Skeletal dysplasia

Gene: TOMM7

Green List (high evidence)

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: 24 Feb 2025, 6:08 p.m. | Last Modified: 24 Feb 2025, 6:08 p.m.

Panel Version: 7.23

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Comment on list classification: 2 cases reported with a skeletal phenotype with additional functional evidence for pathogenicity for the missense variants. A 3rd case with with a homozyous splice variant reports a more severe phenotype, with no skeletal phenotype recorded but earlier death.

Recommend green rating following GMS approval.

Created: 30 Oct 2024, 10:54 p.m. | Last Modified: 30 Oct 2024, 10:54 p.m.

Panel Version: 7.2

Associated with Garg-Mishra progeroid syndrome, 620601 (AR) in OMIM.

As reviewer Hannah Knight states, 2 cases reported with different homozygous missense variants in TOMM7:

PMID: 36282599 - Garg et al 2022, man of Chinese ancestry with an autosomal recessive form of progeria, characterized by severe proportionate short stature with relative macrocephaly, dysmorphisms and significant learning disabilities. The variant c.86C>T; p.Pro29Leu) in TOMM7 was found in a homozygous state in the proband, while parents and unaffected siblings were heterozyous. Functional studies showed reduced interactions between the mutant protein and core TOMM complex proteins in patient fibroblasts, aswell as increased mitochondrial oxygen consumption compared to control cells

PMID: 36299998. Young et al 2022 - report a Japanese patient with a TOMM7 homozygous variant (c.73T>C, p.Trp25Arg). The proband presented with a syndromic short stature, skeletal abnormalities, muscle hypotonia, microvesicular liver steatosis, and developmental delay. Results of studies with mouse models of TOMM7 deletion and also with knockin with the same variant suggest that the missense variant causes partial loss of Tomm7 function, producing a milder but still lethal phenotype compared to deletion. In addition, analysis of tibial growth plates in mutant mice showed shortening of the growth plate, suggesting reduced chondrocyte proliferation which could lead to the skeletal phenotype.

A 3rd case is reported in PMID: 39333057 Yeole et al 2024 in which a homozygous splice variant c.153-2A > C in TOMM7 (NM_019059.5) was identified. The consanguineous parents were heterozygous for this variant. 2 siblings died after 52 days and 4 months of life respectively. Exome analysis was from the older sibling. In this case the phenotype was of neonatal-onset hypotonia, lactic acidosis, optic atrophy, and neuroimaging results suggestive of Leigh disease. Additionally, a known missense variant c.186G > C p.(Arg62Ser) in exon 3 of CASR (NM_001178065.2) was identified in causing hyperparathyroidism. No skeletal examination was performed.

Created: 30 Oct 2024, 10:49 p.m. | Last Modified: 30 Oct 2024, 11:06 p.m.

Panel Version: 7.2

I don't know

PMID: 36282599 (2022) reported a homozygous missense variant in TOMM7 (P29L) in a patient with short stature, dysmorphisms, poor vision, and significant learning disabilities
PMID: 36299998 (2023) reported a homozygous missense variant in TOMM7 (W25R) in a patient with short stature and growth failure

In both cases, parents were tested and found to be heterozygous for the same variant
Sources: Literature

Created: 18 Oct 2024, 10:03 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Garg-Mishra progeroid syndrome; dwarfism; mandibular hypoplasia; microphthalmia; hyperopia; partial lipodystrophy

Publications

• PMID: 36282599
• PMID: 36299998