Hearing impairment is the most frequent sensory deficit in humans. It affects 1 in 500 newborns and 50% of octogenarians and in aggregate affects 360 million people worldwide. Dramatic progress has been made in our understanding of the biology of hearing and deafness through the identification of more than 90 genes. This genetic heterogeneity made comprehensive genetic screening using targeted genomic enrichment and massively parallel sequencing a mandatory approach for molecular diagnosis to minimize the labor, cost and turnaround time. In our lab we have developed OtoSCOPE; a next-generation sequencing platform.
OtoSCOPE ® (version 8) simultaneously screens 152 genes and microRNAs known to cause non-syndromic sensorineural hearing loss, Alström, BOR, Jervell and Lange Nielsen, Pendred, Usher and Wolfram syndromes, or other hearing loss-related phenotypes by using custom-targeted sequence capture for DNA enrichment followed by massively parallel DNA sequencing. Data analysis (including deletion/duplication analysis) is performed and results are discussed at a multidisciplinary meeting. Each patient's variants are discussed individually and in the context of their unique clinical information to provide the most comprehensive diagnosis possible. These meetings are attended by clinical experts, research scientists, bioinformaticians and genetic counselors.
Indications for testing: OtoSCOPE ® testing is recommended for patients with both recessive and dominant forms of hearing loss as well as for patients with suspected Alström, BOR, Jervell and Lange Nielsen, Pendred, Usher and Wolfram syndromes.
OtoSCOPE ® is not recommended for patients with unilateral hearing loss.
Usher Syndrome Panel testing looks for single nucleotide variation and copy number variation of the following genes: CDH23, CIB2, CLRN, GPR98, MYO7A, PCDH15, USH1C, USH1G, USH2A and WHRN (DFNB31).
Indications for testing: Usher Syndrome Panel testing is appropriate for patients with sensorineural hearing loss and either delayed motor milestones or possible onset of retinitis pigmentosa.
GJB2/GJB6 testing includes sequencing of GJB2 plus an assay to detect the two large deletions that include a portion of GJB6. GJB2 encodes the protein CONNEXIN 26 and GJB6 encodes the protein CONNEXIN 30. Variants in these genes are responsible for autosomal recessive non-syndromic hearing loss at the DFNB1 locus. Variants in GJB2 can also cause autosomal dominant non-syndromic hearing loss at the DFNA3 locus and keratitis-ichthyosis-deafness syndrome (KID).
Indications for testing: GJB2 mutation screening is appropriate in all persons with congenital hearing impairment and a negative or recessive family history. GJB2 mutations are the most common cause of hearing loss.
MTRNR1 testing looks for the C1494T and A1555G variants of the 12S rRNA gene.
Indications for testing: MTRNR1 testing is appropriate if aminoglycoside-induced ototoxcicity is suspected.
MTTL1 testing looks for the A3243G mutation that causes MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like epsides).
Indications for testing: MTTL1 testing is appropriate for a patient suspected of having maternally inherited diabetes mellitus and sensorineural hearing loss.
MTTS1 testing looks for the A7445G mutation in the MTTS1 gene, which is associated with maternally inherited, nonsyndromic hearing loss.
Indications for testing: MTTS1 testing is appropriate for a patient suspected of having maternally inherited high frequency hearing loss.