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Atypical and ultra-rare Usher syndrome: a review

Rosalie M. Nolena Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USAView further author information
,
Robert B. Hufnagela Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USAView further author information
,
Thomas B. Friedmanb Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USAORCID Iconhttps://orcid.org/0000-0003-4614-6630View further author information
ORCID Icon,
Amy E. Turriffa Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USAView further author information
,
Carmen C. Brewerc Otolaryngology Branch, National Institute of Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USAView further author information
,
Christopher K. Zalewskic Otolaryngology Branch, National Institute of Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USAView further author information
,
Kelly A. Kingc Otolaryngology Branch, National Institute of Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USAView further author information
,
Talah T. Wafac Otolaryngology Branch, National Institute of Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USAView further author information
,
Andrew J. Griffithc Otolaryngology Branch, National Institute of Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USAView further author information
,
Brian P. Brooksa Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USAORCID Iconhttps://orcid.org/0000-0003-2320-2396View further author information
ORCID Icon &
Wadih M. Zeina Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USACorrespondence[email protected]
ORCID Iconhttps://orcid.org/0000-0002-3771-6120View further author information
ORCID Icon show all
Pages 401-412 | Received 27 Dec 2019, Accepted 15 Mar 2020, Published online: 06 May 2020

ABSTRACT

Usher syndrome has classically been described as a combination of hearing loss and rod-cone dystrophy; vestibular dysfunction is present in many patients. Three distinct clinical subtypes were documented in the late 1970s. Genotyping efforts have led to the identification of several genes associated with the disease. Recent literature has seen multiple publications referring to “atypical” Usher syndrome presentations. This manuscript reviews the molecular etiology of Usher syndrome, highlighting rare presentations and molecular causes. Reports of “atypical” disease are summarized noting the wide discrepancy in the spectrum of phenotypic deviations from the classical presentation. Guidelines for establishing a clear nomenclature system are suggested.

Introduction

Usher syndrome (USH) is the most common hereditary form of deaf-blindness. It has an autosomal recessive inheritance pattern and is characterized by the combination of sensorineural hearing loss (SNHL), rod-cone dystrophy, and variable vestibular dysfunction (Citation1). Early sources reported a prevalence of 3.6 to 6.2 per 100,000 (Citation2–Citation6). However, the prevalence of USH may be as high as 16.7 per 100,000 (Citation7).

Attempts at description of USH clinical subtypes date to the late 1970s (Citation8). Currently, USH has three recognized clinical subtypes distinguished by differences in severity and onset of hearing loss and the presence of vestibular dysfunction. The shared ophthalmic manifestation of all three subtypes is a retinal degeneration classified as rod-cone dystrophy or retinitis pigmentosa (RP). Type 1 (USH1) presents with profound congenital SNHL, peripheral vestibular areflexia, and infantile onset of retinitis pigmentosa (Citation9). Type 2 (USH2) results in mild to severe congenital SNHL and retinitis pigmentosa, but not vestibular dysfunction (Citation9). Type 3 (USH3) results in progressive SNHL, retinitis pigmentosa, and variable vestibular dysfunction (Citation10–Citation12).

A poorly defined clinical subtype called atypical Usher syndrome (atypical USH) has emerged to include USH phenotypes that do not meet the canonical criteria for USH1, USH2, or USH3. Although reports of atypical USH vary, several of the cases described in the literature involve a combination of hearing loss and cone-rod dystrophy (CRD). Another commonly cited cause for atypical USH is related to the degree of severity of classical clinical findings, usually milder presentations. This paper reviews the literature on USH with a focus on summarizing data on atypical USH and the rare genetic causes putatively linked to USH (hitherto referred to as Ultra-rare USH).

Genetic heterogeneity

Usher syndrome is genetically heterogenous. USH1 can be caused by pathogenic variants in one of at least five genes: MYO7A (myosin VIIA) (Citation13), USH1 C (harmonin) (Citation14,Citation15), CDH23 (cadherin 23) (Citation16,Citation17), PCDH15 (protocadherin 15) (Citation18,Citation19), or USH1 G (sans) (Citation20). USH2 can be caused by pathogenic variants in one of the three genes: USH2A (usherin) (Citation21), ADGRV1 (adhesion G-protein coupled receptor V1) (Citation22), or WHRN (whirlin) (Citation23). USH3 can be caused by pathogenic variants in CLRN1 (clarin 1) (Citation24,Citation25).

USH genes encode proteins with a variety of molecular functions, including a motor protein (myosin VIIA), scaffold proteins (harmonin, sans, and whirlin), transmembrane proteins (usherin and clarin 1), adhesion proteins (cadherin 23 and protocadherin 15), and a G-protein coupled receptor (adhesion G-protein coupled receptor v1). USH proteins can interact to produce what is termed the Usher interactome (Citation26,Citation27). The Usher interactome is important for the function of inner ear hair cells and photoreceptors in the retina. Although a full discussion of the various functions of well-established USH proteins is beyond the scope of this manuscript, the reader is referred to a comprehensive review by Cosgrove and Zallocchi (Citation26).

The nine USH genes discussed above underlie the vast majority of molecularly diagnosed cases (Citation24,Citation28–Citation38). However, current methods fail to yield a definitive molecular diagnosis in some USH patients, and bi-allelic pathogenic variants are generally discovered in less than 80% of patients using targeted or whole-exome sequencing methods (Citation39–Citation43). 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% (Citation44,Citation45). 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 bi-allelic variants in two different genes (Citation45,Citation46). Nonetheless, rare variants of hitherto unidentified genes for USH should be considered, noting that these likely account for a minority of patients.

Additional associations of variants in genes previously not described as causative of USH are continuously being proposed; we will refer to these as ultra-rare USH genes throughout this paper. In the past, several candidate genes, including MYO15A, SLC4A, and VEZT, have been proposed and then refuted as potential USH genes (Citation34,Citation40). Furthermore, several genes associated with USH have been proposed more recently. These include PDZD7 (Citation47), HARS (Citation48), ABHD12 (Citation49), CIB2 (Citation50), CEP250 (Citation51), CEP78 (Citation52), ARSG (Citation53), and ESPN (Citation54). Pathogenic variants in these genes likely represent rare causes of USH, and several of them were reported in association with atypical USH. Here, we review reports of these ultra-rare USH genes and atypical USH. For this review, “atypical USH” is based on the description of the authors of cited studies. This includes atypical USH clinical presentations with confirmed pathogenic variants in known USH causative genes. Between September 2018 and November 2019, we searched PubMed for terms including “Usher syndrome,” “Atypical Usher syndrome,” “Atypical USH,” and for each of the genes already identified as causative of USH. RetNet (https://sph.uth.edu/retnet/) and Human Genome Mutation Database (Citation55) were utilized to identify additional ultra-rare USH genes and relevant references. We also reviewed the pertinent references in identified papers and reviews on USH. Additional search methodology including accessing Scopus and Web of Science was used to identify relevant literature.

Ultra-rare USH genes

We identified eight putative ultra-rare USH genes through our literature search. The relevant references which associate each of these ultra-rare genes to USH are summarized in . Information on other important properties of the encoded proteins such as function, localization, and interactions with the USH interactome are summarized in .

Table 1. References for ultra-rare USH genes.

Table 2. Summary of ultra-rare USH proteins function, interactions, localization, and animal models.

One of these genes, PDZD7 (PDZ domain containing 7), is a 23.3-kb, 16-exon gene located on chromosome 10, encoding a scaffold protein (Citation62). The high sequence similarity of PDZD7 with USH1C and WHRN led Schneider et al. to first propose it as an USH gene (Citation62). Subsequently, in 2010, Ebermann et al. identified the first clinical cases of USH associated with pathogenic variants in PDZD7 (Citation47). They described two families in which there is evidence that PDZD7 contributes to the USH phenotype. In one family, they observed that the presence of a mono-allelic variant in PDZD7 appears to modify the severity of the retinal phenotype in the presence of homozygous pathogenic variants in USH2A. In the other family, mono-allelic variants in ADGRV1 and PDZD7 appear to contribute to digenic inheritance (Citation47). There is evidence that PDZD7, USH2A, ADGRV1, and WHRN interact to form an USH2 complex both in vitro and in vivo (Citation67,Citation68,Citation109). The localization and function of PDZD7 in the inner ear have been well characterized but are less well understood in the retina. For example, knockout or knockdown of gene function in animal models results in disorganization of the stereocilia, deafness in mice, and a reduced startle reflex and circling in zebrafish (Citation47,Citation68). However, there is evidence that the USH2 complex can assemble without PDZD7 in photoreceptors, unlike in inner ear hair cells where it is an obligate component (Citation68). A summary of the localization of the PDZD7 protein, interactions with other USH proteins, and animal models can be found in .

The next ultra-rare USH gene to be proposed was HARS (histidyl-tRNA synthetase), a 13-exon, 17.4-kb gene located on chromosome 5 (Citation110,Citation111). The HARS gene product charges tRNA molecules with histidine amino acids for protein translation (Citation75). In 2012, Puffenberger et al. identified a homozygous pathogenic variant in HARS associated with an USH3 phenotype (Citation48). Tiwari et al. also described compound heterozygous pathogenic variants in HARS in a patient with an unspecified type of Usher syndrome in 2016 (Citation56). The specific variant described by Puffenberger et al. was further characterized in vitro by Abbott et al., who observed that it caused a reduction in thermal stability of the protein (Citation78). The localization of HARS in the inner ear and retina and interactions with other USH proteins are unknown and require further investigation.

ABHD12 (α/β-hydrolase domain containing 12) is a membrane-embedded serine hydrolase (Citation113,Citation114). Its substrates include endocannabinoid transmitter 2-arachidonylglycerol (2-AG) and signaling lipids (lysophosphatidylserines, LPS) (Citation83,Citation114). Both Eisenberger et al. and Yoshimura et al. identified bi-allelic ABHD12 pathogenic variants in patients initially presenting with USH3-like symptoms (Citation49,Citation57). However, it is important to note that both sets of authors ultimately diagnosed the patients with a different condition comprising polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and early-onset cataract (PHARC). Nonetheless, ABHD12 has been considered by some to be an USH gene, leading it to be included on panels of genes utilized for Next Generation Sequencing (NGS) specifically targeted at USH. For example, in 2018, Sun et al. performed a screening of 119 clinically diagnosed USH patients and identified bi-allelic pathogenic variants in ABHD12 in one individual (Citation42). Information about whether this patient had undergone a neurological exam was not presented. Abhd12-null mice display many of the phenotypic characteristics of PHARC (Citation83). The localization of ABHD12 in the inner ear and retina and possible interactions with USH proteins require further investigation.

CIB2 (calcium and integrin-binding family member 2) was proposed as another potential USH gene. Previously known as KIP2 (kinase interacting protein 2), CIB2 is located on chromosome 15 and encodes an EF-domain containing protein that binds both calcium and integrin α7b (Citation115,Citation116). In 2012, Riazuddin et al. reported a homozygous pathogenic variant of CIB2 in USH1 patients (Citation50) which affected the function of CIB2 as a calcium sensor. Vallone et al. later demonstrated that, in physiological conditions, CIB2 can function as a magnesium sensor and the variant described by Riazuddin et al. affects this capacity (Citation88). Studies show that knockdown of Cib2 in mice eliminates mechanotransduction in cochlear hair cells (Citation89,Citation90).

CEP250 encodes CEP250 (also known as centrosomal protein 250 or CNAP1), a member of the CEP family of centrosome-associated proteins (Citation92). There have been three separate papers reporting bi-allelic variants in CEP250 linked to retinal degeneration and hearing loss. In 2014, Khateb et al. identified homozygous pathogenic variants in both CEP250 and PCARE in a family diagnosed with atypical USH (Citation51). This family had multiple-affected individuals, and individuals with bi-allelic pathogenic variants in both genes had more severe phenotypes (Citation51). In 2018, Kubota et al. identified compound heterozygous pathogenic variants in CEP250 in patients diagnosed with mild CRD and SNHL (Citation58). Lastly, Fuster-Garcia et al. recently identified compound heterozygous CEP250 pathogenic variants in a patient presenting with similar ocular symptoms and progressive hearing loss (Citation59). CEP250 is important for centriole-centriole cohesion of chromosomes and has been shown to promote cilia formation (Citation91,Citation117). Its localization is described in . Interactions with other USH proteins and the function of CEP250 in the ear and eye are areas for further research.

Another member of the CEP family, CEP78 (centrosomal protein 78), has also been linked to USH. As a ciliary/centrosomal protein, it is important for the cell cycle (Citation118). Three different reports have associated CEP78 with retinal degeneration and hearing loss (Citation52,Citation60,Citation61). In 2016, both Namburi et al. and Nikopolous et al. identified bi-allelic CEP78 pathogenic variants in patients clinically diagnosed with CRD and hearing loss (Citation52,Citation60). The following year, Fu et al. reported bi-allelic CEP78 pathogenic variants in patients with CRD and progressive hearing loss who were clinically diagnosed with atypical USH (Citation61). While a full description of localization patterns can be found in , work performed by both Namburi et al. and Nikopolous et al. indicates that, in the retina, CEP78 is primarily localized to the photoreceptor connecting cilium, and this localization is stronger in cones than rods (Citation52,Citation60). Studies involving adult human tissue samples indicate that CEP78 mRNA is also present in the inner ear (Citation60,Citation119). Interestingly, tandem affinity purification has been used to show that CEP78 interacts with CEP250 (Citation93).

Another putative USH gene is ARSG (arylsulfatase G), which encodes a member of a class of enzymes called sulfatases, which are responsible for hydrolyzing ester sulfate bonds and which are implicated in a wide variety of biochemical processes (Citation101). It catalyzes an important step in the breakdown of heparan sulfate (Citation97). Khateb et al. identified a homozygous pathogenic variant in ARSG in patients clinically diagnosed with atypical USH presenting as a retinal degeneration involving a ring scotoma and moderate to severe SNHL (Citation53). It is noteworthy that the patients were also found to have a normal metabolic and neurological function. The authors also demonstrated that the ARSG variant they identified nearly abolishes all enzyme function and that ARSG is expressed in the human retina. Homozygous Arsg knockout mice displays retinal degeneration as well as behavioral dysfunction indicative of systemic effects (Citation97,Citation98).

Lastly, ESPN (espin) has recently been associated with USH. ESPN, which has several known alternative splice isoforms, encodes an actin-bundling protein important in various neurosensory cell types, including those in the retina and inner ear (Citation106). Ahmed et al. identified an in-frame deletion in ESPN as the cause of a phenotype described as atypical USH1 in a Pakistani family (Citation54). The phenotype included delayed dark adaptation with irregular retinal contour, temporal flecks, and optic nerve pallor. Electroretinography showed a mild reduction in scotopic responses with preserved photopic responses. Upon detailed review of the presented data, we felt that retinal clinical findings and electroretinography are atypical for USH. ESPN is an established cause of non-syndromic hearing loss DFNB36 (Citation104), but this was the first time it has been associated with USH.

Atypical USH

Our literature search identified a variety of articles describing atypical USH, the findings of which are summarized in . These papers generally either describe variants in well-characterized USH genes associated with atypical clinical presentations or they describe atypical USH associated with ultra-rare USH genes, such as the ones discussed above.

Table 3. Atypical USH references.

MYO7A is one of the well-characterized USH1 genes which has been linked to atypical USH. Although all these cases involved RP and SNHL, they were classified as atypical USH because the symptoms deviated from the expected clinical presentation of USH1. Many involve mild RP or progressive SNHL. For example, Liu et al. reported two siblings with bilateral progressive hearing loss and mild RP who were compound heterozygous for pathogenic variants in MYO7A (Citation120). Additional examples of atypical USH are included in . Of note, not all instances of unusual clinical presentations are defined as atypical USH by the authors (Citation132,Citation133).

USH2A has also been associated with atypical USH. Many of these cases involve progressive hearing loss. For example, Liu et al. identified the common c.2299delG USH2A pathogenic variant in four unrelated patients with atypical USH (Citation122). This was in a homozygous state in three of the patients and a heterozygous state in one, with the second disease-causing allele variant unknown. These patients had progressive SNHL and RP, and one patient had vestibular dysfunction as well. Additional examples are described in . As with MYO7A, not all descriptions of similarly unusual phenotypes are classified as atypical USH by the authors (Citation134). There has also been discussion in the literature as to whether progressive hearing loss is necessarily an atypical natural history for some patients with Usher syndrome caused by USH2A (Citation135–138).

Other well-established USH genes described in cases of atypical USH include CDH23 and SANS. These cases, which involved unusual severity or progression of symptoms, also varied in terms of classification as atypical USH. For example, each of the two papers which first identified pathogenic variants of CDH23 as a cause of USH also described a family with a mild form of RP (Citation16,Citation17), but only one of the papers specifically defined this phenotype as atypical USH (Citation16). Similarly, bi-allelic pathogenic variants in SANS have been reported in conjunction with unusual phenotypes characterized by mild RP with or without vestibular dysfunction (Citation130,Citation131), but only the former was described as atypical USH (Citation130).

Several of the previously discussed ultra-rare causes of USH have also been described in association with atypical USH. All of these reports are summarized in . Unlike well-established genetic phenotypes, these cases sometimes present as non-RP retinal degenerations, including CRD. For example, Fu et al. reported either of two different homozygous variants in CEP78 in association with CRD and SNHL in patients clinically diagnosed with atypical USH (Citation61). Authors also differ on the use of the atypical USH diagnosis in these cases, with some simply describing the clinical presentation as CRD and SNHL (Citation52,Citation58,Citation60) or an “Usher-like” phenotype (Citation59).

Lastly, it has become more common for authors to include patients clinically diagnosed with atypical USH as a small subset of a larger cohort of USH patients screened for USH pathogenic variants. Pathogenic variants in many USH genes associated with atypical USH have been reported, including MYO7A, USH2A, CDH23, ADGRV1, and ABHD12. However, there is little clinical information available for these patients. The results of these studies are also included in .

Discussion

The literature shows great variability in the USH phenotype. Although most USH phenotypes meet the current criteria for USH1, USH2, or USH3, a significant number of phenotypes do not meet criteria for any of them, whether in terms of their phenotype or genotype. Clear and established nomenclature guidelines are now needed for patients with these atypical genotypes and phenotypes. Additionally, the routine implementation of massively parallel sequencing has greatly increased the number of variants being discovered. As a result, it is imperative for the community of clinicians and scientists treating and investigating USH to establish clear criteria for the diagnosis of USH and characterization of potential USH genes.

In pursuit of this goal, we raise a few points of consideration. First, it is important to consider the typical clinical definitions for each subtype of USH. Currently, it is not uncommon within the literature for a similar clinical presentation described as USH1 or USH2 in one case to be described as atypical USH in another case. For example, this frequently occurs with cases of progressive hearing loss in USH2. It is important to establish clear criteria for which signs fall within the spectrum of disease for each clinical subtype, and which are truly atypical.

Second, vestibular function is often not evaluated or well characterized in persons with USH. Note that many of the manuscripts in have “not available” in the vestibular column. Furthermore, the methods used to determine vestibular function vary considerably from patient self-report to complex diagnostic assessments. This makes it difficult to determine if the vestibular presentation is typical or atypical and to compare cases across studies. Criteria for normal vestibular function should be defined and based upon accessible testing.

Third, the presence or absence of a retinal degeneration consistent with RP should be a defining criterion for USH. This is a point on which there is no consensus in the literature; however, establishing clearer criteria will allow for more consistency in diagnosis and reporting. We believe that a clinical diagnosis of USH should involve a retinal degeneration categorized as a rod-cone dystrophy.

Finally, it is important to carefully consider whether additional symptoms are present that would be indicative of a disorder affecting additional organ systems other than the eye and ear. This is particularly relevant given that several of the ultra-rare USH genes have been linked to systemic disorders in humans or animal models, such as lysosomal, peroxisomal, or mitochondrial disorders with associated neurological findings ().

We have searched the literature and observed that greater consistency is necessary in the description of USH. Establishing concrete criteria for diagnosis and the characterization of genetic causes will benefit the clinicians and scientists who are working to understand and treat this condition. Furthermore, it will provide clarity in diagnosis to patients and establish a common foundation on which future research can be built.

Declaration of interest statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

This study was supported by the Intramural Research Program of the National Institutes of Health.

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