Genetic Risk Factors

There are many different risk factors for childhood permanent hearing loss (PHL). More than half of all childhood hearing loss has a genetic cause. Others are environmental, such as exposure to certain infections or medications. Here are some common questions about genetic risk factor screening for PHL.

Which genetic risk factors are included in screening?

Risk factor screening for permanent hearing loss (PHL) looks for some common genetic variants (or mutations) in the genes GJB2 and SLC26A4 that can cause PHL. These variants either make the gene not work or cause it to work differently. These genes provide instructions to make proteins that are important to the development of the inner ear or cochlea. The SLC26A4 gene is also involved in the development of the thyroid gland. This gland is found in the neck region and makes important hormones the body needs.

The following table shows the specific variants included in risk factor screening for PHL.

Gene

Variants/mutations

GJB2

c.-23+1G>A p.?

c.35del p.(Gly12Valfs*2)

c.71G>A p.(Trp24*)

c.139G>T p.(Glu47*)

c.167del p.(Leu56Argfs*26)

c.235del p.(Leu79Cysfs*3)

c.231G>A p.(Trp77*)

c.269T>C p.(Leu90Pro)

c.313_326del p.(Lys105Glyfs*5)

c.427C>T p.(Arg143Trp)

GJB6 D13S1830 (342kb deletion)

c.109G>A p.(Val37Ile) (See below)

SLC26A4

c.626G>T p.(Gly209Val)

c.707T>C p.(Leu236Pro)

c.919-2A>G p.?

c.1001+1G>A p.?

c.1003T>C p.(Phe335Leu)

c.1151A>G p.(Glu384Gly)

c.1229C>T p.(Thr410Met)

c.1246A>C p.(Thr416Pro)

c.1541A>G p.(Gln514Arg)

c.1614+1G>A p.?

c.2168A>G p.(His723Arg)

Note. Since October 19, 2020, reflexive screening for the GJB2 c.109G>A p.(Val37Ile) variant has been performed for infants who have a single GJB2 variant identified on the above common variant panel. The GJB2 p.(V37I) variant is therefore only reported in compound heterozygous state with another variant on the panel. That is, homozygosity for this variant is not assessed.

Results showing two or more variants in the same gene are considered screen positive. This indicates an increased risk for permanent hearing loss (PHL).

Results showing one or no variants are considered screen negative. These results do not indicate an increased risk for PHL.

What does a positive genetic risk factor result mean?

A positive genetic risk factor screening result means that there is a high risk for PHL, because the screen found at least two variants in one of the genes tested. You will be contacted by Newborn Screening Ontario or your primary care provider if your baby has a positive genetic risk factor screening result. In this case, follow-up with an audiologist (hearing specialist) will be arranged by the Infant Hearing Program (IHP) to determine whether your baby has PHL.

How does Permanent Hearing Loss (PHL) run in families?

People can inherit hearing loss in different ways, depending on the genes and variants involved. The genetic risk factor screen specifically looks for autosomal recessive hearing loss due to selected variants (or mutations) in the GJB2 and SLC26A4 genes.

 “Autosomal” means that the variants can affect both sexes. People with only one copy of an autosomal recessive variant are not at increased risk for PHL and are called “carriers”. If two carriers have a child together, there is a 25% (1 in 4) chance that the baby will get two copies of the variant and, therefore, be at high risk for PHL.

Children’s Hospital of Eastern Ontario
415 Smyth Road
Ottawa, Ontario K1H 8M8

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