Abstract:
Inherited hearing loss is a genetically heterogeneous disease. Screening patients to detect
genes and mutations represents a major challenge. Next generation sequencing is used to
overcome this challenge. The primary purpose of this study is to determine the causative
gene and mutation in a Palestinian family with congenital recessively inherited hearing
loss in three siblings.
The proband was screened for all know mutations causing hearing loss among Palestinian
populations. Then, her DNA was subjected to massively parallel sequencing of targeted
genomic capture of all suspected hearing loss genes and loci. The data were filtered and
analyzed and the mutation was validated via Sanger sequencing and we fully checked its
co-segregation with the disease in the affected family. The mutation was further
confirmed by testing 100 normal and 263 hearing loss Palestinian controls and
functionally validated to determine the effect of the mutation on mRNA level.
We identified a novel exonic splicing mutation in GPR98 gene. It causes the transition of
the last nucleotide of exon 49 from G (Guanine) to A (Alanine) at chr5: 90024750. The
novel mutation is private to the tested family and it was not detected in tested controls.
This mutation leads to abnormal splicing of exon 49. We predicted that it would lead to
translation of truncated GPR98 message with a deletion of highly conserved EPTP
domain in addition to partial deletion of EAR (3, 4, and 5) repeats.
GPR98 gene is involved in Usher syndrome type 2. Therefore, it is possible that
congenital hearing loss in our family is due to Usher syndrome and may develop Retinitis
Pigmentosa later in their life. However, symptoms of Retinitis Pigmentosa are still absent
in the two elder adolescent sisters and it is likely that this is nonsyndromic condition.
Keywords: Hearing loss, next generation sequencing, heterogeneous, consanguineous,
Usher syndrome type 2, Gpr98 gene.
