Structural eye disease

Gene: TOMM7

Green List (high evidence)

This gene is linked to the syndromic mitochondrial condition Garg-Mishra progeroid syndrome OMIM:620601. The main phenotypes of this condition are severe postnatal growth failure / short stature, often with microcephaly and skeletal dysplasia, developmental delay and hypotonia. Moyamoya disease (cerebrovascular disorder) or a Leigh(-like) syndrome is also seen in some cases.

A subset of patients have an eye phenotype including 10 patients of Chinese/Taiwanese ancestry (all with p.P29L) and 1 patient of Indian ancestry (splice variant). The possibility of a founder effect has been explored but additional evidence comes from functional studies showing that the p.P29L variant affects mitochondrial function and thorough examination of the haplotype block for other candidate variants in Garg et al.

PMID: 36282599 Garg et al 2022 - 21-year-old man of Chinese ancestry with short stature, relative macrocephaly, facial dysmorphia, partial lipodystrophy, pendular nystagmus and high hyperopia with visual acuity of 3/60 in both eyes . He also had bilateral micro-ophthalmia with axial lengths of only 16.8 mm.
Through WES a variant was identified in TOMM7 (NC_000007.13:g.22862313G>A; NM_019059.4:c.86C>T; NP_061932.1:p.Pro29Leu) in the proband, and both the parents and the 2 unaffected siblings were heterozygous for the variant. Heterozygotes of this variant have been seen only in Koreans, Japanese, and other East Asians with a MAF of 0.000048 (gnomAD, v2.1.1).
The parents were found to be more distantly related than third-degree relatives. A 1.0 MB region of homozygosity that included TOMM7 on chromosome 7 was present in the proband, but not in any other family member. WGS)of the proband’s DNA did not identify any copy number variants or rare intronic variants in the regions of homozygosity across the proband’s genome. Functional studies identified that this is an inactivating variant associated with increased mitochondrial oxygen consumption.

PMID: 39615461 Li et al 2024 - 9 patients from 7 unrelated Taiwanese families with microcephaly, short stature, facial dysmorphia, developmental delay, atrophic macular scarring, and moyamoya disease that are homozygous for the TOMM7 p.P29L variant identified in the Garg et al publication. Hyperopia was seen in 4/7 familes, Maculopathy in 5 families, Nystagmus in 3 families, Strabismus in 4 families, Amblyobia in 5 families, and optic atrophy in 2 families. The probands showed higher levels of homozygosity compared to controls. The authors suggest a founder effect due to the high allele frequency of the variant in the Taiwanese population.
However, functional and knock out studies suggest that this is the causative variant. Deletion of tomm7 in zebrafish caused craniofacial and cerebrovascular defects that recapitulated human phenotypes. iPSC-derived endothelial cells with homozygous TOMM7 p.P29L showed increased TOM7 stability, enlarged mitochondria, increased senescence, and defective tube formation.

PMID: 39333057 Yeole et al 2025 - 4-month-old female child of Indian ethnicity significantly affected with neonatal-onset hypotonia, lactic acidosis, optic atrophy with absent foveal reflex, and neuroimaging findings suggestive of Leigh disease with a homozygous novel canonical splice variant, c.153-2A > C in TOMM7 (NM_019059.5). The variant leads to abnormal transcripts. Parents were heterozygous. An additional homozygous variant in CASR linked to hyperparathyroidism, neonatal severe (MIM# 239200) was identified. The proband died at 4.5 months.

Created: 12 Mar 2026, 5:41 p.m. | Last Modified: 12 Mar 2026, 5:41 p.m.

Panel Version: 4.40

The rating of this gene has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 12 Mar 2026, 3:02 p.m. | Last Modified: 12 Mar 2026, 3:02 p.m.

Panel Version: 4.39

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Comment on publications: PMID: 39615461 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.

Created: 25 Mar 2025, 10:08 a.m. | Last Modified: 25 Mar 2025, 10:08 a.m.

Panel Version: 4.4

Ocular features are reported in nine members of seven unrelated Chinese families, who all are homozygous for the same TOMM7 variant ( NM_019059.5:c.86C>T; NP_061932.1:p.P29L)(PMID: 39615461). The common features were Maculopathy (7/9 individuals), Amblyobia (6/9 individuals) and hyperopia (6/9 individuals).
Sources: Literature

Created: 24 Mar 2025, 3:25 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Garg-Mishra progeroid syndrome, OMIM:620601

Publications

• 39615461