Usher Syndrome

Usher syndrome is characterised 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
Type Hearing Impairment Vestibular Impairment Retinitis Pigmentosa
Type I Congenital
Severe-to-profound hearing loss
Severe Onset in first decade of life
Type II Congenital
Moderate to severe hearing loss
None Onset in first or second decade of life
Type III Variable progressive hearing loss Variable Variable


MOLECULAR Classification of Usher Syndrome
Type Locus Gene (OMIM) Genomic Location Inheritance Key Reference (Pubmed)
Usher 1 USH1A - 14q32 Autosomal Recessive Kaplan et al., 1992; Gerber et al., 2006
Usher 1 USH1B MYO7A 11q13.5 Autosomal Recessive Weil et al., 1995
Usher 1 USH1C USH1C 11p15.1 Autosomal Recessive Verpy et al., 2000
Usher 1 USH1D CDH23 10q22.1 Autosomal Recessive Bolz et al., 2001
Usher 1 USH1E - 21q21 Autosomal Recessive Chaib et al., 1997
Usher 1 USH1F PCDH15 10q21.1 Autosomal Recessive Ahmed et al., 2001
Usher 1 USH1G SANS/USH1G 17q25.1 Autosomal Recessive Weil et al., 2003
Usher 1 USH1H - 15q22-23 Autosomal Recessive Ahmed et al., 2009
Usher 1 USH1J See Note A 15q25.1 Autosomal Recessive Ahmed et al., 2009
Usher 1 USH1K - 10p11.21-q21.1 Autosomal Recessive Jaworek et al., 2012
Usher 2 USH2A USH2A 1q41 Autosomal Recessive Eudy et al., 1998
Usher 2 USH2B - 3p23-24.2 Autosomal Recessive Hmani-Aifa et al., 1999,  ***retracted: see Hmnai-Aifa et al., 2009
Usher 2 USH2C ADGRV1/VLGR1/GPR98 (See Note B) 5q14.3 Autosomal Recessive Weston et al., 2004
Usher 2 USH2D WHRN 9q32 Autosomal Recessive Ebermann et al., 2007
Usher 3 USH3A CLRN1 3q25.1 Autosomal Recessive Joensuu et al., 2001
Usher 3 USH3B HARS (See Note C) 5q31.1   Puffenberger et al., 2012

Genes called in to question:
Note A: Mutations in CIB2 were initially reported to cause Usher Syndrome Type 1J (Riazuddin et al., 2012), but this has been called in to question. Mutations in CIB2 have been reported to cause non-syndromic hearing loss only (Booth et al., 2018).

Note B: 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 C: Puffenberger et al identified by whole exome sequencing identified a homozygous mutation c.1361A>C (p.Tyr454Ser) in the HARS 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 HARS. 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.