Tel Aviv Researchers Identify New Gene Responsible for Inherited Hearing Loss in the Jewish Population of Israel

“Hear, O Israel…” (Shma Yisrael) is a prayer recited in the morning and evening that encapsulates the monotheistic essence of Judaism. According to tradition, parents teach their children to say it before they go to sleep at night. 

But not all Jews can actually hear. Until now, mutations in seven genes responsible for inherited hearing loss have been observed in the Jewish population of Israel. Just-published research in the journal Clinical Genetics was led by Dr, Zippora Brownstein and Prof. Karen Avraham from the Sackler Faculty of Medicine at Tel Aviv University (TAU). They found that a total of 32 genes are involved in hearing loss in Jewish families. This remarkable increase has immediate implications for genetic counseling and care for hearing loss.

The discovery has immediate implications for genetic counseling, which can enable families to prevent additional cases of hearing loss through pre-gestational genetic diagnosis (PGD) and in-vitro fertilization (IVF). Comprehensive sequencing enables well-informed genetic counseling and clinical management by medical geneticists, otolaryngologists, audiologists and speech therapists and can be integrated into newborn screening for deafness.

In addition, for many families, treatment and rehabilitation for hearing loss can be tailored to the family’s specific mutation. The findings of this study allow doctors and audiologists in Israel to provide personally tailored treatment to patients with inherited hearing loss.

Entitled “Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene,” the research was carried out in cooperation with scientists from multiple Israeli universities and hospitals, and from the University of Washington in Seattle, the U.S. National Institutes of Health (NIH), Bethlehem University, the University of Iceland, and the University of Maryland. The researchers also identified a mutation in a gene not previously recognized to cause hearing loss in humans. 

One such gene, called ATOH1, was found for the first time to be involved in human hearing loss. An Israeli family is the first known to carry a mutation in this gene as the cause of their hearing loss. These results have immediate implications for genetic counseling for families with hearing loss and for care of children with hearing loss.  

More than 150 genes are known to science as being involved in hearing loss. Genetic diagnoses for inherited hearing loss have previously been difficult, both around the world and in Jewish communities because any one of so many different genes and any of many mutations in each gene could be responsible. 

Until now, mutations in only seven of the 150 genes had been detected among persons with hearing loss in the Jewish population of Israel. In the TAU study, which included 88 Israeli families with hearing loss, the researchers identified mutations in 25 additional genes. 

Although 24 of the 25 genes are known to cause hearing loss in families around the world, most of the specific mutations in Israeli Jewish families are newly observed and thus far known only in the Jewish population.  The 25th gene – ATOH1 – was found for the first time to cause hearing loss in humans. 

“We know that ATOH1 has an important role in the ear,” said Avraham. “Without it, hair cells of the inner ear – the cells responsible for our hearing – cannot develop properly. Until now, a mutation in this gene was identified only in mice, and the mice had a hearing loss. We found a similar mutation in relatives with hearing loss in a large family in Israel – the first people in the world known to have a mutation in this gene. I believe we will find more families, both in Israel and abroad, with mutations in this gene that cause hearing loss. The goal is that with this information, new treatment possibilities for people with hearing loss will be developed – including gene therapy.” 

Centuries of endogamy (marrying only within the limits of a local community, clan or tribe) led to high frequencies of recessive genetic traits. The researchers noted that a few years after the State of Israel was founded, high rates of consanguineous marriage (inbreeding, marriage of first- or second- cousins) were observed, with the lowest rate (2.5%) among Ashkenazi Jews, and higher rates among non-Ashkenazi Jews, with 29% among Jews from Iraq. Since then, marriages between various Jewish ethnic groups have become frequent, and consanguineous marriages are much less common.

Brownstein and Avraham surveyed Jewish families throughout Israel with all types of hearing loss, from congenital to older age at onset and from moderate to profound. “Our survey exploited advanced gene sequencing technology, including a custom gene panel that we created, called HEar-Seq. This custom gene panel allowed us to simultaneously sequence all 150 genes known to be involved in hearing loss, and many “candidate genes” as well,” recalled Avraham. “HEar-Seq revealed the distribution of genes and their mutations responsible for hearing loss in all the Jewish communities that make up modern Israel. It led us to ATOH1.” 

The study was funded by the US National Institute of Deafness and Communication Disorders in the National Institutes of Health, the Israel Precision Medicine Program of the Israel Science Foundation, the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine, the Hedrich Charitable Trust, and travel grants from the University of Washington Virginia Bloedel Hearing Research Institute.

Meanwhile, Bethlehem University Prof. Moien Kanaan, working with  TAU Prof. Karen Avraham and Prof. Mary-Claire King, world-renowned geneticist at the department of genome sciences and the University of Washington’s School of Medicine in Seattle, headed a team that conducted a new genomic analysis of inherited hearing loss among Palestinians. Working with colleagues at Bethlehem University Led by Amal Abu-Raayan, they studied 2,198 individuals from 491 families from all parts of Judea and Samaria and Gaza. 

The current Palestinian population in Judea and Samaria and Gaza is about 5.1 million persons, including 3.2 million residents of Judea and Samaria and 1.9 million residents of Gaza.

They estimated that in Palestinian families with no prior history of deafness, 56% of hearing loss was due to genes and 44% was not. For the great majority (87%) of families with inherited hearing loss, DNA sequencing and other techniques made it possible to identify the genetic mutations causing hearing disability in this population. 

More than half of the deafness in the Palestinian population is due, they said, to inbreeding, which remains common but is declining in this sector – from more than 40% of marriages between 1948 and

1959 to 24% of marriages between 2005 and 2009. “Given the ongoing decline in consanguineous marriage, inherited hearing loss will likely be much rarer in the next generation,” they declared in their article. 

In the short term, identification of the genetic cause of hearing loss in a child makes it possible for parents to anticipate possible progression of the symptoms, while hearing specialists can also judge the potential effectiveness of cochlear implants to improve their hearing and to choose embryos through PGD and IVF to avoid the birth of deaf children. 



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