Table 6b.

Select Common Causes of Autosomal Recessive Syndromic Hearing Loss

Gene(s)SyndromeHearing LossComment
TypeOnsetSeverity
ADGRV1
USH2A
WHRN 		Usher syndrome (USH) type II SNHLCongenitalMild to severe
  • Usher syndrome overall is the most common type of AR syndromic HL.
  • Nonsyndromic HL mimic: HL is congenital; RP begins in late adolescence or early adulthood.
  • Intact or variable vestibular responses
  • WHRN is also assoc w/AR nonsyndromic HL.
BTD Biotinidase deficiency SNHLVariableVariable; some degree of HL is present in ≥75% of children who become symptomatic.If not recognized & corrected by daily addition of biotin to diet, affected persons develop neurologic features (e.g., seizures, hypotonia, DD, ataxia, vision findings, HL, & cutaneous abnormalities.
CDH23
MYO7A
PCDH15
USH1C
USH1G 		Usher syndrome (USH) type I SNHLCongenitalSevere to profound
  • Usher syndrome overall is the most common type of AR syndromic HL; USH1 is the most common type of Usher syndrome.
  • Nonsyndromic HL mimic: HL is congenital; RP begins in late adolescence or early adulthood.
  • Unless fitted w/cochlear implant, affected persons do not typically develop speech.
  • Severe vestibular dysfunction or vestibular areflexia. Imbalance is assoc w/HL & is defining feature of USH1. Children typically walk later than usual, at age ~18 mos-2 yrs.
  • CDH23, PCDH15, & USH1C are also assoc w/AR nonsyndromic HL.
  • MYO7A is also assoc w/AD & AR nonsyndromic HL.
CLRN1 Usher syndrome type III (OMIM PS276900)SNHLCongenitalVariable SNHL severity, progressiveUsher syndrome overall is the most common type of AR syndromic HL.
COL9A1
COL9A2
COL9A3 		AR Stickler syndromeConductive, SNHLVariableVariable
  • 40% have some degree of sensorineural hearing impairment (typically high tone, often subtle).
  • Conductive hearing loss can be seen & may be secondary to recurrent ear infections that are often assoc w/cleft palate &/or may be secondary to a defect of the ossicles of the middle ear.
KCNE1
KCNQ1 		Jervell & Lange-Nielsen syndrome SNHLCongenitalProfound
  • 3rd most common type of AR syndromic HL
  • HL & cardiac conduction anomalies
  • Classic presentation is a child who experiences syncopal episodes during periods of stress, exercise, or fright. 50% of affected persons had cardiac events before age 3 yrs.
PEX1
PEX2
PEX3
PEX5
PEX6
PEX10
PEX11B
PEX12
PEX13
PEX14
PEX16
PEX19
PEX26 		Zellweger spectrum disorder (ZSD)SNHLVariableVariable
  • ZSD is due to peroxisome disorder & incl hearing & vision loss, hypotonia, & other clinical features.
  • Milder ZSD may first come to attention due to failed hearing screening.
PEX7
PHYH 		Adult Refsum disease SNHLVariableSevere, progressive
  • RP, anosmia, neuropathy, ataxia, & HL
  • Auditory nerve involvement (auditory neuropathy) may be evident on testing of auditory brain stem evoked responses. Persons w/auditory nerve involvement may experience hearing difficulty even in presence of normal audiogram.
SLC26A4 1Pendred syndrome (PDS)SNHLCongenital or childhood onsetUsually (but not invariably) severe to profound
  • 2nd most common type of AR syndromic HL
  • HL, vestibular dysfunction, & thyroid goiter
  • HL may fluctuate but often progresses.
  • Vestibular dysfunction should be suspected in infants w/delayed walking.
  • Temporal bones are abnormal radiologically in all persons w/PDS & most commonly incl incomplete partition type II anomaly & enlarged vestibular aqueduct.
  • SLC26A4 is also assoc w/AR nonsyndromic HL.

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; HL = hearing loss; RP = retinitis pigmentosa; SNHL = sensorineural hearing loss

1.

Digenic inheritance, in which an affected individual has double heterozygosity for a pathogenic variant in SLC26A4 and a pathogenic variant in FOXI1 [Yang et al 2007], or double heterozygosity for a pathogenic variant in SLC26A4 and a pathogenic variant in KCNJ10 has also been observed in Pendred syndrome.

From: Genetic Hearing Loss Overview

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