The case for universal genetic hearing screening in newborns

Within the first 24 to 48 hours of life, newborn babies are tested for a comprehensive set of serious but treatable genetic and metabolic disorders. Most of these tests are done by labs using dried blood spots taken via heel prick. Babies also undergo one of two tests for hearing loss: the automated auditory brainstem response, which detects electrical activity in the brain in response to a sound stimulus, or the otoacoustic emissions test, which measures the vibrations of the inner ear’s hair cells.

Both tests, collectively referred to as physiologic hearing screening, are widely implemented — close to 96% of U.S. newborns were screened in 2022, according to data from the Centers for Disease Control and Prevention — and they catch most babies with deafness and hardness of hearing. Congenital hearing loss is by far the most commonly diagnosed condition on the newborn screening panel.

However, there are instances when current newborn screening methods fail to detect hearing impairments. For instance, babies with mild or later-onset hearing loss may present with normal hearing as newborns but then begin struggling with hearing later in childhood. This can lead to long-term social and developmental consequences.

Given these shortcomings, some experts are calling for all newborns to undergo genetic screening for hearing impairment alongside traditional physiologic testing. They argue that this will help catch more cases of hearing loss as early as possible and enable these children to receive interventions before their development is significantly affected.

The current paradigm

The Department of Health and Human Services (HHS) publishes the Recommended Uniform Screening Panel (RUSP), which advises states on which disorders they should include on their newborn screening panels. Hearing loss is one of the 37 conditions on the RUSP, and all 50 U.S states follow this recommendation.

Typically, if a newborn fails physiologic screening, they’re referred to a clinical audiology center, where more comprehensive testing is performed. This includes a blood test for cytomegalovirus infection, which can be transmitted from mother to baby during pregnancy and is responsible for about 15% of congenital hearing loss cases.

Only if the diagnosis is confirmed at this stage will the baby, in most cases, be referred for genetic screening, according to Anne Giersch, PhD, who studies hearing loss genetics at Brigham and Women’s Hospital and Harvard Medical School in Boston. There are more than 120 genes known to be associated with hearing loss, and different genes might be assessed depending on the nature of the condition. If a baby only has high-frequency deafness, for instance, it might not be relevant to look at genetic variants tied to low-frequency deafness.

Even though a diagnosis has been confirmed at this point, genetic testing remains critical because it provides information on the nature and origin of the condition and if and how it might continue to progress. “It helps predict how stable this child’s deafness is going to be,” Giersch said.

Furthermore, such testing can identify the presence of an underlying condition that might manifest in other ways in addition to hearing loss. "[This] might influence your decision on what sort of language acquisition modality the family chooses,” Giersch added. These cases are known as syndromic deafness and account for approximately 30% of all congenital cases. Usher syndrome, for example, is a rare disorder that results in vision and hearing impairment, so if it turns up in a genetic test, sign language should be ruled out as an intervention.

Similarly, there are forms of congenital deafness that affect the cochlear nerve, which would render cochlear implants ineffective.

Insights from genetic and genomic testing

Giersch and others worry that if genetic testing is administered only after a baby fails the initial physiologic screen, then those with milder forms of hearing impairment will fall through the cracks. Experts are also particularly concerned about missing late-onset deafness — hearing loss that sets in any time after birth, usually during childhood — which might be more common than congenital deafness.

“Unfortunately, the current paradigm of only doing genetic testing on babies who fail their newborn hearing screen will miss those kids with later-onset deafness,” Giersch said.

This is why the Newborn Hearing Screening Working Group of the National Coordinating Center for the Regional Genetics Networks proposed the addition of genetic testing and cytomegalovirus testing to the standard newborn screening regimen all infants undergo. Substantial evidence shows that children who receive hearing interventions before 6 months have much stronger language and speech skills — potentially on par with their hearing peers — compared with those who receive interventions later. Furthermore, this genetic screening would use the same blood spots that are already sampled for other tests on the newborn screening panel.

One of the genes that the group recommends testing for in this context is the mitochondrial gene MT-RNR1. Approximately 1 in 500 people carry a mutation in this gene that makes them sensitive to aminoglycoside antibiotics, such that exposure to the drugs could result in ear damage and hearing impairment. These antibiotics are commonly used for treating sepsis in newborns. Although it’s rare for a baby with sepsis to also carry this mutation, sequencing for this gene shortly after birth would be a relatively easy way to avoid inadvertently inducing hearing loss.

Another possibility is to sequence a baby’s entire exome or genome. Although whole exome or genome sequencing isn’t commonly done in clinical settings right now, it could prove beneficial in cases where a genetic panel doesn’t turn up anything unusual, since there may be hundreds of genes associated with deafness that haven’t been discovered yet.

“Genomic sequencing would be useful when you’ve got a very rare form of deafness and that gene is not on the panel,” Giersch said. “Or maybe it’s never been associated with deafness before.” If the baby carries an unusual variant, you might then also sequence the parents. If they don’t have the variant and are not hearing impaired, you might begin to suspect that it’s causative.

A potential model in China and obstacles in the U.S.

Thus far, evidence supporting the efficacy of newborn genetic hearing screening has come mostly from China, where several clinical trials have assessed a panel of hearing-associated genes in newborns. Across the trials, investigators looked at 20 variants in four genes and independently found that they could identify the genetic cause behind each case of a failed physiologic test. They also were able to predict which babies among those who passed physiologic testing were likely to develop later-onset deafness or hardness of hearing.

While these results are encouraging and back the idea of implementing genetic testing in newborn hearing screening, it’s unclear if they translate to American populations, which have different genetic backgrounds than those in China. To achieve similar results in the U.S., a screening panel would need to have more than four genes, which adds to the cost and complexity of interpreting the results.

Regardless, clinical studies like these, along with basic research, have informed what’s included in the RUSP.

Historically, the Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC), a volunteer group of experts convened by HHS, would make recommendations based on the latest evidence that would heavily influence updates to the RUSP. For example, 20 years ago, newborns weren’t screened for lysosomal storage diseases because these conditions weren't really detectable or treatable, which is a requirement for inclusion in the RUSP, said Dennis Dietzen, PhD, the division chief of pathology and laboratory medicine at Phoenix Children’s Hospital in Phoenix. After advances in research enabled treatments for some of these disorders, ACHDNC recommended some of them, which were added to the RUSP and are tested for today.

One could have imagined ACHDNC meeting in the not-too-distant future to weigh the merits of genetic screening for hearing loss in newborns. Unfortunately, as part of a campaign to downsize and restructure HHS, the Trump administration disbanded the committee in April, effectively freezing the RUSP as it currently is.

“To throw this committee away, it lacks a lot of foresight, in my opinion,” Dietzen said. “It’s frustrating, because medical science does not stand still.” Public health departments in every state are free to make their own decision about what’s in their panel and don’t have to follow the RUSP. “But for the most part, that committee was seen as an unconflicted panel of experts, and their recommendations were usually adopted without much controversy,” Dietzen noted. If the RUSP no longer undergoes continuous updates, states will be left without an important standard for care, potentially leading to health disparities.

“Every baby born in every state ought to be treated in the same way — that was the whole idea behind forming this group in the first place,” Dietzen added.

In spite of the loss of ACHDNC, there are still reasons to be optimistic about the advancement of newborn hearing screening. More clinical trials that take a look at genetic testing are underway and the early data is positive. This is the first step toward making universal genetic hearing screening a reality — and giving children with hearing challenges a better chance at the best possible outcomes.

Yaakov Zinberg is a writer based in the Boston area. +Email: [email protected]

Read the full September-October issue of CLN here.