From the Guidelines
GJB2 and ZDHHC9 mutations are significant genetic causes of binaural sensorineural hearing loss, with GJB2 mutations being the most common cause of congenital hearing loss worldwide, accounting for up to 50% of autosomal recessive non-syndromic hearing loss, as reported in a 2022 study by the American College of Medical Genetics and Genomics 1.
Key Points
- GJB2 mutations affect the gene encoding connexin 26, disrupting the formation of gap junctions in the cochlea and preventing proper potassium ion recycling essential for normal hearing function 1.
- GJB2-related hearing loss is typically non-progressive, bilateral, and ranges from mild to profound in severity, with more than 150 deafness-causing variants identified in the GJB2 gene 1.
- ZDHHC9 mutations are less common but notable for causing X-linked intellectual disability with sensorineural hearing loss, with the ZDHHC9 gene encoding a palmitoyltransferase enzyme that regulates protein trafficking and function in neurons 1.
- For patients with suspected genetic hearing loss, comprehensive genetic testing is recommended for accurate diagnosis, as outlined in the 2022 clinical practice resource by the American College of Medical Genetics and Genomics 1.
Importance of Early Diagnosis
- Early identification of genetic hearing loss allows for timely intervention with hearing aids or cochlear implants, which is crucial for language development in children, as emphasized in the 2022 study 1.
- Genetic counseling is also important for affected individuals and families to understand inheritance patterns and recurrence risks for future pregnancies, with the goal of enabling implementation of an individualized health maintenance strategy 1.
Genetic Testing and Counseling
- The diagnostic yield of comprehensive HL NGS panels that cover all genes known to be associated with nonsyndromic HL and more common syndromic HL is approximately 40%, as reported in the 2022 study 1.
- Genome-wide sequencing such as exome sequencing (ES) and genome sequencing (GS) have reported diagnostic yields between 30% and 35% for ES, highlighting the importance of comprehensive genetic testing for accurate diagnosis 1.
From the Research
Gjb2 Mutations and Binaural Sensorineural Hearing Loss
- Gjb2 mutations are a common cause of non-syndromic sensorineural hearing loss, accounting for approximately 30% of all cases of childhood sensorineural hearing loss 2.
- Studies have shown that Gjb2 mutations can result in progressive hearing loss, with losses of more than 10 dB per decade 3, 4.
- The phenotypic spectrum of Gjb2-related disease has been extended to include progressive hearing loss and recurrent sudden sensorineural hearing loss 4.
- Gjb2 mutations have been associated with a broad spectrum of hearing loss, from mild to profound, and can occur in both syndromic and non-syndromic forms 2.
Zdhhc9 Mutations and Binaural Sensorineural Hearing Loss
- There is no direct evidence in the provided studies to suggest that Zdhhc9 mutations are significant for binaural sensorineural hearing loss.
- However, studies have shown that mutations in other genes, such as MYO6, OTOA, SLC26A4, and TMPRSS3, can also cause sensorineural hearing loss 3.
Genetic Diagnosis and Treatment
- Genetic diagnosis can inform the progression of hearing loss, indicate potential syndromic features, and suggest the best timing for individualized treatment 3.
- Next-generation sequencing-based diagnostic panels can be used to confirm the genetic diagnosis in patients with nonconfirmative Gjb2 genotypes on conventional genetic examinations 5.
- Clarifying the pathological mechanism of Gjb2-related hearing loss can help develop new prevention and treatment strategies 6.