Expanding the Genetic Landscape of Usher-Like Phenotypes

Abstract

PURPOSE. Usher syndrome (USH) is a rare disorder characterized by retinitis pigmentosa (RP) and sensorineural hearing loss. Several genes are responsible for the disease, but not all cases are explained by mutations in any of these, supporting the fact that there remain other unknown genes that have a role in the syndrome. We aimed to find the genetic cause of presumed USH patients lacking pathogenic mutations in the known USH genes. METHODS. Whole exome sequencing was performed on a priori USH-diagnosed subjects from nine unrelated families, which had shown negative results for an USH-targeted panel in a previous study. RESULTS. We identified possible pathogenic variants in six of the studied families. One patient harbored mutations in REEP6 and TECTA, each gene tentatively causative of one of the two main symptoms of the disease, mimicking the syndrome. In three patients, only the retinal degeneration causative mutations were detected (involving EYS, WDR19, and CNGB1 genes). Another family manifested a dementia-linked retinal dystrophy dependent on an allele dosage in the GRN gene. Last, another case presented a homozygous mutation in ASIC5, a gene not yet associated with USH. CONCLUSIONS. Our findings demonstrate that pending cases should be clinically and genetically carefully assessed, since more patients than expected may be either related phenocopies or affected by a more complex disease encompassing additional symptoms rather than classical USH.

Review of Genotype-Phenotype Correlations in Usher Syndrome

“…This includes variants in common USH genes which result in atypical USH phenotypes, complicating the paradigm of assigning certain USH genes to either USH1, USH2, or USH3 (Pennings et al 2004; Bashir et al 2010; Pérez-Carro et al 2018; Zhang et al 2018; D’Esposito et al 2019; Lee et al 2019; Valero et al 2019). Another study which used whole exome sequencing to screen clinically diagnosed USH patients who lacked pathogenic mutations in known USH genes found potentially causative mutations in a variety of hearing and retina-related non-USH genes, again highlighting the disconnection between clinical and molecular classifications (Fuster-García et al 2019). This is in line with data from the University of Iowa’s Genetic Eye-Ear Clinic, which found that the combination of expert clinical evaluation and molecular testing led to a change in diagnosis in 52% of deaf-blind families who presented to the clinic, 29% of who received molecularly confirmed final diagnoses of USH (Stiff et al 2020).…”

“…However, none of these treatment modalities address the pathophysiologic mechanisms underlying USH. A variety of gene therapy approaches to the inner ear and retina are being investigated, and research is ongoing to develop mutation-specific treatment modalities (Geleoc & El-Amraoui 2020). A currently recruiting trial for RP is investigating an intravitreal injection of an antisense oligonucleotide for mutation-specific treatment of the most common variants of exon 13 in the USH2A gene (ProQR, Stellar; Trial #NCT03780257).…”

“…Twelve genes have been identified as corresponding to the three clinical subtypes, although three of these genes ( CIB2, PDZD7 , and HARS ) have been called into question (http://hereditaryhearingloss.org). A growing list of additional genes has been associated with atypical USH phenotypes (Mathur & Yang 2015; Fuster-García et al 2019). For each associated gene, the clinical phenotype can also vary based on the type and location of the causative mutation, further complicating the clinical picture (Table 1) (Ahmed et al 2008; Pérez-Carro et al 2018; Ramzan et al 2018; Lin et al 2020).…”

Atypical and ultra-rare Usher syndrome: a review

“…Utilizing a combination of methods or a more comprehensive approach to genetic testing may increase the detection of bi- allelic pathogenic variants to above 90% (44,45). For example, including genes implicated in both non-syndromic hearing loss and retinal degenerations may reveal rare cases with a clinical presentation similar to that of USH but with biallelic variants in two different genes (45,46). Nonetheless, rare variants of hitherto unidentified genes for USH should be considered, noting that these likely account for a minority of patients.…”

The genetic and phenotypic landscapes of Usher syndrome: from disease mechanisms to a new classification

“…These three clinical subtypes are associated with nine causal genes encoding various proteins expressed in the inner ear and retina and playing key roles in auditory sensory cell development and function, and photoreceptor maintenance. However, a growing list of additional genes have been reported to be associated with a poorly defined clinical subtype called "atypical Usher syndrome" that does not meet the canonical criteria for the three recognized Usher syndrome subtypes (Bolz 2020;Castiglione and Moller 2022;Fuster-Garcia et al 2019;Nisenbaum et al 2021;Nolen et al 2020;Stiff et al 2020). Moreover, for each Usher syndrome-associated gene, Sedigheh Delmaghani and Aziz El-Amraoui are Joint senior.…”