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, Alagramam 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.