Genetic Testing Leading to Early Identification of Childhood Ocular Manifestations of Usher Syndrome

Abstract

Objectives: Hearing-loss gene panel testing (HLGPT) is increasingly accessible as a first-line test in determining the etiology of sensorineural hearing loss (SNHL) in children. A major advantage of HLGPT is early identification of syndromic forms of SNHL, especially Usher syndrome, prior to the development of overt syndromic phenotype, which may impact management and counseling. Here, we describe early ocular findings in children with clinically non-syndromic SNHL identified by HLGPT as having two variants associated with Usher Syndrome.Methods: A total of 184 children, ages 1 month -15 years of age, evaluated at one tertiary pediatric children's hospital for clinically non-syndromic SNHL, underwent next-generation sequencing of 150 genes involved in hearing loss. Children with two variants in genes associated with Usher syndrome were referred for evaluation by pediatric ophthalmology.Results: A total of 18/184 tested children had two variants in Usher syndrome-associated genes, including MYO7A, GPR98 (ADGRV1), USH2A, and PDZD7. SNHL varied from moderate to profound. 29% of the children who underwent clinical ophthalmology evaluation were found to have previously unidentified retinal abnormalities on retinal imaging or electroretinography consistent with inherited retinal degeneration.Conclusion: Among this ethnically and racially diverse pediatric population with apparently non-syndromic SNHL, HLGPT yielded a high proportion (10%) of children with two variants in genes associated with Usher syndrome. Early genetic testing allows early identification of variants conferring a diagnosis of Usher syndrome at a stage prior to visual symptoms. This allows for more informed genetic counseling, reproductive planning, and sensory deficit interventions.

Racial and ethnic disparities in genetic testing for hearing loss: a systematic review and synthesis

“…Sensorineural hearing loss (SNHL) is the most common congenital sensory disorder, affecting 1 in 500 newborns, and over 80% of those 85 years of age and older (Morton and Nance 2006;Fortnum et al 2001). Identifying a genetic etiology of hearing loss provides valuable prognostic information, allows early detection of syndromic forms of SNHL prior to overt syndromic phenotypes, and facilitates timesensitive counseling (Kimberling et al 2010;Brodie et al 2020;Shearer et al 2019). Establishing etiologic diagnoses for deafness, however, is challenging due to the multitude of potential causes, clinical variability, phenotypic overlap and genetic heterogeneity of hearing loss (Hilgert et al 2009).…”

Hearing Screening Combined with Target Gene Panel Testing Increased Etiological Diagnostic Yield in Deaf Children

“…Furthermore, in adolescents, it will rise to 3.5/1000 [1][2][3]. According to the latest date, approximately 50%-60% of congenital HL is caused by genetic factors [4,5]. However, genetic disorder can also cause late-onset deafness in children and adolescents [2].…”

“…Besides, genetic testing was beneficial to protecting children with some variants such as m.1555A > G or variants in KCNQ1 gene from avoidable risk factors [9][10][11][12]. DNA sequencing first described 44 years ago has evolved from single-mutation sequencing (Sanger sequencing) to high-throughput sequencing (Next generation sequencing, NGS) [5,13]. Compared to Sanger sequencing, NGS was able to simultaneously sequence millions of small fragments at a reasonable cost and reduced runtime [13].…”

Racial and Ethnic Disparities in Genetic Testing for Hearing Loss: a Systematic Review and Synthesis

“…1,2 Identifying a genetic etiology of hearing loss provides valuable prognostic information, allows early detection of syndromic forms of SNHL prior to overt syndromic phenotypes, and facilitates time-sensitive counseling. [3][4][5] Establishing etiologic diagnoses for deafness, however, is challenging due to the multitude of potential causes, clinical variability, phenotypic overlap and extreme genetic heterogeneity of hearing loss. 6 The advance of nextgeneration sequencing (NGS) technologies has made genetic testing cost-effective, increasing availability of testing and transforming clinical diagnostic practice.…”