Table 3.

Genes of Interest in the Differential Diagnosis of Usher Syndrome Type I

Gene(s)DisorderMOIClinical CharacteristicsComment
Digenic 1
  • Congenital bilateral SNHL (predominantly in the higher frequencies); ranges from mild to severe
  • Adolescent- to adult-onset RP
  • Normal vestibular function
Children w/USH1 are usually delayed in walking until age 18 mos to 2 yrs because of vestibular involvement, whereas children w/USH2 usually begin walking at ~1 yr.
ALMS1 Alström syndrome AR
  • SNHI
  • Progressive cone-rod dystrophy leading to blindness
  • Childhood obesity associated w/hyperinsulinemia, & type 2 diabetes
  • Cardiomyopathy occurs in ~70% of affected persons in infancy or adolescence.
  • Kidney failure & pulmonary, hepatic, & urologic dysfunction are frequent.
  • Systemic fibrosis develops w/age.
CEP250 Cone-rod dystrophy and hearing loss 2 (OMIM 618358)AR
  • Variable onset & severity of hearing loss
  • Variable onset & severity of visual loss
Can be diagnosed as atypical USH1 2
CEP78 Cone-rod dystrophy & hearing loss 1 (OMIM 617236)AR
  • Late-onset hearing loss
  • Late-onset visual loss
Can be diagnosed as atypical USH2 3
Wolfram syndrome (DIDMOAD) (See WFS1 Spectrum Disorder.)ARSevere neurodegenerative disease w/diabetes insipidus, diabetes mellitus, OA, & deafnessAffected persons may also have kidney abnormalities, ataxia, dementia, or ID & diverse psychiatric illnesses.
USH3 (OMIM 276902, 614504)AR
  • Postlingual progressive SNHL
  • Late-onset RP
  • Variable impairment of vestibular function
Some persons w/USH3 have profound hearing loss & vestibular disturbance & thus may be clinically misdiagnosed as having USH1 or USH2.
Alport syndrome XL
  • Variable SNHL
  • Variable ocular anomalies
  • Progressive deterioration of glomerular basement membranes resulting in progressive kidney failure
Both Alport syndrome & USH1 have hearing & visual loss, but Alport syndrome also has progressive kidney disease. Urinalysis abnormalities in Alport are clinically distinctive.
Heimler syndrome (OMIM 234580, 616617)AR
  • SNHL
  • Retinal degeneration
  • Enamel dysplasia & nail abnormalities
Both Heimler syndrome & USH1 have hearing & visual loss, but Heimler syndrome also has a defect of the teeth in which the enamel is hypoplastic.
(13 genes) 4
Zellweger spectrum disorder ARSevere neurologic dysfunction, craniofacial abnormalities, liver dysfunction, & absent peroxisomesPersons w/Zellweger syndrome typically die in the 1st yr of life.
PEX6 Peroxisome biogenesis disorder 4B (OMIM 614863)AD
  • SNHL
  • RP
  • Hypotonia
Overlapping phenotype w/neonatal adrenoleukodystrophy, infantile Refsum disease, & Zellweger spectrum disorder
PRPS1 PRPS1 hereditary motor & sensory neuropathy (CMTX5) (See Phosphoribosylpyrophosphate Synthetase Deficiency.)XL
  • Deafness
  • OA
  • Polyneuropathy
Males tend to be severely affected.
PRPS1 Arts syndrome (See Phosphoribosylpyrophosphate Synthetase Deficiency.)XL
  • Hearing impairment
  • OA
  • ID, early-onset hypotonia, ataxia, delayed motor development
Both Arts syndrome & USH1 have hearing & visual loss, but Arts syndrome also has neurologic & immune system deficits.
RPGR RPGR nonsyndromic RP (See Nonsyndromic Retinitis Pigmentosa Overview.)XLProgressive RP2% of persons w/RPGR nonsyndromic RP also have ciliary dyskinesia & hearing loss. 5
TIMM8A Deafness-dystonia-optic neuronopathy syndrome (DDON)XL
  • Males: prelingual or postlingual SNHL in early childhood; slowly progressive ↓ visual acuity from OA beginning at age ~20 yrs; dementia beginning at age ~40 yrs; slowly progressive dystonia or ataxia in the teens
  • Females: mild hearing impairment & focal dystonia
In DDON, appearance of the retina, night vision, & ERG are usually normal; in USH, impaired vision results from retinal dystrophy, which first manifests as impaired dark adaptation.

AR = autosomal recessive; CMTX5 = Charcot-Marie-Tooth neuropathy X type 5; DIDMOAD = diabetes insipidus, diabetes mellitus, optic atrophy, and deafness; ID = intellectual disability; MOI = mode of inheritance; OA = optic atrophy; RP = retinitis pigmentosa; SNHI = sensorineural hearing impairment; SNHL = sensorineural hearing loss; USH = Usher syndrome; XL = X-linked; USH1 = Usher syndrome type I; USH2 = Usher syndrome type II; USH3 = Usher syndrome type III


Digenic USH2 is caused by pathogenic variants in ADGRV1 and PDZD7.


Nikopoulos et at [2016], Fu et al [2017]


60.5% of Zellweger spectrum disorder (ZSD) is associated with biallelic pathogenic variants in PEX1, 14.5% with pathogenic variant in PEX6, and 7.6% with pathogenic variants in PEX12. In total, 13 genes are known to be associated with ZSD.


From: Usher Syndrome Type I

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