Comprehensive Gene Panel Testing for Hearing Loss in Children: Understanding Factors Influencing Diagnostic Yield.
Nobuko Yamamoto1, Jorune Balciuniene2, Tiffiney Hartman3
1Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Roberts Individualized Medical Genetics Center (RIMGC), Children's Hospital of Philadelphia, Philadelphia, PA; Division of Otolaryngology, Department of Surgical Specialties, National Center for Children's Health and Development, Tokyo, Japan; Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.
Comprehensive gene panel testing (CGPT) for childhood hearing loss (HL) has a 44% diagnostic yield. Further genetic testing can help diagnose cases initially missed by CGPT, especially in children with developmental delays.
Area of Science:
- Genetics
- Pediatrics
- Otolaryngology
Background:
- Hearing loss (HL) is a common congenital disorder with a significant genetic component.
- Comprehensive gene panel testing (CGPT) is increasingly utilized for diagnosing the genetic causes of childhood-onset HL.
- Identifying genetic etiologies is crucial for understanding disease mechanisms and guiding clinical management.
Purpose of the Study:
- To determine factors influencing the diagnostic yield of CGPT in pediatric hearing loss.
- To characterize probands with hearing loss who remain undiagnosed after CGPT.
- To evaluate the utility of follow-up genetic testing for initially inconclusive cases.
Main Methods:
- Retrospective cohort study of 474 children with hearing loss undergoing CGPT.
- Analysis of clinical variables associated with diagnostic yield.
- Assessment of genetic and clinical characteristics of undiagnosed probands.
- Follow-up studies and exome sequencing for initially inconclusive or undiagnosed cases.
Main Results:
- Overall diagnostic yield of CGPT was 44% (209/474), identifying variants in 41 genes.
- Higher yield observed in congenital, bilateral, and severe HL; lower yield in unilateral, noncongenital, mild HL, cochlear nerve deficiency, preterm birth, NICU admission, certain ancestries, and developmental delay.
- Follow-up studies on 49 initially inconclusive cases yielded positive or negative results in 80% (39/49).
- Exome sequencing in 128 undiagnosed probands identified genetic findings in 8 individuals (6.25%), particularly those with developmental delays.
- Of 255 undiagnosed probands, 173 had a single variant in autosomal recessive HL genes, with 28% showing a matched phenotype.
Conclusions:
- CGPT is an effective tool for identifying genetic causes of hearing loss in children.
- Children with initially negative or inconclusive CGPT results may benefit from further genetic investigations, including exome sequencing.
- Understanding factors associated with low diagnostic yield can help refine genetic testing strategies for pediatric hearing loss.
