Usher Syndrome

Usher syndrome is characterized by hearing impairment and retinitis pigmentosa. Usher syndrome can be classified into 3 different types on the basis of clinical findings.

Clinical Classification of Usher Syndrome
TypeHearing ImpairmentVestibular ImpairmentRetinitis Pigmentosa
Type ICongenital
Severe-to-profound hearing loss
SevereOnset in first decade of life
Type IICongenital
Moderate-to-severe hearing loss
NoneOnset in first or second decade of life
Type IIIVariable progressive hearing lossVariableVariable


MOLECULAR Classification of Usher Syndrome
TypeLocus (OMIM)Gene (OMIM)InheritanceKey Locus References (PubMed)Key Gene References (PubMed)
Evidence (ClinGen)
Usher 1USH1A (see note 1)n/aAutosomal RecessiveKaplan et al., 1992; Gerber et al., 2006n/an/a
Usher 1USH1BMYO7AAutosomal RecessiveKimberling et al., 1992; Smith et al., 1992Weil et al., 1995Definitive
Usher 1USH1CUSH1CAutosomal RecessiveSmith et al., 1992; Keats et al., 1994Verpy et al., 2000Definitive
Usher 1USH1DCDH23Autosomal RecessiveWayne et al., 1996Bolz et al., 2001Definitive
Usher 1USH1EunknownAutosomal RecessiveCha├»b et al., 1997n/an/a
Usher 1USH1FPCDH15Autosomal RecessiveWayne et al., 1997Ahmed et al., 2001Alagramam et al., 2001Definitive
Usher 1USH1GUSH1G/SANSAutosomal RecessiveMustapha et al., 2002Weil et al., 2003Definitive
Usher 1USH1HunknownAutosomal RecessiveAhmed et al., 2009n/an/a
Usher 1USH1Junknown (see note 2)Autosomal RecessiveRiazuddin et al., 2012n/an/a
Usher 1USH1KunknownAutosomal RecessiveJaworek et al., 2012n/an/a
Usher 2USH2AUSH2AAutosomal RecessiveKimberling et al., 1990; Kimberling et al., 1995Eudy et al., 1998Definitive
Usher 2USH2B (see note 3)n/aAutosomal RecessiveHmani et al., 1999; Hmani-Aifa et al., 2009n/an/a
Usher 2USH2CADGRV1/VLGR1/GPR98 (see note 4)Autosomal RecessivePieke-Dahl et al., 2000Weston et al., 2004Definitive
Usher 2USH2DWHRNAutosomal RecessiveEbermann et al., 2007Ebermann et al., 2007Definitive
Usher 3USH3ACLRN1Autosomal RecessiveSankila et al., 1995; Joensuu et al., 1996Joensuu et al., 2001Definitive
Usher 3USH3BHARS1 (see note 5)Autosomal RecessivePuffenberger et al., 2012Puffenberger et al., 2012Refuted

n/a = not applicable

Note 1: The existence of the USH1A locus has been refuted by Gerber et al., 2006.

Note 2: Mutations in CIB2 were initially reported to cause Usher syndrome type 1J (Riazuddin et al., 2012), but this has been refuted. Mutations in CIB2 have been reported to cause non-syndromic hearing loss only (Booth et al., 2018).

Note 3: USH2B, initially reported in Hmani et al., 1999, was later retracted by Hmani-Aifa et al., 2009.

Note 4: Mutations in PDZD7 initially reported to cause digenic Usher syndrome type 2 with ADGRV1 (Ebermann et al., 2010), but this association has been called in to question. Mutations in PDZD7 have been shown to cause non-syndromic hearing loss only and not Usher syndrome (Booth et al., 2015).

Note 5: Puffenberger et al., 2012 by whole exome sequencing identified a homozygous mutation c.1361A>C (p.Tyr454Ser) in the HARS1 gene in a patient with RP, progressive hearing loss and episodic psychosis. The patient is part of the Old Order Amish community. The authors identified three other individuals with a similar phenotype to be homozygous for the same variant. The frequency of this allele in the Old Order Amish community is ~1.5%, the authors suggest it is a founder mutation. Functional assays suggest the pathogenic mechanism is due to over activity of HARS1. Of note 80 other homozygous variants were identified in this individual. This manuscript also reports 4 other novel genes for other phenotypes, with similar limited evidence. Some have called this report in to question and the gene has not yet been replicated as a cause of Usher syndrome in other populations.