewish individuals.

A significant collaboration across four institutions was led by scientists at the National Institute on Deafness and Other Communication Disorders at the National Institutes of Health including Thomas B. Friedman, Chief, Laboratory of Molecular Genetics, Tamar Ben-Yosef, the key scientist on this project, and Andrew J. Griffith. Additional collaborators on this project were Seth Ness, Mount Sinai School of Medicine, Karen Avraham at the Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, and Harry Ostrer, and Carole Oddoux at the Department of Molecular Genetics, NYU Medical Center.

Dr. Ben-Yosef identified a mutation, R245X, of an Usher syndrome type 1 gene, PCDH15, which appears to account for a large proportion of USH1 in the Ashkenazi Jewish population today. Ashkenazi describes those Jewish people who came from eastern Europe.

In earlier studies in Dr. Friedman's laboratory, a founder mutation, 167delT, was identified in the GJB2 gene, which is carried by 4% of Ashkenazi Jewish individuals. It is one of the major causes of autosomal-recessive, nonsyndromic hearing loss in the same population. Dr. Friedman hypothesized that at least one USH1 mutation, which arose in an ancestral population, is a significant cause of current USH1. Dr. Friedman noted, "Using DNA contributions from affected families in the United States and Israel, we searched for a haplotype of genetic markers closely linked to any of six reported USH1 loci in families of Ashkenazi Jewish descent."

This approach allowed identification of the R245X founder mutation. They found high carrier frequencies of R245X in the Ashkenazi Jewish population. Carriers are individuals who, although having no symptoms of the disorder, transmit their single copy of the disabled gene to their descendants.

There are no data to indicate that there is an increased frequency of Usher syndrome in this population, only that the inheritance of the disorder is more clearly identifiable. There is indication, through the study's controls of other non-Ashkenazi Jewish and non-Jewish populations, that this mutation may be unique to the Ashkenazi population.

Uncovering the R245X mutation as a significant cause of USH1 in Ashkenazi Jewish individuals, means there are diagnostic and intervention strategies that can be helpful in ameliorating the devastation of this disorder.

Molecular screening is an important tool for use with children in this population, who are born with bilateral, profound hearing loss, not associated with GJB2 mutations. From these finding, it has become clear that these children should be tested for R245X and have ophthalmologic evaluation, including funduscopic examination and electroretinography. These evaluations will detect retinitis pigmentosa at a presymptomatic state. From this early identification, the child who is an appropriate candidate and who has the ability to see and read lips for some 10-12 years pre-onset of the blindness, would be able to benefit from a cochlear implant.

A cochlear implant is a small, complex electronic device. The implant is surgically implanted under the skin behind the ear and, with the use of a highly sensitive speech processor, can provide a sense of interpretable sound to a profoundly deaf or severely hearing impaired.

Carrier screening and genetic counseling will allow parents to prepare for the educational and social needs of a child who has Usher syndrome type I and for his or her progressive loss of sight. Parents will be able to focus on communication skills that will be needed by their child.

Screening for R245X would allow additional information to be provided to individuals who will already be screened for Tay-Sachs, Gaucher and Canavan diseases as they seek to have more information about their genetic history.