Genetics of Hearing Loss

Key Points

  • More than half of childhood hearing loss is genetic
  • Any child with sensorineural hearing loss (SNHL) should have a genetic evaluation
  • Approximately 70% of genetic hearing loss is nonsyndromic
  • In most cases of genetic hearing loss, there is no family history
  • The most common cause of congenital nonsyndromic SNHL is mutations in the GJB2 (connexin 26) gene
  • Symptoms like vision loss, thyroid problems, fainting episodes, pigmentary abnormalities, and hematuria may be indications that hearing loss is part of a genetic syndrome
  • Clinical genetic testing is available for several genes associated with syndromic and nonsyndromic hearing loss
  • Genetic counseling is highly recommended for individuals and families before and after pursuing genetic testing for hearing loss
  • The prevalence of congenital (present at birth) hearing loss is estimated at 1.4 in 1000 births and 3.5 per 1000 by adolescence making it the most frequently occurring birth defect
  • Genetic causes contribute to a child's hearing loss in ~50% of the cases
  • Half on nonsyndromic recessive hearing loss is caused by mutations in the GJB2 gene, which encodes the connexin 26 protein (Cx26)

Basic Genetics and Inheritance Patterns

  • There are 23 pairs of chromosomes in each cell​
  • Genes are segments of the chromosome that provide the body with instruction for growth, development and function
  • The two copies may differ from each other; the different versions are called variants; mutations
  • Some genetic conditions arise when only one copy of a gene is altered
    • this is referred to as a dominant genetic condition as the altered gene "dominates" over the other (normal) copy
    • Dominance: Every child of that person will have a 50% (1 in 2) chance of having the mutation and therefore the condition
  • Recessive arise when both copies of a gene are the same variant
    • Carriers are not affected by the condition
    • Each child has a 25% (1 in 4) chance of having the condition and a 50% chance of being an unaffected carrier
  • If something is said to be inherited it means as it is passed on from one or both parents to the child, though parents or other family members may not be clinically affected
  • Inheritance on any chromosome other than sex chromosomes is said to be autosomal​

Causes of Permanent Hearing Loss

  • There are many causes of permanent hearing loss, which can be broadly grouped into genetic and non-genetic etiologies
  • Historical estimates indicate that approximately half of children identified with a permanent hearing loss have a genetic cause
  • Genetic causes of hearing loss may be classified as syndromic or non-syndromic
  • Approximately 1/3 of genetic hearing loss is syndromic indicating that it is associated with medical problems
  • ~77% of cases of hereditary hearing losses are recessive, 22% are dominant, and 1% are X-linked
  • Less than 1% represents those families with mitochondrial inheritance in which the trait is passed through the maternal lineage
  • In all cases of genetic or "inherited" hearing loss, the genetic variant is present in every cell of a child at birth
  • The hearing loss may not begin until late childhood or adulthood
  • A large proportion (77%) of non-syndromic genetic hearing loss is recessive, where each parent is a carrier of a mutation but has normal hearing
  • At least 90% of children born with a hearing loss are born to parents with normal hearing
  • A genetic evaluation is a very important part of the child's workup and is recommended for all children with sensorineural hearing loss (SNHL)
  • A complete review of the child's medical and developmental histories and a complete physical and dysmorphology examination are necessary to identify specific risk factors as well as clinical findings that may indicate a syndromic form of hearing loss
  • Currently, more than 500 genes have been identified and found to be associated with syndromic and non-syndromic forms of hearing loss

Nonsyndromic Genetic Hearing Loss

  • Most genetic hearing loss is non-syndromic
  • The diagnosis of vestibular problems is often challenging, especially at young ages
  • An early clue to vestibular problems can be a delay in walking
  • There is immense genetic heterogeneity in non-syndromic forms of hearing loss
  • 120 independent loci for non syndromic hearing loss
  • In general, autosomal recessive forms of hearing loss are usually pre-lingual and autosomal dominant ones often result in progressive, post-lingual hearing loss

Connexin Hearing Loss

  • DFNB1 was the first recessive hearing loss locus identified in 1994 and the responsible gene GJB2 encodes the gap junction b2 protein, known as connexin 26
  • 12 to 24% of permanent childhood SNHL