Hiding in plain sight: genetic deaf-blindness is not always Usher syndrome

Abstract

Introduction: Hearing loss (HL) is the most common congenital sensory impairment. Usher syndrome (USH) is the leading genetic etiology of congenital deafness combined with progressive vision loss, and individuals presenting with these symptoms are often assumed to have USH. This can be an erroneous assumption, as there are additional genetic causes of deafblindness.Objective: To describe and accurately diagnose non-USH genetic causes of deaf-blindness.Methods: We present three children with hearing and vision loss with clinical and genetic findings suggestive of USH. However, ongoing clinical assessment did not completely support an USH diagnosis, and exome analysis was pursued for all three individuals.Results: Updated genetic testing showed pathogenic variants in ALMS1 in the first individual and TUBB4B in the second and third. Although HL in all three was consistent with USH type 2, vision impairment with retinal changes was noted by age two years, which is unusual for USH.In all three the updated genotype more accurately fit the clinical phenotype. Conclusion:Because USH is the most common form of genetic deaf-blindness, individuals with HL, early vision impairment, and retinal dysfunction are often assumed to have USH. However, additional genes associated with HL and retinal impairment include ALMS1, TUBB4B, CEP78, ABHD12, and PRPS1. Accurate genetic diagnosis is critical to these individuals' understanding of their genetic conditions, prognosis, vision and hearing loss management, and future access to molecular therapies. If clinically or genetically USH seems uncertain, updated genetic testing for non-USH genes is essential.

Comprehensive analysis of two hotspot codons in the TUBB4B gene and associated phenotypes

“…Luscan et al reported five patients from four families with retinal pathology including features such as yellowish peripheral retina with round pigmented spots, thin retinal vessels, and macular alterations 3 . Medina et al reported two patients with early onset vision and hearing loss without a detailed description of the retinal phenotype 4 . Maasz et al reported three patients from a single family with a phenotype similar to that reported by Luscan et al 3 , 5 .…”

Navigating the Usher Syndrome Genetic Landscape: An Evaluation of the Associations between Specific Genes and Quality Categories of Cochlear Implant Outcomes

“…These debilitating conditions, arising from genetic mutations, converge to create a unique clinical landscape [ 8 ]. In addition to auditory and visual impairments, certain subtypes of US involve vestibular dysfunction, impacting the sense of balance in the affected individuals [ 9 , 10 , 11 , 12 ]. Therefore, the syndrome has been clinically subdivided into three main clinical types, USH1, USH2, and USH3, based on the severity and age at onset of symptoms [ 3 , 12 ].…”

Variants of LRP2, encoding a multifunctional cell‐surface endocytic receptor, associated with hearing loss and retinal dystrophy

“…Multiple pathogenic mechanisms and numerous genes are associated with deafness or retinal dystrophy 1,2 . There are also monogenic syndromes including loss of hearing and vision.…”

“…Multiple pathogenic mechanisms and numerous genes are associated with deafness or retinal dystrophy. 1,2 There are also monogenic syndromes including loss of hearing and vision. Usher syndrome (USH, OMIM 276900) is one such example and is the most common deafblindness disorder.…”