EURETINA 2024: Unraveling the genetic spectrum of combined retinal dystrophy and hearing impairment
Researchers in Portugal investigated Usher syndrome, Senior-Loker syndrome and other ciliopathies
(Image credit: AdobeStock/dmytro_khlystun)
João Pedro Marques, MD, MSc, PhD, FEBOphth, and colleagues investigated the genetic spectrum of retinal dystrophy and hearing loss in Portugal. While Usher syndrome is the most common cause, he and his team identified several other less frequent causes that should be considered in the diagnosis. Dr Marques is the senior study author from the Hospitais da Universidade de Coimbra, Coimbra, Portugal.
Other inherited causes of deafness and blindness, they explained, may present with retinal phenotypes and hearing impairment that may overlap with Usher syndrome, including other ciliopathies, eg, Senior-Loker syndrome; cone-rod dystrophy and hearing loss; or polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract (PHARC) syndrome. “A timely and accurate diagnosis is essential to provide each patient and their family with genetic counseling, prognostic information, and appropriate resources,” Dr Marques emphasised.
The investigative team conducted a cross-sectional study at a tertiary care hospital in Portugal. Patients were included in the study who had a clinical diagnosis of an inherited retinal disease and hearing impairment up to November 2023, and were identified through the national, web-based inherited retinal dystrophies registry (IRD-PT, retina.com.pt).
The investigators collected the patientdemographics, clinical, and genetic data from each patient’s file. All patients underwent a complete ophthalmologic evaluation in the cross-sectional visit, that included measurement of the best-corrected visual acuity, dilated fundus examination, and multimodal retinal imaging that included ultra-widefield color fundus photographs, ultra-widefield fundus autofluorescence, spectral-domain optical coherence tomography, and Humphrey visual field testing.
The patients also underwent a complete otolaryngology examination, complemented by otoacoustic emissions or brainstem audio-evoked response in newborns, and audiograms in children and adults, the authors explained.
They used a clinically oriented next-generation sequencing (NGS) approach comprised of whole-exome sequencing (WES) or WES-based NGS panels with copy number variation screening, along with multiplex ligation-dependent probe amplification, as needed. Available family members underwent segregation analysis. The investigators classified the genetic variants according to the American College of Medical Genetics and Genomics, with only likely pathogenic or pathogenic variants considered relevant for disease etiology, Dr Marques explained.
The study included 84 patients (58.3% males; mean age, 40.0 ± 17.9 years) from 71 families. The investigators reported, “Usher syndrome was the most frequent etiology (71.4%) followed by PHARC (6.0%), autosomal dominant optic atrophy plus (4.8%), and cone-rod dystrophy and hearing loss (4.8%).”
Other findings that occurred less frequently were Alport syndrome (2.4%), mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (2.4%), Heimler syndrome (2.4%), Senior-Loken syndrome (1.2%), Waardenburg syndrome (1.2%), maternally inherited diabetes and deafness (1.2%), and Stickler syndrome (1.2%).
Other characteristics that the investigators uncovered were that most patients (60.7%, n=51) had hearing loss before reaching adulthood; 34 patients (40.1%) had prelingual deafness.
Ophthalmologists referred 50 patients (59.5%) for genetic testing/counseling, and an otolaryngologist did so for 16.7% of genetic referrals.
“The overall diagnostic yield in our deaf-blind cohort was 73.2%. In 12 families, a presumptive genetic result was observed (partially solved cases); 9 families presented with a single variant classified as variant of unknown significance (VUS) in an autosomal recessive (AR) gene consistent with the phenotype, while 3 families harbored one pathogenic/likely pathogenic variant and VUS in an AR gene consistent with the phenotype. Overall, 56 genetic variants were identified across 16 different genes, 11 of which are novel,” Dr Marques reported.
According to the authors, this is the first report to describe the genetic profile of patients with dual sensory impairment in Portugal, which highlights the genetic heterogeneity associated with combined hearing and visual deficits.
Considering the high overall diagnostic yield of 73.2%, this suggests that most genes underlying dual sensory loss have already been identified.
The authors commented, “Since most causes of combined inherited retinal disease and hearing impairment have age-dependent symptoms, raising awareness among healthcare professionals of these neurosensory disorders is essential to have timely referrals to multidisciplinary care. Our study highlights the importance of establishing a final molecular diagnosis, because inheritance patterns, phenotypes, management, and prognosis differ between the several causes of combined inherited retinal disease and hearing impairment.”
