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

MOLECULAR Classification of Usher Syndrome

Type	Locus (OMIM)	Gene (OMIM)	Inheritance	Key Locus References (PubMed)	Key Gene References (PubMed)	Evidence (ClinGen)
Usher 1	USH1A (see note 1)	n/a	Autosomal Recessive	Kaplan et al., 1992; Gerber et al., 2006	n/a	n/a
Usher 1	USH1B	MYO7A	Autosomal Recessive	Kimberling et al., 1992; Smith et al., 1992	Weil et al., 1995	Definitive
Usher 1	USH1C	USH1C	Autosomal Recessive	Smith et al., 1992; Keats et al., 1994	Verpy et al., 2000	Definitive
Usher 1	USH1D	CDH23	Autosomal Recessive	Wayne et al., 1996	Bolz et al., 2001	Definitive
Usher 1	USH1E	unknown	Autosomal Recessive	Chaïb et al., 1997	n/a	n/a
Usher 1	USH1F	PCDH15	Autosomal Recessive	Wayne et al., 1997	Ahmed et al., 2001; Alagramam et al., 2001	Definitive
Usher 1	USH1G	USH1G/SANS	Autosomal Recessive	Mustapha et al., 2002	Weil et al., 2003	Definitive
Usher 1	USH1H	unknown	Autosomal Recessive	Ahmed et al., 2009	n/a	n/a
Usher 1	USH1J	unknown (see note 2)	Autosomal Recessive	Riazuddin et al., 2012	n/a	n/a
Usher 1	USH1K	unknown	Autosomal Recessive	Jaworek et al., 2012	n/a	n/a
Usher 2	USH2A	USH2A	Autosomal Recessive	Kimberling et al., 1990; Kimberling et al., 1995	Eudy et al., 1998	Definitive
Usher 2	USH2B (see note 3)	n/a	Autosomal Recessive	Hmani et al., 1999; Hmani-Aifa et al., 2009	n/a	n/a
Usher 2	USH2C	ADGRV1/VLGR1/GPR98 (see note 4)	Autosomal Recessive	Pieke-Dahl et al., 2000	Weston et al., 2004	Definitive
Usher 2	USH2D	WHRN	Autosomal Recessive	Ebermann et al., 2007	Ebermann et al., 2007	Definitive
Usher 3	USH3A	CLRN1	Autosomal Recessive	Sankila et al., 1995; Joensuu et al., 1996	Joensuu et al., 2001	Definitive
Usher 3	USH3B	HARS1 (see note 5)	Autosomal Recessive	Puffenberger et al., 2012	Puffenberger et al., 2012	Refuted

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.