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Structural eye disease v4.40 TOMM7 Eleanor Williams edited their review of gene: TOMM7: Added comment: 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.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v0.76 MAF Nicola Ragge reviewed gene: MAF: Rating: GREEN; Mode of pathogenicity: Other - please provide details in the comments; Publications: 12642301, 17982426, 16470690; Phenotypes: Cataract 21, multiple types 610202; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Structural eye disease v0.71 MAF Ivone Leong edited their review of gene: MAF: Added comment: Promoted from amber to green as there is sufficient evidence.; Changed publications: 12642301, 17982426
Structural eye disease v0.38 MAF Ivone Leong reviewed gene: MAF: Rating: GREEN; Mode of pathogenicity: Other - please provide details in the comments; Publications: 12642301, 17982426; Phenotypes: Cataract 21, multiple types 610202; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Structural eye disease v0.15 MAF Ivone Leong Source NHS GMS was added to MAF.
Source Expert Review Green was added to MAF.
Mode of pathogenicity for gene MAF was changed from to Other - please provide details in the comments
Added phenotypes Cataract 21, multiple types 610202 for gene: MAF
Publications for gene MAF were changed from 11772997 to 12642301; 17982426
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.2 MAF Ellen McDonagh gene: MAF was added
gene: MAF was added to Structural eye disease. Sources: Expert Review Amber
Mode of inheritance for gene: MAF was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAF were set to 11772997
Phenotypes for gene: MAF were set to Cataract 21, multiple types 610202