Monogenic hearing loss

Gene: TIMM8A

Green List (high evidence)

Comment on mode of inheritance: As there are at least 3 unrelated symptomatic females (1 presenting with deafness) reported in literature with heterozygous TIMM8A variants, the MOI should be changed to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males).

Created: 22 Jul 2026, 12:57 p.m. | Last Modified: 22 Jul 2026, 12:57 p.m.

Panel Version: 6.28

PMID: 40597358 Ventura et al., 2025
Report of a 16yo male with 6-year history of progressive dystonia, motor coordination difficulties, and iron deposits in the basal ganglia detected by brain MRI; no hearing loss. WES detected a hemizygous TIMM8A variant c.98_101dupAGCA.
The variant was inherited from a heterozygous mother, 43yo, who had recurrent muscle spasms - confirmed generalized dystonia, particularly affecting the upper extremities and cervical muscles. Maternal uncle showed motor clumsiness and finger spasms in childhood. Neither had hearing loss or visual impairment.

PMID: 22736418 Ha et al., 2012
Report of a female proband (kindred B) heterozygous for a TIMM8A variant c.127del, p.Cys43Valfs*22. She presented with deafness (onset in early 40s) and dystonia (initially in right upper limb) with onset in mid 40s. Dystonia progressed to oromandibular, upper limbs, and lower limbs. Cognitive decline was noted in her 50s.

PMID: 11601506 Swerdlow & Wooten, 2001
Kindred with Mohr-Tranebjaerg syndrome. Proband is a 30yo male with congenital deafness, and generalised dystonia starting around 28yo. Proband's mother reported head shaking, chronic neck muscle pain, and writer's cramp since age 25yrs. 1 female sibling of the proband was unaffected, while the other reported head shaking and writer's cramp with onset in late teens / early 20s. Affected patients harboured TIMM8A (old name DDP1) c.108del.

Created: 22 Jul 2026, 12:57 p.m. | Last Modified: 22 Jul 2026, 12:57 p.m.

Panel Version: 6.28

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Mohr-Tranebjaerg syndrome, OMIM:304700; deafness dystonia syndrome, MONDO:0010578

Publications

• 11601506
• 22736418
• 40597358

PMID: 32820032 (2020) - Animal mouse model with a hemizygous variant (p.I23fs49X) in the Timm8a1 gene, recapitulated features of deafness-dystonia-optic neuronopathy (DDON) syndrome. Mutant male mice exhibited hearing impairment, cognitive decline, and some age-dependant alteration in motor coordination and balance. Abnormal mitochondrial morphology was detected in several brain regions of mutant mice using electron microscopy.

Created: 2 Sep 2020, 2:06 p.m. | Last Modified: 2 Sep 2020, 2:06 p.m.

Panel Version: 2.45

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Publications

• 32820032

Green List (high evidence)

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
#304700:Mohr-Tranebjaerg syndrome[Sensorineural deafness, postlingual, progressive; PhotophobiaCortical blindnessMyopiaDecreased visual acuityConstricted visual fieldsAbnormal electroretinogram; Fractures; DystoniaSpasticityAbnormal posturingDysphagiaDysarthriaTremorHyperreflexiaMental deterioration; Behavioral/psychiatric abnormalities]; #311150:Jensen syndrome[Optic atrophy; Blindness; Infantile sensorineural hearing loss; Dementia; Moderate diffuse skeletal muscle wasting; Extensive CNS calcification in all structures, including meninges, vessels, and neurons at autopsy]; #:Deafness, X-linked 1, progressive

Publications

• PMID:10051608
• 10878669
• 11405816
• 11601506
• 11875042
• 11956200
• 15037720
• 15254020
• 15710860
• 16411215
• 8380905
• 8841189

Comment on list classification: Good evidence from expert reviewer and OMIM

Created: 31 Jan 2016, 8 p.m.

Green List (high evidence)

Good evidence for causing Mohr-Tranebjaerg syndrome and the diagnosis could be missed so put on green list. Neurodegenerative

Created: 19 Oct 2015, 6:14 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Variants in this GENE are reported as part of current diagnostic practice