Table 3:
Atypical USH references
| Gene | Variant(s): | Vision manifestations | Hearing manifestations | Vestibular manifestations | Source(s) |
|---|---|---|---|---|---|
| MYO7A (NM_000260.3, NP_000251.3) | c.[4805G>A; 1952T>C] (p.[R1602Q; L651P]) | RP | Progressive SNHL | Normal caloric responses (not available in one of two patients) | Liu et al 1998 (89) |
| MYO7A | c.[5227C>T; c.5227C>T] (p.R1743W; p.R1743W) | Not available | Not available | Not available | Cremers et al 2007 (131) |
| MYO7A | c.[5581C>T; 5581C>T] (p.[R1861*; R1861*]) | Not available | Not available | Not available | Cremers et al 2007 (131) |
| MYO7A | c.655_660delATCCAC (p.I219_H220del)a | Not available | Not available | Not available | Aparisi et al 2014 (40) |
| MYO7A | c.[849+5G>A; 3907_3910dupATTG] (p.[?;Ala1304Aspfs*5]) | Not availableb | Not availableb | Not availableb | Neuhaus et al 2017 (45) |
| MYO7A | c.[3262C>T; 6439–2A>G] (p[.Q1088*; ?]) | Not availableb | Not availableb | Not availableb | Neuhaus et al 2017 (45) |
| MYO7A | c.[3503G>A; 6025delG] (p.[R1168Q; A2009Pfs*32]) | Not availableb | Not availableb | Not availableb | Neuhaus et al 2017 (45) |
| MYO7A | c.[3503G>A; 5573T>C] (p.[R1168Q; L1858P]) | Not availableb | Not availableb | Not availableb | Neuhaus et al 2017 (45) |
| MYO7A | c.[3718C>T; 4814C>A] (p.[R1240W; S1605Y]) | Not availableb | Not availableb | Not availableb | Neuhaus et al 2017 (45) |
| USH2A (NM_206933.2, NP_996816.2) | c.[2299delG; 2299delG] (p.[Glu767Serfs*21;Glu767Serfs*21]) | RP | Variable (progressive SNHL or non-progressive SNHL in patient with absent vestibular responses) | Variable (absent vestibular responses, normal vestibular function, or not available) | Liu et al 1999 (92), Blanco-Kelly 2015c (132) |
| USH2A | c.2299delG (p.E767Sfs*21) | RP | Progressive SNHL | Normal | Liu et al 1999 (92), Blanco-Kelly 2015c (132) |
| USH2A | c.[2276G>T; 3096_3099dupTGAT] ([p.C759F; A1034*]) | RP | Progressive SNHL (did not undergo audiometry) | Normal | Aller et al 2004 (133) |
| USH2A | c.2276G>T (p.C759F) | RP | Progressive SNHL (self-reported) | Not available | Aller et al 2004 (clinical information found in Najera et al 2002) (133, 134), Blanco-Kelly et al 2015c (132) |
| USH2A | c.[2299delG; 2276G>T] (p.[E767Sfs*21; p.C759F]) | RP | Progressive SNHL | Normal | Aller et al 2004 (133), Blanco-Kelly et al 2015c (132) |
| USH2A | c.1663C>G (p.L555V) | Not available | Not available | Not available | Cremers et al 2007 (131) |
| USH2A | c.11864G>A (p.W3955*) | Not available | Not available | Not available | Cremers et al 2007 (131) |
| USH2A | c.[1214delA; 9799T>C] (p.[N405Ifs*3; C3267R]) | RP | Profound SNHL | Vestibular dysfunction | Garcia-Garcia et al 2011 (135) |
| USH2A | c.[2299delG; 908G>A]; (p.[E767Sfs*2; R303H]) | RP | Moderate progressive SNHL | Not available | Garcia-Garcia et al 2011 (135) |
| USH2A | c.[9799T>C; 10073G>A](p.[C3267R; C3358Y]) | RP | SNHL with onset at 64 years | Not available | Garcia-Garcia et al 2011 (135) |
| USH2A | c.[2276G>T; 14175G>A] (p.[C759F; W4725*]) | RP | Moderate progressive SNHL | Central vestibular pathology | Garcia-Garcia et al 2011 (135) |
| USH2A | c.7595–2144A>G | RP | Progressive SNHL | L canal paresis | Steele-Stallard et al 2013 (136) |
| USH2A | c.[1036A>C; 7967delA] (p.[N346H; N2656Ifs*18]) | Not availableb | Not availableb | Not availableb | Neuhaus 2017 (45) |
| USH2A | c.13316C>T (p.T4439I) | Not availableb | Not availableb | Not availableb | Neuhaus 2017 (45) |
|
CDH23 (NM_022124.5, NP_071407.4) |
c.[9510+1G>A; 9510+1G>A] | Late onset of RP | SNHL | “Borderline” vestibular function | Bork et al 2001 (16) |
| CDH23 | c.2289+1G>A | RP | Profound SNHL | Not available (independent ambulation at 12 or 18 months) | Astuto et al 2002 (137) |
| CDH23 | c.6050–9G>A | RP | Variable (Profound or Severe to Profound SNHL) | Not available (independent ambulation at 36 months) | Astuto et al 2002 (137) |
| CDH23 | c.[5237G>A; 5237G>A]; (p.[R1746Q; R1746Q]) | Mild RPd | Profound SNHL | Mild vestibular dysfunction or not available | Astuto et al 2002 (137) |
| CDH23 | c.[2289+1G>A; c.3105A>C] (p.[?; T1035T] | RP | Progressive (symmetrical or asymmetrical) | Not available (independent ambulation at 12 or 14 months) | Astuto et al 2002 (137) |
| CDH23 | c.[193delC; 3844dup_3847dupAATG] (p.[L65Wfs*49; V1283Efs*6]) | RP | Profound SNHL | Absent vestibular function | Astuto et al 2002 (137) |
| CDH23 | c.[1112delT; 5237G>A] (p.[I371Tfs*12; R1746Q]) | RP | Profound SNHL | Not available (independent ambulation at 15 or 26 months) | Astuto et al 2002 (137) |
| CDH23 | c.1112delT (p.I371Tfs*12) | RP | Profound SNHL | Absent vestibular function (independent ambulation at 18 months) | Astuto et al 2002 (137) |
| CDH23 | c.6155delC (p.T2052Rfs*28) | RP | Profound SNHL | Absent vestibular function (independent ambulation at 10 months) | Astuto et al 2002 (137) |
| CDH23 | c.6968delC (p.P232Lfs*50) | RP | Profound, progressive SNHL | Not available (independent ambulation at 22 months) | Astuto et al 2002 (137) |
| CDH23 | c.5237G>A (p.R1746Q) | RP | Severe to profound SNHL, asymmetric | Not available (independent ambulation at 13 months) | Astuto et al 2002 (137) |
| CDH23 | c.8230G>A (p.G2744S)e | Variable (RP or retinal symptoms limited to subnormal ERG) | Variable (severe SNHL or none) | Not available (independent ambulation at 22 or 36 months) | Astuto et al 2002 (137) |
| CDH23 | c.[2289+1G>A; 6050–9G>A] | RP | Profound SNHL | Mild vestibular dysfunction | Astuto et al 2002 (137) |
| CDH23 | c.[4504C>T; 4504C>T] (p.[R1502*; R1502*]) | RP | Profound SNHL | Normal vestibular function or not available (independent ambulation at 14 or 15 months) | Astuto et al 2002 (137) |
| CDH23 | c.[336+1G>A; 4054C>T] (p.[?; R1502*]) | RP | Profound SNHL | Normal vestibular function or not available (independent ambulation at 20 or 24 months) | Astuto et al 2002 (137) |
| CDH23 | c.8497C>G (p.R2833G) | RP | Moderate to profound, progressive SNHL | Normal vestibular function | Astuto et al 2002 (137) |
| CDH23 | c.3625A>G (p.T1209A) | Not available | Not available | Not available | Cremers et al 2007 (131) |
| CDH23 | c.[3178C>T + 4021G>A] (p.[R1060W + D1341N]) | Not available | Not available | Not available | Cremers et al 2007 (131) |
| CDH23 | Dup ex19–27; Dup ex19–27 | Not availableb | Not availableb | Not availableb | Neuhaus et al 2017 (45) |
| CDH23 | c.6050–15G>A; c.6050–9G>A | RP | Congenital severe SNHL | Normal vestibular function | Valero et al 2019 (138) |
| USH1G (NM_173477.4, NP_775748.2) | c.[1373A>T;1373A>T] (p.[D458V; D458V]) | Mild RP | Moderate to profound SNHL | Normal vestibular function | Kalay et al 2005 (99), Neuhaus et al 2017 (phenotype not available) (45) |
| USH1G | c.[163_164+13del15; 163_164+13del15] | Mild RP | Moderate to several SNHL | Normal vestibular function | Bashir et al 2010 (98) |
| CEP250 (NM_007186.5, NP_009117.2) | c.[3463C>T; 3463C>T] (p.[R1155*; R1155*]) | RP (variable severity depending on zygosity of additional variant in PCARE)f | Severe SNHL | Normal vestibular function | Khateb et al 2014 (51) |
| CEP78 (NM_001098802.2) | c.[1254+5G>A; 1254+5G>A] | CRD | SNHL | Not available | Fu et al 2017 (81) |
| CEP78 | c.[1629–2A>G; 1629–2A>G] | CRD | SNHL | Not available | Fu et al 2017 (81) |
| ADGRV1 (NM_032119.3, NP_115495.3) | c.[6981delT; c.14044–1G>A] (p.[G2328V; ?]) | Not availableb | Not availableb | Not availableb | Neuhaus et al 2017 (45) |
| ARSG (NM_014960.4, NP_055775.2) | c.[133G>T; 133G>T] (p.[D45Y; D45Y]) | “Distinctive retinal dystrophy” | Moderate to severe progressive SNHL | Normal vestibular function | Khateb et al 2018 (53) |
| ABHD12 (NM_001042472.2) | c.[477G>A; 316+5G>A] (p.[W159*; ?]) | Not available | Severe SNHL | Not available | Sun 2018 (42) |
| ESPN (NM_031475.2) | c.[2369_2386delAGGCGGG-ACCTCCTGCGG; 2369_2386delAGGCGGG-ACCTCCTGCGG] (p.[R790_R795del; R790_795del]) | Mild RP | Profound SNHL | Vestibular dysfunction | Ahmed et al 2018 (54) |
a
This variant was present in a patient in the test group only. Due to technical problems, this variant was not replicated in the methods of this particular paper.
b
The authors define atypical Usher syndrome as cases with unusual clinical course or symptoms not typically observed in Usher syndrome.
c
No phenotypic information available for Blanco-Kelly et al 2015. The authors also describe cases of atypical USH associated with other genotypes which are not given.
d
Not confirmed in one 5-year-old patient.
e
Other symptoms also present, including ataxia and developmental delay.
f
Patients presented with severe RP when a homozygous pathogenic variant in PCARE was also present (NM_001029883.2: c.3289C>T; NP_00102504.1: p.Q1097*). When this variant was present in a heterozygous state, patients presented with mild RP.
CRD=Cone-rod dystrophy
RP=Retinitis Pigmentosa
SNHL=Sensorineural hearing loss