ClinGen Dosage Sensitivity Curation Page

TIMM8A

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
11405816 Ujike et al (2001) identified a nonsense variant of TIMM8A in a family with multiple affected males with X-linked dystonia-deafness syndrome (Mohr-Tranebjaerg syndrome; MTS).
17471106 Bahmad Jr. et al (2007) reported a frameshift variant in TIMM8A in 16 affected males from a large, multigeneration, Norwegian family with MTS.
22736418 Ha et al (2012) reported six MTS patients from three Australian families. The affected members had exon 2 deletion (Family A), a single base pair deletion resulting in frameshift (Family B), and a nonsense variant (Family 3) of TIMM8A.
17851739 Sediva et al (2007) reported several male patients with contiguous X-chromosome deletions encompassing the BTK and TIMM8A genes, resulting in the combination of X-linked agammaglobulinemia (XLA) (associated with loss of the BTK gene) and with sensorineural deafness.
30634948 Wang et al (2019) identified a novel frameshift variant (p.Leu78SerfsX21) of TIMM8A in a Chinese family with auditory neuropathy using next generation sequencing. In addition, another patient had an inframe variant (c.133_135delGAG). The third patient showed a deletion involving TIMM8A and BTK genes.
31903733

Haploinsufficiency phenotype comments:

The rare, X-linked recessive neurodegenerative disorder, Mohr?Tranebjaerg syndrome (also called deafness-dystonia-optic neuronopathy [DDON] syndrome), is caused by loss-of-function variants or a contiguous gene deletion of Xp22.1 involving DDP1/TIMM8A gene. Frameshifts or premature stops represent the majority of variants in TIMM8A; however, missense variants have also been reported that result in loss of the TIMM8A gene product. Further, contiguous X-chromosome deletions, encompassing the BTK and TIMM8A genes, are associated with the combination of immunodeficiency and sensorineural deafness. The DDP1 protein is located in the intermembrane space of human mitochondria.TIMM8A comprises only two exons, and is involved in the transport and sorting of proteins to the mitochondrial inner membrane. It appears unlikely that pseudogene TIMM8AP1 will interfere with the analysis of TIMM8A. DDON syndrome is characterized by dystonia, early-onset deafness, and various other neurological manifestations. Males are always affected and female carriers may have mild hearing loss and mild dystonia symptoms. Affected males have sensorineural hearing impairment in early childhood, slowly progressive dystonia or ataxia in the teens, slowly progressive decreased visual acuity from optic atrophy beginning at approximately age 20 years, and dementia beginning at approximately age 40 years. Psychiatric symptoms such as personality change and paranoia may appear in childhood and progress. Females may have mild hearing impairment and focal dystonia (https://www.ncbi.nlm.nih.gov/books/NBK1216/).

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Triplosensitivity of the DDP1/TIMM8A has not yet been established.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.