Garg-Mishra Progeroid Syndrome

Mendelian MONDO:0957953 Pathograph 25 Show in embeddings browser Progeroid syndrome Mitochondrial disease

Garg-Mishra progeroid syndrome is an ultra-rare autosomal recessive disorder caused by biallelic hypomorphic variants in TOMM7, which encodes a small regulatory subunit of the translocase of the outer mitochondrial membrane (TOM complex). Missense variants such as p.Pro29Leu and p.Trp25Arg weaken TOMM7 binding to the TOMM40 pore and alter import of a subset of the mitochondrial proteome, producing an unusual bioenergetic state in which oxygen consumption can rise while ATP synthesis is inefficient, and, in endothelium, a shift toward glycolysis. Clinically it presents with severe postnatal growth failure and proportionate dwarfism, progeroid facies with mandibular hypoplasia and abnormal dentition, high hyperopia, microphthalmia, nystagmus, amblyopia and atrophic macular scarring, narrow chest and hip and spine deformities, variable developmental delay or mild intellectual disability, occasional partial lipodystrophy, and in more than half of evaluated patients childhood-onset moyamoya cerebral vasculopathy with ischemic stroke. Several patients have died in childhood.

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1
Inheritance
11
Pathophys.
39
Phenotypes
25
Pathograph
1
Genes
2
Medical Actions
3
Models
4
References
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
All reported affected individuals are homozygous for a TOMM7 variant, with heterozygous unaffected parents and siblings. The p.Pro29Leu allele recurs in East Asian families (Chinese-Malaysian, Taiwanese, Han Chinese), while p.Trp25Arg was found in a single Japanese proband.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:36282599 SUPPORT Human Clinical
"Analyses of exome sequencing data from the entire family revealed only 1 rare homozygous missense variant (c.86C>T; p.Pro29Leu) in TOMM7 in the proband, while the parents and 2 unaffected siblings were heterozygous for the variant."
Segregation of a homozygous TOMM7 variant with heterozygous unaffected relatives establishes recessive inheritance in the index family.
PMID:36299998 SUPPORT Human Clinical
"The parents are heterozygous and the proband is homozygous for TOMM7 c.73T>C variant."
Independent recessive segregation of a second TOMM7 allele.
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Pathophysiology

11
TOMM7 Hypomorphic Loss of Function
Biallelic missense variants at conserved residues in the kinked transmembrane helix of TOMM7 (p.Pro29Leu, p.Trp25Arg). Mouse knock-in data show the variants are hypomorphic rather than null: homozygous W25R mice are milder than Tomm7 deletion mice.
TOMM7 hgnc:21648 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TOMM7 (hgnc:21648). hgnc:21648 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
Downstream
Weakened TOMM7-TOMM40 Core Complex Interaction
Show evidence (1 reference)
PMID:36299998 SUPPORT Model Organism
"Analysis of mouse models strongly suggested that the identified variant is hypomorphic because mice homozygous for this variant showed a milder phenotype than those with homozygous Tomm7 deletion."
Knock-in versus deletion mice show the patient allele is hypomorphic.
Weakened TOMM7-TOMM40 Core Complex Interaction
TOMM7 is a small regulatory subunit that contacts the TOMM40 beta-barrel pore and modulates TOM complex assembly and stability. Pro29 breaks the alpha-helix of the kinked transmembrane segment, and Trp25 sits beside Arg24, which is needed for TOMM40 interaction. The P29L protein still localizes to mitochondria but binds TOMM40 and TOMM22 poorly.
TOM complex GO:0005742 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves TOM complex, annotated with mitochondrial outer membrane translocase complex (GO:0005742). GO:0005742 is a cellular component from the Gene Ontology.
Downstream
Altered Mitochondrial Preprotein Import
Show evidence (1 reference)
PMID:36282599 SUPPORT In Vitro
"This effect was not due to mislocalization, as GFP-tagged TOMM7wt and TOMM7P29L both localized to mitochondria"
The defect is in complex binding, not in targeting of TOMM7 itself.
Altered Mitochondrial Preprotein Import
Altered TOM complex function changes the abundance of a subset of the mitochondrial proteome rather than causing a global import block. In patient fibroblasts 91 of 587 detected mitochondrial proteins differed, with oxidative phosphorylation subunits increased and phospholipid metabolism proteins reduced, leading the authors to propose that wild-type TOMM7 acts as a negative regulator of import for some precursors. In endothelium, Tomm7 deficiency increases mitochondrial import of Rac1. The direction of the proteomic change differs by cell type (see notes).
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
mitochondrial preprotein import GO:0070585 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal mitochondrial preprotein import, annotated with protein localization to mitochondrion (GO:0070585). GO:0070585 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Mitochondrial Uncoupling With Inefficient ATP Synthesis
Reduced Mitochondrial Phospholipid Metabolism Proteins
Endothelial Metabolic Reprogramming Toward Glycolysis
Endothelial Mitochondrial Rac1 Redox Signaling
Show evidence (1 reference)
PMID:36282599 SUPPORT In Vitro
"Of the 587 detected mitochondrial proteins, 91 were differentially expressed (P < 0.05), indicating that a subset of the mitochondrial proteome is affected by the presence of the TOMM7P29L variant"
Patient-fibroblast proteomics shows a selective import-dependent change.
Mitochondrial Uncoupling With Inefficient ATP Synthesis
Tomm7-deficient cells show increased basal and maximal oxygen consumption with preserved electron transport chain responses but inefficient coupling to ATP synthesis, a bioenergetic deficiency despite high respiration. Patient and Tomm7 P29L mouse fibroblasts show the same elevated oxygen consumption with upregulated respiratory chain subunits.
fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology. growth plate chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves growth plate chondrocyte, annotated with chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
oxidative phosphorylation GO:0006119 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal oxidative phosphorylation (GO:0006119). GO:0006119 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Tomm7 W25R knock-in and deletion mice Mouse recapitulates
Downstream
Adipose Tissue Lipoatrophy
Growth Plate Chondrocyte Hypoproliferation
Microvesicular Hepatic Steatosis
Show evidence (2 references)
PMID:36299998 SUPPORT In Vitro
"despite the bioenergetic deficiency, mutant cells show increased oxygen consumption with normal responses to electron transport chain (ETC) inhibitors, suggesting that Tomm7 deficiency leads to an uncoupling between oxidation and ATP synthesis"
Seahorse assays on primary cells cultured from Tomm7 mutant mice show the uncoupled bioenergetic state.
PMID:36282599 SUPPORT In Vitro
"We also observed elevated basal and maximal oxygen consumption rates in the fibroblasts from the proband as compared with control fibroblasts."
Patient fibroblasts show the same elevated respiration.
Reduced Mitochondrial Phospholipid Metabolism Proteins
Proteins of phospholipid metabolic pathways were less abundant in patient mitochondria. Because defects in phospholipid biosynthesis enzymes (AGPAT2, PIK3R1, PCYT1A) cause human lipodystrophies, the index report proposes this as a contributor to partial lipodystrophy; the link is a hypothesis, not a demonstrated mechanism.
Downstream
Adipose Tissue Lipoatrophy
Show evidence (1 reference)
PMID:36282599 SUPPORT In Vitro
"A proteomic comparison of mitochondria from control and proband-derived cultured fibroblasts revealed an increase in abundance of several proteins involved in oxidative phosphorylation, as well as a reduction in abundance of proteins involved in phospholipid metabolism."
Patient-fibroblast mitochondrial proteomics.
Adipose Tissue Lipoatrophy
Loss of subcutaneous adipose tissue. Tomm7 mutant mice show severe lipoatrophy as their most prominent gross phenotype, and the Japanese W25R proband had small white adipocytes at autopsy.
white adipocyte CL:0000448 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves white adipocyte (CL:0000448). CL:0000448 is a cell type from the Cell Ontology.
Animal models
Tomm7 W25R knock-in and deletion mice Mouse recapitulates
Downstream
Partial Lipodystrophy
Show evidence (2 references)
PMID:36299998 SUPPORT Model Organism
"The most prominent gross phenotype in these mouse models is lipoatrophy"
Lipoatrophy dominates the Tomm7 mouse phenotype.
PMID:36299998 SUPPORT Human Clinical
"relatively small white adipocytes in the retroperitoneal fat tissue"
Autopsy adipose histology in the W25R proband.
Growth Plate Chondrocyte Hypoproliferation
Tomm7 mutant mice have shortened tibial growth plates with reduced cell density and reduced chondrocyte proliferation (EdU, Ki-67) across the W25R and deletion genotypes. Growth plate chondrocytes rely mainly on glycolysis, so the authors propose a regulatory rather than purely energetic role for mitochondria here. Not yet examined in patients.
growth plate chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves growth plate chondrocyte, annotated with chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
Downstream
Systemic Growth Failure
Platyspondyly
Show evidence (1 reference)
PMID:36299998 SUPPORT Model Organism
"Histological analysis of tibial growth plates of mutant mice showed a shortening of the growth plate with reduced cellular densities and cellular proliferation"
Direct histological measurement in Tomm7 mutant mice.
Systemic Growth Failure
Progressive postnatal growth failure with normal birth size, despite normal growth hormone, IGF-1 and thyroid function, consistent with a cell-intrinsic energetic limitation rather than an endocrine deficiency. Tomm7 mutant mice have small body size and growth defects.
Downstream
Severe Short Stature
Postnatal Growth Retardation
Low Body Weight
Show evidence (1 reference)
PMID:36299998 SUPPORT Model Organism
"These Tomm7 mutant mice show pathological changes consistent with mitochondrial dysfunction, including growth defects, severe lipoatrophy, and lipid accumulation in the liver."
Mouse model reproduces growth failure alongside mitochondrial dysfunction.
Endothelial Metabolic Reprogramming Toward Glycolysis
In iPSC-derived endothelial cells homozygous for P29L, mitochondria are enlarged, ATP-synthesis and TCA-cycle proteins are reduced, respiration falls slightly and glycolytic ATP production and hexokinase 2 rise; cells show increased senescence and defective tube formation. Note this is the opposite respiratory direction from fibroblasts.
endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
glycolysis GO:0006096 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased glycolysis, annotated with glycolytic process (GO:0006096). GO:0006096 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Impaired Cerebral Angiogenesis
Show evidence (1 reference)
PMID:39615461 SUPPORT In Vitro
"mitochondrial respiration was slightly decreased while ATP production from glycolysis was significantly increased"
CRISPR-edited and patient iPSC-derived endothelial cells show glycolytic reprogramming.
Endothelial Mitochondrial Rac1 Redox Signaling
In zebrafish and mice, Tomm7 loss increases import of Rac1 into endothelial mitochondria, driving mitochondrial Rac1-coupled redox signaling that impairs angiogenesis. Endothelial-specific restoration of tomm7 rescues the cerebrovascular defect.
endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
Downstream
Impaired Cerebral Angiogenesis
Show evidence (1 reference)
PMID:30354240 SUPPORT Model Organism
"Restoration of the cerebrovascular anomaly by an endothelial-specific transgenesis of tomm7 further indicated a defect in endothelial function."
Endothelial rescue localizes the defect to the endothelium.
Impaired Cerebral Angiogenesis
Defective brain angiogenesis and cerebrovascular network formation, with cerebrovascular abnormalities in knockout mice and craniofacial and cerebrovascular defects in tomm7 zebrafish mutants. In patients this is proposed to underlie moyamoya vasculopathy, although moyamoya itself has not been modeled in animals.
angiogenesis GO:0001525 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased angiogenesis (GO:0001525). GO:0001525 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
tomm7 loss-of-function zebrafish Zebrafish partially recapitulates
Tomm7 knockout mouse (cerebrovascular) Mouse partially recapitulates
Downstream
Moyamoya Disease
Show evidence (2 references)
PMID:30354240 SUPPORT Model Organism
"selective inactivation of the tomm7 (translocase of outer mitochondrial membrane 7) gene, which encodes a small subunit of the Tom complex, specially impaired cerebrovascular network formation. Ablation of the ortholog Tomm7 in mice recapitulated cerebrovascular abnormalities."
Zebrafish and mouse Tomm7 loss impairs cerebrovascular development.
PMID:39615461 SUPPORT Model Organism
"deletion of tomm7 in zebrafish caused craniofacial and cerebrovascular defects that recapitulated human phenotypes"
Independent zebrafish replication.
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Pathograph

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Pathograph: causal mechanism network for Garg-Mishra Progeroid Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

39
Cardiovascular 4
Moyamoya Disease FREQUENT Moyamoya phenomenon HP:0011834 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Moyamoya phenomenon (HP:0011834). HP:0011834 is a phenotype from the Human Phenotype Ontology.
Sequelae: Ischemic Stroke
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"Moyamoya disease | + | − | NA | − | + | + | + | + | − | 63% (5/8)"
Moyamoya in five of eight evaluated cohort patients.
Mitral Regurgitation HP:0001653 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mitral regurgitation (HP:0001653). HP:0001653 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36282599 SUPPORT Human Clinical
"At age 11, echocardiography showed mild mitral regurgitation with normal chamber sizes and a left ventricular ejection fraction of 73%."
Echocardiographic finding in the index patient.
PMID:41460760 SUPPORT Human Clinical
"Cardiac ultrasound showed mild regurgitation of the bicuspid and tricuspid valves."
Mild mitral and tricuspid regurgitation in the Han Chinese boy.
Ischemic Stroke FREQUENT HP:0002140 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral infarction, annotated with Ischemic stroke (HP:0002140). HP:0002140 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"Infarction | + | − | NA | − | − | + | + | + | − | 50% (4/8)"
Cerebral infarction in four of eight evaluated cohort patients.
Cardiomegaly OCCASIONAL HP:0001640 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiomegaly (HP:0001640). HP:0001640 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"Cardiomegaly | − | − | NA | NA | + | − | − | + | − | 29% (2/7)"
Cardiomegaly in two of seven evaluated cohort patients.
Digestive 1
Microvesicular Hepatic Steatosis HP:0001414 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microvesicular hepatic steatosis (HP:0001414). HP:0001414 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36299998 SUPPORT Human Clinical
"Histological analysis showed microvesicular steatosis in the liver"
Autopsy finding in the W25R proband.
PMID:39615461 REFUTE Human Clinical
"Hepatosteatosis | − | NA | NA | NA | NA | NA | NA | − | NA | 0% (0/2)"
No hepatosteatosis in the two P29L patients who were scanned, arguing against steatosis as a common feature of the P29L form.
Ear 1
Protruding Ears OCCASIONAL HP:0000411 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Protruding ear (HP:0000411). HP:0000411 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"Prominent ears | − | − | + | − | − | − | − | + | − | 22% (2/9)"
Prominent ears in two of nine cohort patients.
Eye 7
High Hyperopia FREQUENT High hypermetropia HP:0008499 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High hypermetropia (HP:0008499). HP:0008499 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36282599 SUPPORT Human Clinical
"He had pendular nystagmus and high hyperopia with visual acuity of 3/60 in both eyes"
High hyperopia in the index patient.
PMID:39615461 SUPPORT Human Clinical
"Hyperopia | + | + | + | + | + | − | + | − | − | 67% (6/9)"
Hyperopia in six of nine cohort patients; degree not tabulated.
Microphthalmia HP:0000568 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microphthalmia (HP:0000568). HP:0000568 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36282599 SUPPORT Human Clinical
"He also had bilateral micro-ophthalmia with axial lengths of only 16.8 mm"
Bilateral microphthalmia by axial length.
Nystagmus FREQUENT HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:36282599 SUPPORT Human Clinical
"He had pendular nystagmus and high hyperopia with visual acuity of 3/60 in both eyes"
Pendular nystagmus in the index patient.
PMID:36299998 SUPPORT Human Clinical
"Other clinical features include narrow thorax, broad hands, small nails, nystagmus, muscular hypotonia with frog-leg posture and poor head control"
Nystagmus in the W25R proband.
PMID:39615461 SUPPORT Human Clinical
"Nystagmus | + | − | + | + | + | − | − | − | − | 44% (4/9)"
Nystagmus in four of nine cohort patients.
Atrophic Macular Scarring FREQUENT HP:0200056 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrophic macular scar, annotated with Macular scar (HP:0200056). HP:0200056 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39615461 SUPPORT Human Clinical
"macular scarring is likely to be the most common symptom that can be diagnosed at a younger age"
Macular scarring as the earliest, most common sign.
PMID:39615461 SUPPORT Human Clinical
"Maculopathy | + | + | + | + | + | + | − | − | + | 78% (7/9)"
Maculopathy in seven of nine cohort patients.
Amblyopia FREQUENT HP:0000646 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Amblyopia (HP:0000646). HP:0000646 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"Amblyobia | + | + | + | + | + | − | + | − | − | 67% (6/9)"
Amblyopia (tabulated as 'Amblyobia') in six of nine cohort patients.
Strabismus FREQUENT HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"Strabismus | + | − | + | + | − | − | − | + | − | 44% (4/9)"
Strabismus in four of nine cohort patients.
Optic Atrophy OCCASIONAL HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"Optic atrophy | − | − | − | − | − | − | + | + | − | 22% (2/9)"
Optic atrophy in two of nine cohort patients.
Head and Neck 6
Mandibular Hypoplasia VERY_FREQUENT Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mandibular hypoplasia, annotated with Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36282599 SUPPORT Human Clinical
"He had triangular facies with broad forehead, prominent nasal bridge, bulbous nose, severe mandibular hypoplasia, and dental crowding"
Severe mandibular hypoplasia in the index patient.
PMID:39615461 SUPPORT Human Clinical
"Micrognathia | + | + | + | + | + | + | + | + | + | 100% (9/9)"
Micrognathia in all nine Taiwanese cohort patients.
Triangular Face OCCASIONAL HP:0000325 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Triangular face (HP:0000325). HP:0000325 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36282599 SUPPORT Human Clinical
"He had triangular facies with broad forehead, prominent nasal bridge, bulbous nose, severe mandibular hypoplasia, and dental crowding"
Triangular facies in the index patient.
PMID:39615461 SUPPORT Human Clinical
"Triangular face | + | + | − | − | − | − | − | − | − | 22% (2/9)"
Triangular face in two of nine cohort patients.
Dental Crowding and Protruding Incisors FREQUENT HP:0000678 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dental crowding (HP:0000678). HP:0000678 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39615461 SUPPORT Human Clinical
"Protruding maxillary central incisors, crowded and irregular teeth, hair thinning with obvious hair loss."
Characteristic dentition in the cohort.
PMID:39615461 SUPPORT Human Clinical
"Dental crowding | + | − | − | + | − | + | − | − | + | 44% (4/9)"
Dental crowding in four of nine cohort patients.
Microcephaly FREQUENT HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"Microcephaly | + | − | + | + | + | + | − | + | + | 78% (7/9)"
Microcephaly in seven of nine cohort patients.
Relative Macrocephaly HP:0004482 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Relative macrocephaly (HP:0004482). HP:0004482 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36282599 SUPPORT Human Clinical
"He had proportionate short stature with relative macrocephaly"
Relative macrocephaly in the index patient.
Broad Forehead FREQUENT HP:0000337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad forehead (HP:0000337). HP:0000337 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"Broad forehead | + | − | − | + | + | − | − | − | + | 44% (4/9)"
Broad forehead in four of nine cohort patients.
Integument 3
Progeroid Facial Appearance HP:0005328 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progeroid facial appearance (HP:0005328). HP:0005328 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36282599 SUPPORT INDIRECT Human Clinical
"We concluded that altered mitochondrial protein import due to biallelic loss-of-function TOMM7 can cause severe growth retardation and progeroid features."
The index report frames the phenotype as progeroid; no source gives a dedicated description of a progeroid face beyond the individual dysmorphic features curated separately.
Sparse Hair FREQUENT HP:0008070 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse hair (HP:0008070). HP:0008070 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36282599 SUPPORT Human Clinical
"He had some café au lait spots on his limbs, coarse eyebrows, and sparse hair."
Sparse hair in the index patient.
PMID:39615461 SUPPORT Human Clinical
"Sparse hair | + | + | − | + | − | + | + | − | + | 67% (6/9)"
Sparse hair in six of nine cohort patients.
Nail Dystrophy FREQUENT HP:0008404 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nail dystrophy (HP:0008404). HP:0008404 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"Dystrophic nails | + | − | + | − | − | + | + | − | − | 44% (4/9)"
Dystrophic nails in four of nine cohort patients.
Limbs 3
Coxa Valga FREQUENT HP:0002673 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coxa valga (HP:0002673). HP:0002673 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"Coxa valga | − | − | − | + | + | + | + | + | + | 67% (6/9)"
Coxa valga in six of nine cohort patients; also seen in the W25R proband.
Stubby Fingers FREQUENT Brachydactyly HP:0001156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachydactyly (HP:0001156). HP:0001156 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"Stubby fingers | + | + | + | + | − | − | − | − | − | 44% (4/9)"
Stubby fingers in four of nine cohort patients.
Acetabular Dysplasia FREQUENT HP:0008807 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acetabular dysplasia (HP:0008807). HP:0008807 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"Acetabular dysplasia | − | − | − | − | − | + | + | + | − | 39% (3/9)"
Acetabular dysplasia in three of nine cohort patients (33%; the table prints 39%).
Metabolism 1
Increased Serum Lactate Dehydrogenase Increased circulating lactate dehydrogenase concentration HP:0025435 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased circulating lactate dehydrogenase, annotated with Increased circulating lactate dehydrogenase concentration (HP:0025435). HP:0025435 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36299998 SUPPORT Human Clinical
"The results of his laboratory tests at 12 and 20 months showed increased serum lactate dehydrogenase (LDH) levels"
Elevated LDH in the W25R proband.
Musculoskeletal 7
Partial Lipodystrophy OCCASIONAL HP:0009125 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Partial lipodystrophy, annotated with Lipodystrophy (HP:0009125). HP:0009125 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36282599 SUPPORT Human Clinical
"Most of the skinfold thickness measurements over the trunk and thighs were below the tenth percentile for normal males"
Anthropometric evidence of partial fat loss.
PMID:39615461 SUPPORT Human Clinical
"Lipodystrophy-like appearance | + | − | NA | − | − | − | − | − | − | 13% (1/8)"
Lipodystrophy-like appearance is uncommon in the larger cohort.
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscular hypotonia, annotated with Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36299998 SUPPORT Human Clinical
"Other clinical features include narrow thorax, broad hands, small nails, nystagmus, muscular hypotonia with frog-leg posture and poor head control"
Infantile hypotonia in the W25R proband.
Platyspondyly HP:0000926 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Platyspondyly (HP:0000926). HP:0000926 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36299998 SUPPORT Human Clinical
"Note thin ribs, mild platyspondyly with ovoid vertebral bodies, gracile long tubular bones with relatively large epiphyses in upper and lower extremities"
Skeletal survey findings in the W25R proband.
Narrow Chest FREQUENT HP:0000774 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Narrow chest (HP:0000774). HP:0000774 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"Narrow chest | + | − | − | + | − | + | + | + | + | 67% (6/9)"
Narrow chest in six of nine cohort patients; also noted in the W25R proband.
Scoliosis FREQUENT HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"Scoliosis | + | − | − | + | − | − | − | + | + | 44% (4/9)"
Scoliosis in four of nine cohort patients.
Kyphosis FREQUENT HP:0002808 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Kyphosis (HP:0002808). HP:0002808 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"Kyphosis | + | − | − | − | − | + | + | + | − | 44% (4/9)"
Kyphosis in four of nine cohort patients.
Rib Deformities OCCASIONAL Abnormal rib morphology HP:0000772 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal rib morphology (HP:0000772). HP:0000772 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"Rib deformities | − | − | − | − | − | − | − | + | + | 22% (2/9)"
Rib deformities in two of nine cohort patients; thin ribs were also seen in the W25R proband.
Nervous System 2
Mild Intellectual Disability FREQUENT HP:0001256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild intellectual disability (HP:0001256). HP:0001256 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:36282599 SUPPORT Human Clinical
"Although he communicated well verbally, he had significant learning disabilities."
Learning disability in the index patient.
PMID:39615461 SUPPORT Human Clinical
"Further neurocognitive examination showed that the proband had a mild intellectual disability requiring special education."
Mild intellectual disability in the cohort.
PMID:39615461 SUPPORT Human Clinical
"Cognition impairment | + | + | − | − | − | − | + | − | + | 44% (4/9)"
Cognitive impairment frequency in the cohort.
Global Developmental Delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36299998 SUPPORT Human Clinical
"muscular hypotonia with frog-leg posture and poor head control (head raising at 6 months)"
Delayed head control in the W25R infant.
Growth 3
Severe Short Stature VERY_FREQUENT HP:0003510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe short stature (HP:0003510). HP:0003510 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36282599 SUPPORT Human Clinical
"characterized by severe dwarfism, mandibular hypoplasia, hyperopia, and partial lipodystrophy"
Severe dwarfism in the index patient.
PMID:39615461 SUPPORT Human Clinical
"Height (cm) | 110 (−4.5 SD) | 91 (−1.9SD) | 117.5 (−9 SD) | 106.3 (−6.7 SD) | 125 (−4.6 SD) | 95 (−7.3 SD) | 91 (−6.0 SD) | 115.5 (−4.1 SD) | 104 (−6.0 SD) | Short stature 100% (9/9)"
Short stature in all nine cohort patients.
Postnatal Growth Retardation VERY_FREQUENT HP:0008897 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postnatal growth retardation (HP:0008897). HP:0008897 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36299998 SUPPORT Human Clinical
"He showed progressive postnatal growth retardation."
Normal birth size with progressive postnatal growth failure.
Low Body Weight VERY_FREQUENT Decreased body weight HP:0004325 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased body weight (HP:0004325). HP:0004325 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"Low body weight | + | + | + | + | + | + | + | − | NA | 89% (8/9)"
Low body weight in eight of nine cohort patients.
Other 1
Death in Childhood
Show evidence (2 references)
PMID:36299998 SUPPORT Human Clinical
"The patient died at the age of 2 years and 7 months after developing pneumonia and respiratory failure."
Death in early childhood of the W25R proband.
PMID:36282599 SUPPORT Human Clinical
"His eldest sister also had dwarfism, sparse hair, high hyperopia and died at age 10 during a febrile illness associated with cough and shortness of breath."
Childhood death of an affected sibling in the index family.
🧬

Genetic Associations

1
TOMM7
Gene: TOMM7 hgnc:21648 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TOMM7 (hgnc:21648). hgnc:21648 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"This report showed the segregation of the variant allele in nine members from seven unrelated families and solidified that TOMM7 is the disease-causing gene of a syndrome with unique phenotypes."
Multi-family segregation establishes TOMM7 as causal.
💊

Medical Actions

2
Growth Hormone Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: somatropin NCIT:C837 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses somatropin (NCIT:C837). NCIT:C837 is a therapeutic agent from the NCI Thesaurus.
Platform: Other
Long-acting recombinant human growth hormone was given to a 2-year-old P29L homozygote with growth arrest despite normal endocrine testing. It slowed further loss of height SDS over 10 months. Growth hormone and IGF-1 were normal, so this is pharmacological growth promotion rather than hormone replacement. Single case, no control; efficacy and safety in this mitochondrial disorder are unestablished.
Target Phenotypes: Severe short stature HP:0003510 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Severe short stature (HP:0003510). HP:0003510 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41460760 SUPPORT Human Clinical
"After 10 months of treatment, his length increased by 3.8 cm (change in standard deviation score [SDS] of -0.34)."
Single-case report of partial growth response to GH.
Cerebral Revascularization Surgery
Action: encephaloduroarteriosynangiosisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is encephaloduroarteriosynangiosis, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Indirect revascularization (encephaloduroarteriosynangiosis) has been used for moyamoya in this disorder; no outcome series exists.
Target Phenotypes: Moyamoya phenomenon HP:0011834 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Moyamoya phenomenon (HP:0011834). HP:0011834 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39615461 SUPPORT Human Clinical
"She underwent encephaloduroarteriosynangiosis (EDAS) at age of 7."
EDAS used for moyamoya in a cohort patient.
🐁

Animal Models

3
Tomm7 W25R knock-in and deletion mice
Knock-in of the patient W25R allele and a splice-disrupting null deletion allele. All genotypes show growth defects, severe lipoatrophy and hepatic lipid accumulation with premature death, graded by allele severity.
Species
Mouse
Genotype
Tomm7 W25R/W25R, W25R/deletion and deletion/deletion
Publication
PMID:36299998
Pathograph links
Adipose Tissue Lipoatrophy recapitulates fidelity: moderate
Limitations: Lipoatrophy in mice is generalized and severe, whereas patients have partial lipodystrophy; mice die prematurely after rapid weight loss, which is not the human course.
Show evidence (1 reference)
PMID:36299998 SUPPORT Model Organism
"The most prominent gross phenotype in these mouse models is lipoatrophy"
Mouse lipoatrophy models the adipose phenotype.
Mitochondrial Uncoupling With Inefficient ATP Synthesis recapitulates fidelity: moderate
Show evidence (1 reference)
PMID:36299998 SUPPORT In Vitro
"despite the bioenergetic deficiency, mutant cells show increased oxygen consumption with normal responses to electron transport chain (ETC) inhibitors, suggesting that Tomm7 deficiency leads to an uncoupling between oxidation and ATP synthesis"
Mutant mouse cells show the uncoupled state.
tomm7 loss-of-function zebrafish
tomm7 loss impairs cerebrovascular network formation; endothelial-specific restoration of tomm7 rescues the vascular defect. A CRISPR tomm7 deletion line (PMID:39615461) independently shows craniofacial and cerebrovascular defects.
Species
Zebrafish
Genotype
tomm7 loss of function
Publication
PMID:30354240
Pathograph links
Impaired Cerebral Angiogenesis partially recapitulates fidelity: low
Limitations: Models a developmental cerebrovascular patterning defect, not the progressive large-artery stenosis and collateral formation of human moyamoya; no patient allele was tested.
Show evidence (1 reference)
PMID:30354240 SUPPORT Model Organism
"Tomm7 drives brain angiogenesis and cerebrovascular network formation through modulating mitochondrial Rac1 signaling within the endothelium."
Model establishes the endothelial angiogenic defect.
Tomm7 knockout mouse (cerebrovascular)
Constitutive Tomm7 ablation reproduces the cerebrovascular abnormalities seen in zebrafish.
Species
Mouse
Genotype
Tomm7 knockout
Publication
PMID:30354240
Pathograph links
Impaired Cerebral Angiogenesis partially recapitulates fidelity: low
Limitations: Null allele rather than the hypomorphic patient alleles; developmental vascular defect rather than progressive moyamoya arteriopathy.
Show evidence (1 reference)
PMID:30354240 SUPPORT Model Organism
"Ablation of the ortholog Tomm7 in mice recapitulated cerebrovascular abnormalities."
Mouse knockout reproduces the cerebrovascular defect.
{ }

Source YAML

click to show 
name: Garg-Mishra Progeroid Syndrome
creation_date: "2026-09-23T00:00:00Z"
category: Mendelian
parents:
- Progeroid syndrome
- Mitochondrial disease
synonyms:
- GMPGS
- TOMM7-associated syndrome
- Microcephalic osteodysplastic dwarfism with moyamoya disease
description: >-
  Garg-Mishra progeroid syndrome is an ultra-rare autosomal recessive disorder
  caused by biallelic hypomorphic variants in TOMM7, which encodes a small
  regulatory subunit of the translocase of the outer mitochondrial membrane
  (TOM complex). Missense variants such as p.Pro29Leu and p.Trp25Arg weaken
  TOMM7 binding to the TOMM40 pore and alter import of a subset of the
  mitochondrial proteome, producing an unusual bioenergetic state in which
  oxygen consumption can rise while ATP synthesis is inefficient, and, in
  endothelium, a shift toward glycolysis. Clinically it presents with severe
  postnatal growth failure and proportionate dwarfism, progeroid facies with
  mandibular hypoplasia and abnormal dentition, high hyperopia, microphthalmia,
  nystagmus, amblyopia and atrophic macular scarring, narrow chest and hip
  and spine deformities, variable developmental delay or mild intellectual
  disability, occasional partial lipodystrophy, and in more than half of
  evaluated patients childhood-onset moyamoya cerebral vasculopathy with
  ischemic stroke. Several patients have died in childhood.
disease_term:
  preferred_term: Garg-Mishra progeroid syndrome
  term:
    id: MONDO:0957953
    label: Garg-Mishra progeroid syndrome
references:
- reference: PMID:36282599
  title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
- reference: PMID:36299998
  title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
- reference: PMID:39615461
  title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
- reference: PMID:41460760
  title: "Growth Hormone Response in a Child With a Homozygous TOMM7 Mutation: Novel Therapeutic Insights."
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    All reported affected individuals are homozygous for a TOMM7 variant, with
    heterozygous unaffected parents and siblings. The p.Pro29Leu allele recurs
    in East Asian families (Chinese-Malaysian, Taiwanese, Han Chinese), while
    p.Trp25Arg was found in a single Japanese proband.
  evidence:
  - reference: PMID:36282599
    reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analyses of exome sequencing data from the entire family revealed only 1 rare homozygous missense variant (c.86C>T; p.Pro29Leu) in TOMM7 in the proband, while the parents and 2 unaffected siblings were heterozygous for the variant."
    explanation: >-
      Segregation of a homozygous TOMM7 variant with heterozygous unaffected
      relatives establishes recessive inheritance in the index family.
  - reference: PMID:36299998
    reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The parents are heterozygous and the proband is homozygous for TOMM7 c.73T>C variant."
    explanation: Independent recessive segregation of a second TOMM7 allele.
pathophysiology:
- name: TOMM7 Hypomorphic Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic missense variants at conserved residues in the kinked
    transmembrane helix of TOMM7 (p.Pro29Leu, p.Trp25Arg). Mouse knock-in data
    show the variants are hypomorphic rather than null: homozygous W25R mice are
    milder than Tomm7 deletion mice.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
  genes:
  - preferred_term: TOMM7
    term:
      id: hgnc:21648
      label: TOMM7
  evidence:
  - reference: PMID:36299998
    reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Analysis of mouse models strongly suggested that the identified variant is hypomorphic because mice homozygous for this variant showed a milder phenotype than those with homozygous Tomm7 deletion."
    explanation: Knock-in versus deletion mice show the patient allele is hypomorphic.
  downstream:
  - target: Weakened TOMM7-TOMM40 Core Complex Interaction
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36282599
      reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The TOMM7P29L protein interacted poorly with the core TOMM complex proteins — TOMM40 and TOMM22 — in contrast to TOMM7wt"
      explanation: >-
        Co-immunoprecipitation in HEK293 and TOMM7-null HeLa cells shows the
        patient variant directly weakens binding to the core TOM complex.
- name: Weakened TOMM7-TOMM40 Core Complex Interaction
  biological_scale: MOLECULAR
  description: >-
    TOMM7 is a small regulatory subunit that contacts the TOMM40 beta-barrel
    pore and modulates TOM complex assembly and stability. Pro29 breaks the
    alpha-helix of the kinked transmembrane segment, and Trp25 sits beside
    Arg24, which is needed for TOMM40 interaction. The P29L protein still
    localizes to mitochondria but binds TOMM40 and TOMM22 poorly.
  cellular_components:
  - preferred_term: TOM complex
    term:
      id: GO:0005742
      label: mitochondrial outer membrane translocase complex
  evidence:
  - reference: PMID:36282599
    reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This effect was not due to mislocalization, as GFP-tagged TOMM7wt and TOMM7P29L both localized to mitochondria"
    explanation: The defect is in complex binding, not in targeting of TOMM7 itself.
  downstream:
  - target: Altered Mitochondrial Preprotein Import
    causal_link_type: DIRECT
- name: Altered Mitochondrial Preprotein Import
  biological_scale: CELLULAR
  description: >-
    Altered TOM complex function changes the abundance of a subset of the
    mitochondrial proteome rather than causing a global import block. In
    patient fibroblasts 91 of 587 detected mitochondrial proteins differed,
    with oxidative phosphorylation subunits increased and phospholipid
    metabolism proteins reduced, leading the authors to propose that wild-type
    TOMM7 acts as a negative regulator of import for some precursors. In
    endothelium, Tomm7 deficiency increases mitochondrial import of Rac1. The
    direction of the proteomic change differs by cell type (see notes).
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: mitochondrial preprotein import
    modifier: ABNORMAL
    term:
      id: GO:0070585
      label: protein localization to mitochondrion
  evidence:
  - reference: PMID:36282599
    reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Of the 587 detected mitochondrial proteins, 91 were differentially expressed (P < 0.05), indicating that a subset of the mitochondrial proteome is affected by the presence of the TOMM7P29L variant"
    explanation: Patient-fibroblast proteomics shows a selective import-dependent change.
  downstream:
  - target: Mitochondrial Uncoupling With Inefficient ATP Synthesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Reduced Mitochondrial Phospholipid Metabolism Proteins
    causal_link_type: DIRECT
  - target: Endothelial Metabolic Reprogramming Toward Glycolysis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Endothelial Mitochondrial Rac1 Redox Signaling
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30354240
      reference_title: Endothelial Mitochondrial Preprotein Translocase Tomm7-Rac1 Signaling Axis Dominates Cerebrovascular Network Homeostasis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Tomm7 deficit in endothelial cells induced an increased import of Rac1 (Ras-related C3 botulinum toxin substrate 1) protein into mitochondria and facilitated the mitochondrial Rac1-coupled redox signaling"
      explanation: Import of a specific precursor is increased when Tomm7 is lost.
- name: Mitochondrial Uncoupling With Inefficient ATP Synthesis
  biological_scale: CELLULAR
  description: >-
    Tomm7-deficient cells show increased basal and maximal oxygen consumption
    with preserved electron transport chain responses but inefficient coupling
    to ATP synthesis, a bioenergetic deficiency despite high respiration.
    Patient and Tomm7 P29L mouse fibroblasts show the same elevated oxygen
    consumption with upregulated respiratory chain subunits.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: growth plate chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  biological_processes:
  - preferred_term: oxidative phosphorylation
    modifier: ABNORMAL
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  evidence:
  - reference: PMID:36299998
    reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "despite the bioenergetic deficiency, mutant cells show increased oxygen consumption with normal responses to electron transport chain (ETC) inhibitors, suggesting that Tomm7 deficiency leads to an uncoupling between oxidation and ATP synthesis"
    explanation: >-
      Seahorse assays on primary cells cultured from Tomm7 mutant mice show
      the uncoupled bioenergetic state.
  - reference: PMID:36282599
    reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We also observed elevated basal and maximal oxygen consumption rates in the fibroblasts from the proband as compared with control fibroblasts."
    explanation: Patient fibroblasts show the same elevated respiration.
  downstream:
  - target: Adipose Tissue Lipoatrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36299998
      reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Since OXPHOS defects cause tissue-autonomous lipoatrophy,25,26 these findings suggest that Tomm7 deficiency impairs mitochondrial bioenergetics."
      explanation: >-
        The authors link the lipoatrophy of Tomm7 mutant mice to impaired
        mitochondrial bioenergetics by analogy with OXPHOS defects.
  - target: Growth Plate Chondrocyte Hypoproliferation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36299998
      reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "these results suggest that the normal mitochondrial function plays an important regulatory role in growth plate chondrocytes"
      explanation: >-
        The authors attribute the chondrocyte defect to disturbed
        mitochondrial function; the specific role of uncoupling is inferred.
  - target: Microvesicular Hepatic Steatosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36299998
      reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "These Tomm7 mutant mice show pathological changes consistent with mitochondrial dysfunction, including growth defects, severe lipoatrophy, and lipid accumulation in the liver."
      explanation: >-
        Hepatic lipid accumulation is attributed to mitochondrial dysfunction
        in Tomm7 mutant mice; the specific link to uncoupling is inferred.
- name: Reduced Mitochondrial Phospholipid Metabolism Proteins
  biological_scale: CELLULAR
  description: >-
    Proteins of phospholipid metabolic pathways were less abundant in patient
    mitochondria. Because defects in phospholipid biosynthesis enzymes
    (AGPAT2, PIK3R1, PCYT1A) cause human lipodystrophies, the index report
    proposes this as a contributor to partial lipodystrophy; the link is a
    hypothesis, not a demonstrated mechanism.
  evidence:
  - reference: PMID:36282599
    reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A proteomic comparison of mitochondria from control and proband-derived cultured fibroblasts revealed an increase in abundance of several proteins involved in oxidative phosphorylation, as well as a reduction in abundance of proteins involved in phospholipid metabolism."
    explanation: Patient-fibroblast mitochondrial proteomics.
  downstream:
  - target: Adipose Tissue Lipoatrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36282599
      reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "it is possible that the lipodystrophy in our patient may be related to downregulation of these pathways"
      explanation: Explicitly hypothesized, not demonstrated, by the index report.
- name: Adipose Tissue Lipoatrophy
  biological_scale: TISSUE
  description: >-
    Loss of subcutaneous adipose tissue. Tomm7 mutant mice show severe
    lipoatrophy as their most prominent gross phenotype, and the Japanese
    W25R proband had small white adipocytes at autopsy.
  cell_types:
  - preferred_term: white adipocyte
    term:
      id: CL:0000448
      label: white adipocyte
  evidence:
  - reference: PMID:36299998
    reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The most prominent gross phenotype in these mouse models is lipoatrophy"
    explanation: Lipoatrophy dominates the Tomm7 mouse phenotype.
  - reference: PMID:36299998
    reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "relatively small white adipocytes in the retroperitoneal fat tissue"
    explanation: Autopsy adipose histology in the W25R proband.
  downstream:
  - target: Partial Lipodystrophy
    causal_link_type: DIRECT
- name: Growth Plate Chondrocyte Hypoproliferation
  biological_scale: TISSUE
  description: >-
    Tomm7 mutant mice have shortened tibial growth plates with reduced cell
    density and reduced chondrocyte proliferation (EdU, Ki-67) across the
    W25R and deletion genotypes. Growth plate chondrocytes rely mainly on
    glycolysis, so the authors propose a regulatory rather than purely
    energetic role for mitochondria here. Not yet examined in patients.
  cell_types:
  - preferred_term: growth plate chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:36299998
    reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Histological analysis of tibial growth plates of mutant mice showed a shortening of the growth plate with reduced cellular densities and cellular proliferation"
    explanation: Direct histological measurement in Tomm7 mutant mice.
  downstream:
  - target: Systemic Growth Failure
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36299998
      reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "suggesting that the reduced chondrocyte proliferation contributes to the skeletal phenotype"
      explanation: The authors link growth-plate hypoproliferation to the growth and skeletal phenotype.
  - target: Platyspondyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:36299998
      reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "The longitudinal growth of vertebral bodies and appendicular bones is driven by the growth plate."
      explanation: >-
        Vertebral body growth depends on the growth plate; flattening of the
        vertebrae is inferred to follow from its hypoproliferation.
- name: Systemic Growth Failure
  biological_scale: ORGANISM
  description: >-
    Progressive postnatal growth failure with normal birth size, despite
    normal growth hormone, IGF-1 and thyroid function, consistent with a
    cell-intrinsic energetic limitation rather than an endocrine deficiency.
    Tomm7 mutant mice have small body size and growth defects.
  evidence:
  - reference: PMID:36299998
    reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These Tomm7 mutant mice show pathological changes consistent with mitochondrial dysfunction, including growth defects, severe lipoatrophy, and lipid accumulation in the liver."
    explanation: Mouse model reproduces growth failure alongside mitochondrial dysfunction.
  downstream:
  - target: Severe Short Stature
    causal_link_type: DIRECT
  - target: Postnatal Growth Retardation
    causal_link_type: DIRECT
  - target: Low Body Weight
    causal_link_type: DIRECT
- name: Endothelial Metabolic Reprogramming Toward Glycolysis
  biological_scale: CELLULAR
  description: >-
    In iPSC-derived endothelial cells homozygous for P29L, mitochondria are
    enlarged, ATP-synthesis and TCA-cycle proteins are reduced, respiration
    falls slightly and glycolytic ATP production and hexokinase 2 rise; cells
    show increased senescence and defective tube formation. Note this is the
    opposite respiratory direction from fibroblasts.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: glycolysis
    modifier: INCREASED
    term:
      id: GO:0006096
      label: glycolytic process
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "mitochondrial respiration was slightly decreased while ATP production from glycolysis was significantly increased"
    explanation: CRISPR-edited and patient iPSC-derived endothelial cells show glycolytic reprogramming.
  downstream:
  - target: Impaired Cerebral Angiogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39615461
      reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "iPSC-derived endothelial cells with homozygous TOMM7 p.P29L showed increased TOM7 stability, enlarged mitochondria, increased senescence, and defective tube formation."
      explanation: The same cells that reprogram metabolism fail to form tubes in vitro.
- name: Endothelial Mitochondrial Rac1 Redox Signaling
  biological_scale: CELLULAR
  description: >-
    In zebrafish and mice, Tomm7 loss increases import of Rac1 into endothelial
    mitochondria, driving mitochondrial Rac1-coupled redox signaling that
    impairs angiogenesis. Endothelial-specific restoration of tomm7 rescues the
    cerebrovascular defect.
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  evidence:
  - reference: PMID:30354240
    reference_title: Endothelial Mitochondrial Preprotein Translocase Tomm7-Rac1 Signaling Axis Dominates Cerebrovascular Network Homeostasis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Restoration of the cerebrovascular anomaly by an endothelial-specific transgenesis of tomm7 further indicated a defect in endothelial function."
    explanation: Endothelial rescue localizes the defect to the endothelium.
  downstream:
  - target: Impaired Cerebral Angiogenesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30354240
      reference_title: Endothelial Mitochondrial Preprotein Translocase Tomm7-Rac1 Signaling Axis Dominates Cerebrovascular Network Homeostasis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "which incurred angiogenic impairment that underlies cerebrovascular network malformation"
      explanation: Mitochondrial Rac1 signaling causes the angiogenic defect.
- name: Impaired Cerebral Angiogenesis
  biological_scale: TISSUE
  description: >-
    Defective brain angiogenesis and cerebrovascular network formation, with
    cerebrovascular abnormalities in knockout mice and craniofacial and
    cerebrovascular defects in tomm7 zebrafish mutants. In patients this is
    proposed to underlie moyamoya vasculopathy, although moyamoya itself has
    not been modeled in animals.
  biological_processes:
  - preferred_term: angiogenesis
    modifier: DECREASED
    term:
      id: GO:0001525
      label: angiogenesis
  evidence:
  - reference: PMID:30354240
    reference_title: Endothelial Mitochondrial Preprotein Translocase Tomm7-Rac1 Signaling Axis Dominates Cerebrovascular Network Homeostasis.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "selective inactivation of the tomm7 (translocase of outer mitochondrial membrane 7) gene, which encodes a small subunit of the Tom complex, specially impaired cerebrovascular network formation. Ablation of the ortholog Tomm7 in mice recapitulated cerebrovascular abnormalities."
    explanation: Zebrafish and mouse Tomm7 loss impairs cerebrovascular development.
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "deletion of tomm7 in zebrafish caused craniofacial and cerebrovascular defects that recapitulated human phenotypes"
    explanation: Independent zebrafish replication.
  downstream:
  - target: Moyamoya Disease
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39615461
      reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Notably, five patients developed moyamoya disease, that correlates to cerebrovascular abnormalities found in animal studies."
      explanation: >-
        The authors link patient moyamoya to the angiogenic defect seen in
        models; the step is inferred rather than shown in patient vessels.
phenotypes:
- name: Severe Short Stature
  category: Growth
  frequency: VERY_FREQUENT
  description: >-
    Proportionate dwarfism, present in all nine Taiwanese P29L patients, with
    heights mostly between -4 and -9 SD; one 2-year-old sibling was -1.9 SD.
  phenotype_term:
    preferred_term: Severe short stature
    term:
      id: HP:0003510
      label: Severe short stature
  evidence:
  - reference: PMID:36282599
    reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by severe dwarfism, mandibular hypoplasia, hyperopia, and partial lipodystrophy"
    explanation: Severe dwarfism in the index patient.
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Height (cm) | 110 (−4.5 SD) | 91 (−1.9SD) | 117.5 (−9 SD) | 106.3 (−6.7 SD) | 125 (−4.6 SD) | 95 (−7.3 SD) | 91 (−6.0 SD) | 115.5 (−4.1 SD) | 104 (−6.0 SD) | Short stature 100% (9/9)"
    explanation: Short stature in all nine cohort patients.
- name: Postnatal Growth Retardation
  category: Growth
  frequency: VERY_FREQUENT
  description: Normal birth size followed by progressive postnatal growth failure.
  phenotype_term:
    preferred_term: Postnatal growth retardation
    term:
      id: HP:0008897
      label: Postnatal growth retardation
  evidence:
  - reference: PMID:36299998
    reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He showed progressive postnatal growth retardation."
    explanation: Normal birth size with progressive postnatal growth failure.
- name: Progeroid Facial Appearance
  category: Craniofacial
  description: >-
    Overall progeroid appearance; the component features (mandibular
    hypoplasia, triangular face, sparse hair, dental anomalies) are curated as
    separate phenotypes. Two Taiwanese patients had aged skin.
  phenotype_term:
    preferred_term: Progeroid facial appearance
    term:
      id: HP:0005328
      label: Progeroid facial appearance
  evidence:
  - reference: PMID:36282599
    reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We concluded that altered mitochondrial protein import due to biallelic loss-of-function TOMM7 can cause severe growth retardation and progeroid features."
    directness: INDIRECT
    explanation: >-
      The index report frames the phenotype as progeroid; no source gives a
      dedicated description of a progeroid face beyond the individual
      dysmorphic features curated separately.
- name: Mandibular Hypoplasia
  category: Craniofacial
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Mandibular hypoplasia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:36282599
    reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had triangular facies with broad forehead, prominent nasal bridge, bulbous nose, severe mandibular hypoplasia, and dental crowding"
    explanation: Severe mandibular hypoplasia in the index patient.
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Micrognathia | + | + | + | + | + | + | + | + | + | 100% (9/9)"
    explanation: Micrognathia in all nine Taiwanese cohort patients.
- name: Triangular Face
  category: Craniofacial
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Triangular face
    term:
      id: HP:0000325
      label: Triangular face
  evidence:
  - reference: PMID:36282599
    reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had triangular facies with broad forehead, prominent nasal bridge, bulbous nose, severe mandibular hypoplasia, and dental crowding"
    explanation: Triangular facies in the index patient.
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Triangular face | + | + | − | − | − | − | − | − | − | 22% (2/9)"
    explanation: Triangular face in two of nine cohort patients.
- name: Dental Crowding and Protruding Incisors
  category: Dental
  frequency: FREQUENT
  description: >-
    Crowded, irregular teeth with protruding maxillary central incisors of
    normal size, which helps distinguish this disorder from MOPD type II
    (small teeth).
  phenotype_term:
    preferred_term: Dental crowding
    term:
      id: HP:0000678
      label: Dental crowding
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Protruding maxillary central incisors, crowded and irregular teeth, hair thinning with obvious hair loss."
    explanation: Characteristic dentition in the cohort.
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dental crowding | + | − | − | + | − | + | − | − | + | 44% (4/9)"
    explanation: Dental crowding in four of nine cohort patients.
- name: Microcephaly
  category: Neurological
  frequency: FREQUENT
  description: >-
    Microcephaly in 7 of 9 Taiwanese P29L patients. The adult index patient's
    head circumference was also below the third percentile, though large
    relative to his body size.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microcephaly | + | − | + | + | + | + | − | + | + | 78% (7/9)"
    explanation: Microcephaly in seven of nine cohort patients.
- name: Relative Macrocephaly
  category: Craniofacial
  phenotype_term:
    preferred_term: Relative macrocephaly
    term:
      id: HP:0004482
      label: Relative macrocephaly
  evidence:
  - reference: PMID:36282599
    reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had proportionate short stature with relative macrocephaly"
    explanation: Relative macrocephaly in the index patient.
- name: High Hyperopia
  category: Ophthalmological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: High hypermetropia
    term:
      id: HP:0008499
      label: High hypermetropia
  evidence:
  - reference: PMID:36282599
    reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had pendular nystagmus and high hyperopia with visual acuity of 3/60 in both eyes"
    explanation: High hyperopia in the index patient.
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hyperopia | + | + | + | + | + | − | + | − | − | 67% (6/9)"
    explanation: Hyperopia in six of nine cohort patients; degree not tabulated.
- name: Microphthalmia
  category: Ophthalmological
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: PMID:36282599
    reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He also had bilateral micro-ophthalmia with axial lengths of only 16.8 mm"
    explanation: Bilateral microphthalmia by axial length.
- name: Nystagmus
  category: Ophthalmological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:36282599
    reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had pendular nystagmus and high hyperopia with visual acuity of 3/60 in both eyes"
    explanation: Pendular nystagmus in the index patient.
  - reference: PMID:36299998
    reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other clinical features include narrow thorax, broad hands, small nails, nystagmus, muscular hypotonia with frog-leg posture and poor head control"
    explanation: Nystagmus in the W25R proband.
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nystagmus | + | − | + | + | + | − | − | − | − | 44% (4/9)"
    explanation: Nystagmus in four of nine cohort patients.
- name: Atrophic Macular Scarring
  category: Ophthalmological
  frequency: FREQUENT
  description: >-
    Atrophic macular scarring is proposed as the most common and earliest
    detectable sign, seen as early as age 2.
  phenotype_term:
    preferred_term: Atrophic macular scar
    term:
      id: HP:0200056
      label: Macular scar
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "macular scarring is likely to be the most common symptom that can be diagnosed at a younger age"
    explanation: Macular scarring as the earliest, most common sign.
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Maculopathy | + | + | + | + | + | + | − | − | + | 78% (7/9)"
    explanation: Maculopathy in seven of nine cohort patients.
- name: Partial Lipodystrophy
  category: Metabolic
  frequency: OCCASIONAL
  description: >-
    Reduced truncal and thigh subcutaneous fat with well-defined musculature
    in the index patient, but a lipodystrophy-like appearance in only 1 of 8
    evaluable Taiwanese patients. Severe lipoatrophy is much more prominent
    in Tomm7 mutant mice than in patients.
  phenotype_term:
    preferred_term: Partial lipodystrophy
    term:
      id: HP:0009125
      label: Lipodystrophy
  evidence:
  - reference: PMID:36282599
    reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the skinfold thickness measurements over the trunk and thighs were below the tenth percentile for normal males"
    explanation: Anthropometric evidence of partial fat loss.
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lipodystrophy-like appearance | + | − | NA | − | − | − | − | − | − | 13% (1/8)"
    explanation: Lipodystrophy-like appearance is uncommon in the larger cohort.
- name: Sparse Hair
  category: Integument
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Sparse hair
    term:
      id: HP:0008070
      label: Sparse hair
  evidence:
  - reference: PMID:36282599
    reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had some café au lait spots on his limbs, coarse eyebrows, and sparse hair."
    explanation: Sparse hair in the index patient.
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sparse hair | + | + | − | + | − | + | + | − | + | 67% (6/9)"
    explanation: Sparse hair in six of nine cohort patients.
- name: Mild Intellectual Disability
  category: Neurological
  frequency: FREQUENT
  description: >-
    Cognitive impairment in 4 of 9 Taiwanese patients; significant learning
    disability with good verbal communication in the index adult.
  phenotype_term:
    preferred_term: Mild intellectual disability
    term:
      id: HP:0001256
      label: Mild intellectual disability
  evidence:
  - reference: PMID:36282599
    reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although he communicated well verbally, he had significant learning disabilities."
    explanation: Learning disability in the index patient.
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further neurocognitive examination showed that the proband had a mild intellectual disability requiring special education."
    explanation: Mild intellectual disability in the cohort.
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cognition impairment | + | + | − | − | − | − | + | − | + | 44% (4/9)"
    explanation: Cognitive impairment frequency in the cohort.
- name: Global Developmental Delay
  category: Neurological
  description: >-
    Delayed motor milestones in infant-onset cases, such as poor head control
    in the W25R proband.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:36299998
    reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "muscular hypotonia with frog-leg posture and poor head control (head raising at 6 months)"
    explanation: Delayed head control in the W25R infant.
- name: Hypotonia
  category: Neurological
  phenotype_term:
    preferred_term: Muscular hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:36299998
    reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other clinical features include narrow thorax, broad hands, small nails, nystagmus, muscular hypotonia with frog-leg posture and poor head control"
    explanation: Infantile hypotonia in the W25R proband.
- name: Moyamoya Disease
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    Progressive stenosis of the distal internal carotid arteries with
    collateral networks, presenting in childhood with stroke or hemiparesis;
    5 of 8 evaluated P29L patients in the Taiwanese cohort. Not reported in
    the index Chinese-Malaysian patient, whose brain MRI was normal.
  phenotype_term:
    preferred_term: Moyamoya phenomenon
    term:
      id: HP:0011834
      label: Moyamoya phenomenon
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moyamoya disease | + | − | NA | − | + | + | + | + | − | 63% (5/8)"
    explanation: Moyamoya in five of eight evaluated cohort patients.
  sequelae:
  - target: Ischemic Stroke
    causal_link_type: DIRECT
- name: Microvesicular Hepatic Steatosis
  category: Hepatic
  description: >-
    Seen at autopsy in the W25R proband and as liver lipid accumulation in
    Tomm7 mutant mice; not detected on ultrasound in two P29L patients.
  phenotype_term:
    preferred_term: Microvesicular hepatic steatosis
    term:
      id: HP:0001414
      label: Microvesicular hepatic steatosis
  evidence:
  - reference: PMID:36299998
    reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histological analysis showed microvesicular steatosis in the liver"
    explanation: Autopsy finding in the W25R proband.
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatosteatosis | − | NA | NA | NA | NA | NA | NA | − | NA | 0% (0/2)"
    explanation: >-
      No hepatosteatosis in the two P29L patients who were scanned, arguing
      against steatosis as a common feature of the P29L form.
- name: Increased Serum Lactate Dehydrogenase
  category: Laboratory
  phenotype_term:
    preferred_term: Increased circulating lactate dehydrogenase
    term:
      id: HP:0025435
      label: Increased circulating lactate dehydrogenase concentration
  evidence:
  - reference: PMID:36299998
    reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The results of his laboratory tests at 12 and 20 months showed increased serum lactate dehydrogenase (LDH) levels"
    explanation: Elevated LDH in the W25R proband.
- name: Platyspondyly
  category: Skeletal
  description: >-
    Mild platyspondyly with ovoid vertebral bodies, thin ribs and gracile long
    bones in the W25R proband.
  phenotype_term:
    preferred_term: Platyspondyly
    term:
      id: HP:0000926
      label: Platyspondyly
  evidence:
  - reference: PMID:36299998
    reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Note thin ribs, mild platyspondyly with ovoid vertebral bodies, gracile long tubular bones with relatively large epiphyses in upper and lower extremities"
    explanation: Skeletal survey findings in the W25R proband.
- name: Mitral Regurgitation
  category: Cardiovascular
  description: >-
    Mild mitral regurgitation with later mild left ventricular dilatation and
    preserved ejection fraction in the index patient; no structural heart
    defect.
  phenotype_term:
    preferred_term: Mitral regurgitation
    term:
      id: HP:0001653
      label: Mitral regurgitation
  evidence:
  - reference: PMID:36282599
    reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At age 11, echocardiography showed mild mitral regurgitation with normal chamber sizes and a left ventricular ejection fraction of 73%."
    explanation: Echocardiographic finding in the index patient.
  - reference: PMID:41460760
    reference_title: "Growth Hormone Response in a Child With a Homozygous TOMM7 Mutation: Novel Therapeutic Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac ultrasound showed mild regurgitation of the bicuspid and tricuspid valves."
    explanation: Mild mitral and tricuspid regurgitation in the Han Chinese boy.
- name: Ischemic Stroke
  category: Neurological
  frequency: FREQUENT
  description: >-
    Cerebral infarctions, with hemiparesis in some, secondary to moyamoya vasculopathy.
  phenotype_term:
    preferred_term: Cerebral infarction
    term:
      id: HP:0002140
      label: Ischemic stroke
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infarction | + | − | NA | − | − | + | + | + | − | 50% (4/8)"
    explanation: Cerebral infarction in four of eight evaluated cohort patients.
- name: Amblyopia
  category: Ophthalmological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Amblyopia
    term:
      id: HP:0000646
      label: Amblyopia
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Amblyobia | + | + | + | + | + | − | + | − | − | 67% (6/9)"
    explanation: Amblyopia (tabulated as 'Amblyobia') in six of nine cohort patients.
- name: Strabismus
  category: Ophthalmological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Strabismus | + | − | + | + | − | − | − | + | − | 44% (4/9)"
    explanation: Strabismus in four of nine cohort patients.
- name: Optic Atrophy
  category: Ophthalmological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Optic atrophy | − | − | − | − | − | − | + | + | − | 22% (2/9)"
    explanation: Optic atrophy in two of nine cohort patients.
- name: Narrow Chest
  category: Skeletal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Narrow chest
    term:
      id: HP:0000774
      label: Narrow chest
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Narrow chest | + | − | − | + | − | + | + | + | + | 67% (6/9)"
    explanation: Narrow chest in six of nine cohort patients; also noted in the W25R proband.
- name: Coxa Valga
  category: Skeletal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Coxa valga
    term:
      id: HP:0002673
      label: Coxa valga
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coxa valga | − | − | − | + | + | + | + | + | + | 67% (6/9)"
    explanation: Coxa valga in six of nine cohort patients; also seen in the W25R proband.
- name: Scoliosis
  category: Skeletal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Scoliosis | + | − | − | + | − | − | − | + | + | 44% (4/9)"
    explanation: Scoliosis in four of nine cohort patients.
- name: Cardiomegaly
  category: Cardiovascular
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Cardiomegaly
    term:
      id: HP:0001640
      label: Cardiomegaly
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiomegaly | − | − | NA | NA | + | − | − | + | − | 29% (2/7)"
    explanation: Cardiomegaly in two of seven evaluated cohort patients.
- name: Low Body Weight
  category: Growth
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Decreased body weight
    term:
      id: HP:0004325
      label: Decreased body weight
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Low body weight | + | + | + | + | + | + | + | − | NA | 89% (8/9)"
    explanation: Low body weight in eight of nine cohort patients.
- name: Broad Forehead
  category: Craniofacial
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Broad forehead
    term:
      id: HP:0000337
      label: Broad forehead
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Broad forehead | + | − | − | + | + | − | − | − | + | 44% (4/9)"
    explanation: Broad forehead in four of nine cohort patients.
- name: Protruding Ears
  category: Craniofacial
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Protruding ear
    term:
      id: HP:0000411
      label: Protruding ear
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prominent ears | − | − | + | − | − | − | − | + | − | 22% (2/9)"
    explanation: Prominent ears in two of nine cohort patients.
- name: Stubby Fingers
  category: Skeletal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Stubby fingers | + | + | + | + | − | − | − | − | − | 44% (4/9)"
    explanation: Stubby fingers in four of nine cohort patients.
- name: Nail Dystrophy
  category: Integument
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nail dystrophy
    term:
      id: HP:0008404
      label: Nail dystrophy
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dystrophic nails | + | − | + | − | − | + | + | − | − | 44% (4/9)"
    explanation: Dystrophic nails in four of nine cohort patients.
- name: Kyphosis
  category: Skeletal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Kyphosis
    term:
      id: HP:0002808
      label: Kyphosis
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kyphosis | + | − | − | − | − | + | + | + | − | 44% (4/9)"
    explanation: Kyphosis in four of nine cohort patients.
- name: Acetabular Dysplasia
  category: Skeletal
  frequency: FREQUENT
  description: >-
    Three of nine cohort patients; the source table's 39% does not match its own 3/9 count.
  phenotype_term:
    preferred_term: Acetabular dysplasia
    term:
      id: HP:0008807
      label: Acetabular dysplasia
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acetabular dysplasia | − | − | − | − | − | + | + | + | − | 39% (3/9)"
    explanation: Acetabular dysplasia in three of nine cohort patients (33%; the table prints 39%).
- name: Rib Deformities
  category: Skeletal
  frequency: OCCASIONAL
  description: >-
    Rib deformities of unspecified type in two of nine cohort patients.
  phenotype_term:
    preferred_term: Abnormal rib morphology
    term:
      id: HP:0000772
      label: Abnormal rib morphology
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rib deformities | − | − | − | − | − | − | − | + | + | 22% (2/9)"
    explanation: Rib deformities in two of nine cohort patients; thin ribs were also seen in the W25R proband.
- name: Death in Childhood
  category: Mortality
  description: >-
    Reduced survival in some patients: the index patient's affected sister
    died at 10 during a febrile respiratory illness, the W25R proband died at
    2 years 7 months of pneumonia and respiratory failure, and one Taiwanese
    patient with moyamoya died at 12. The index patient was well at 21.
  phenotype_term:
    preferred_term: Death in childhood
    description: >-
      Left unbound: HP:0003819 is a clinical-course modifier outside the
      PhenotypeTerm dynamic enum, so it cannot be bound here.
  evidence:
  - reference: PMID:36299998
    reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient died at the age of 2 years and 7 months after developing pneumonia and respiratory failure."
    explanation: Death in early childhood of the W25R proband.
  - reference: PMID:36282599
    reference_title: Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His eldest sister also had dwarfism, sparse hair, high hyperopia and died at age 10 during a febrile illness associated with cough and shortness of breath."
    explanation: Childhood death of an affected sibling in the index family.
genetic:
- name: TOMM7
  gene_term:
    preferred_term: TOMM7
    term:
      id: hgnc:21648
      label: TOMM7
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  notes: >-
    Reported pathogenic alleles: c.86C>T p.(Pro29Leu), recurrent in East Asian
    families (index Chinese-Malaysian patient; nine patients in seven
    Taiwanese families; a Han Chinese boy), and c.73T>C p.(Trp25Arg) in one
    Japanese proband. A biallelic canonical splice variant, c.153-2A>C, was
    reported with neonatal Leigh syndrome (PMID:39333057); whether that is the
    severe end of the same disorder or a distinct entity is unresolved.
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This report showed the segregation of the variant allele in nine members from seven unrelated families and solidified that TOMM7 is the disease-causing gene of a syndrome with unique phenotypes."
    explanation: Multi-family segregation establishes TOMM7 as causal.
animal_models:
- name: Tomm7 W25R knock-in and deletion mice
  species: Mouse
  genotype: Tomm7 W25R/W25R, W25R/deletion and deletion/deletion
  publication: PMID:36299998
  description: >-
    Knock-in of the patient W25R allele and a splice-disrupting null deletion
    allele. All genotypes show growth defects, severe lipoatrophy and hepatic
    lipid accumulation with premature death, graded by allele severity.
  modeled_mechanisms:
  - target: Adipose Tissue Lipoatrophy
    relationship: RECAPITULATES
    fidelity: MODERATE
    limitations: >-
      Lipoatrophy in mice is generalized and severe, whereas patients have
      partial lipodystrophy; mice die prematurely after rapid weight loss,
      which is not the human course.
    evidence:
    - reference: PMID:36299998
      reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The most prominent gross phenotype in these mouse models is lipoatrophy"
      explanation: Mouse lipoatrophy models the adipose phenotype.
  - target: Mitochondrial Uncoupling With Inefficient ATP Synthesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    evidence:
    - reference: PMID:36299998
      reference_title: A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "despite the bioenergetic deficiency, mutant cells show increased oxygen consumption with normal responses to electron transport chain (ETC) inhibitors, suggesting that Tomm7 deficiency leads to an uncoupling between oxidation and ATP synthesis"
      explanation: Mutant mouse cells show the uncoupled state.
- name: tomm7 loss-of-function zebrafish
  species: Zebrafish
  genotype: tomm7 loss of function
  publication: PMID:30354240
  description: >-
    tomm7 loss impairs cerebrovascular network formation; endothelial-specific
    restoration of tomm7 rescues the vascular defect. A CRISPR tomm7 deletion
    line (PMID:39615461) independently shows craniofacial and cerebrovascular
    defects.
  modeled_mechanisms:
  - target: Impaired Cerebral Angiogenesis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    limitations: >-
      Models a developmental cerebrovascular patterning defect, not the
      progressive large-artery stenosis and collateral formation of human
      moyamoya; no patient allele was tested.
    evidence:
    - reference: PMID:30354240
      reference_title: Endothelial Mitochondrial Preprotein Translocase Tomm7-Rac1 Signaling Axis Dominates Cerebrovascular Network Homeostasis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Tomm7 drives brain angiogenesis and cerebrovascular network formation through modulating mitochondrial Rac1 signaling within the endothelium."
      explanation: Model establishes the endothelial angiogenic defect.
- name: Tomm7 knockout mouse (cerebrovascular)
  species: Mouse
  genotype: Tomm7 knockout
  publication: PMID:30354240
  description: >-
    Constitutive Tomm7 ablation reproduces the cerebrovascular abnormalities
    seen in zebrafish.
  modeled_mechanisms:
  - target: Impaired Cerebral Angiogenesis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    limitations: >-
      Null allele rather than the hypomorphic patient alleles; developmental
      vascular defect rather than progressive moyamoya arteriopathy.
    evidence:
    - reference: PMID:30354240
      reference_title: Endothelial Mitochondrial Preprotein Translocase Tomm7-Rac1 Signaling Axis Dominates Cerebrovascular Network Homeostasis.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Ablation of the ortholog Tomm7 in mice recapitulated cerebrovascular abnormalities."
      explanation: Mouse knockout reproduces the cerebrovascular defect.
treatments:
- name: Growth Hormone Therapy
  description: >-
    Long-acting recombinant human growth hormone was given to a 2-year-old
    P29L homozygote with growth arrest despite normal endocrine testing. It
    slowed further loss of height SDS over 10 months. Growth hormone and
    IGF-1 were normal, so this is pharmacological growth promotion rather
    than hormone replacement. Single case, no control; efficacy and safety in
    this mitochondrial disorder are unestablished.
  therapeutic_modality: OTHER
  notes: >-
    Modality is OTHER rather than PROTEIN_REPLACEMENT on purpose: the patient
    had normal growth hormone and IGF-1, so the hormone was given to promote
    growth pharmacologically, not to replace a deficiency.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: somatropin
      term:
        id: NCIT:C837
        label: Somatropin
  target_phenotypes:
  - preferred_term: Severe short stature
    term:
      id: HP:0003510
      label: Severe short stature
  evidence:
  - reference: PMID:41460760
    reference_title: "Growth Hormone Response in a Child With a Homozygous TOMM7 Mutation: Novel Therapeutic Insights."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After 10 months of treatment, his length increased by 3.8 cm (change in standard deviation score [SDS] of -0.34)."
    explanation: Single-case report of partial growth response to GH.
- name: Cerebral Revascularization Surgery
  description: >-
    Indirect revascularization (encephaloduroarteriosynangiosis) has been used
    for moyamoya in this disorder; no outcome series exists.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: encephaloduroarteriosynangiosis
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Moyamoya phenomenon
    term:
      id: HP:0011834
      label: Moyamoya phenomenon
  evidence:
  - reference: PMID:39615461
    reference_title: Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She underwent encephaloduroarteriosynangiosis (EDAS) at age of 7."
    explanation: EDAS used for moyamoya in a cohort patient.
notes: >-
  The three case reports disagree on the direction of the respiratory defect.
  Patient and P29L mouse fibroblasts show increased oxygen consumption with
  upregulated respiratory chain subunits (PMID:36282599); Tomm7 mutant mouse
  cells show increased oxygen consumption but inefficient ATP synthesis
  (PMID:36299998); iPSC-derived endothelial cells show slightly decreased
  respiration with a glycolytic shift (PMID:39615461). These may be cell-type
  effects of a selective import defect rather than contradictions. TOMM7 is
  also needed to stabilize PINK1 on depolarized mitochondria (PMID:24270810),
  but Parkin recruitment and mitochondrial clearance were normal in P29L
  patient fibroblasts, so impaired mitophagy is not currently supported as a
  disease mechanism. The Taiwanese study also found increased TOM7 stability
  in P29L endothelial cells and cites partial ER mislocalization of P29L in
  yeast, whereas GFP-tagged P29L localized to mitochondria in human cells
  (PMID:36282599); the authors still conclude P29L is hypomorphic. No GeneReviews chapter or Orphanet record exists for this
  disorder (OMIM:620601).
📚

References & Deep Research

References

4
PMID:36282599
Autosomal recessive progeroid syndrome due to homozygosity for a TOMM7 variant.
No top-level findings curated for this source.
PMID:36299998
A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.
No top-level findings curated for this source.
PMID:39615461
Homozygous variant in translocase of outer mitochondrial membrane 7 leads to metabolic reprogramming and microcephalic osteodysplastic dwarfism with moyamoya disease.
No top-level findings curated for this source.
PMID:41460760
Growth Hormone Response in a Child With a Homozygous TOMM7 Mutation: Novel Therapeutic Insights.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Garg-Mishra_Progeroid_Syndrome · 2026-09-23T03:55:54Z · View source

New entry for MONDO:0957953 (TOMM7, OMIM:620601), taken from the stub queue (stub deleted). Deep research used the claude_code provider (research/Garg-Mishra_Progeroid_Syndrome-deep-research-claude_code.md). All 8 of its references resolved. None of the terms its term validation flagged were bound: HP:0005440 (unresolved), GO:0006626 (obsolete), and the mislabelled NCIT:C1502, HP:0000238 and HP:0001635. The report missed the nine-patient Taiwanese P29L cohort (PMID:39615461), which a direct PubMed search found. Its Table 1 frequency rows are quoted as snippets for most phenotype frequencies. Also curated beyond the report: the zebrafish and mouse Tomm7-Rac1 cerebrovascular model (PMID:30354240) and the PINK1 stabilization paper (PMID:24270810, cited only in notes). The Leigh syndrome splice-variant report (PMID:39333057) is recorded in the genetic notes as an unresolved allelic question and is not folded into the phenotype. A red-team subagent review before the PR led to these changes: - added cohort-backed phenotypes: ischemic stroke (a sequela of moyamoya), amblyopia, strabismus, optic atrophy, narrow chest, coxa valga, scoliosis, cardiomegaly, and death in childhood (unbound, because HP:0003819 is outside the PhenotypeTerm enum); - downgraded partial lipodystrophy to OCCASIONAL (1/8 in the cohort); - added a growth-plate chondrocyte hypoproliferation node (mouse histology) between uncoupling and growth failure; - regraded the Seahorse uncoupling snippet from mouse primary cells as IN_VITRO; - rebound hyperopia to HP:0008499 High hypermetropia; - split learning disability into mild intellectual disability and global developmental delay; - broadened the import GO term to GO:0070585; - split the zebrafish and mouse cerebrovascular models into separate records, marked PARTIALLY_RECAPITULATES; - retargeted GH therapy to short stature, with modality OTHER, because GH and IGF-1 were normal. Validation: just validate passes, and 75/75 snippets are verified. Also passing: check-entity-refs, check-causal-targets, check-enum-values, check-duplicate-keys, and the snippet-length, title and grading gates. check-genereviews reports NO_CHAPTER. 7 of 31 phenotypes are causally connected. The rest have no sourced upstream step and are left unwired rather than given invented edges.

Claude Code ▸
Garg-Mishra Progeroid Syndrome (GMPGS): A Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 17 citations 2026-09-23T03:44:06.190406

Garg-Mishra Progeroid Syndrome (GMPGS): A Comprehensive Research Report

Executive Summary

Garg-Mishra Progeroid Syndrome (GMPGS; OMIM #620601) is an ultra-rare autosomal recessive mitochondrial disorder first described in 2022 and formally named by the McKusick-Nathans Institute of Genetic Medicine (Johns Hopkins/OMIM) in January 2025 in honor of its discoverers, Abhimanyu Garg, M.D. (UT Southwestern Medical Center) and Prashant Mishra, M.D., Ph.D. (UT Southwestern / Children's Medical Center Research Institute). The syndrome is caused by biallelic hypomorphic (partial loss-of-function) variants in TOMM7 (translocase of outer mitochondrial membrane 7; OMIM *607980), the first human disease ever attributed to a subunit of the mitochondrial outer-membrane protein-import (TOM) complex. Only a handful of patients have been reported worldwide (as of this writing: three independently ascertained probands plus two deceased affected siblings), making this among the rarest described Mendelian disorders. No MONDO, Orphanet, or GeneReviews entry could be confirmed to exist yet for this newly named condition (see Section 1 caveats below).

1. Disease Information

Overview. GMPGS is a syndromic form of severe postnatal growth failure/proportionate dwarfism with progeroid (prematurely-aged) facial appearance, craniofacial dysmorphism (mandibular hypoplasia), severe ophthalmologic abnormalities (high hyperopia, microphthalmia/nystagmus), partial lipodystrophy, developmental delay, and in the most severe reported case, early death. It results from biallelic partial loss-of-function variants in TOMM7, which disrupt assembly/stability of the TOM (translocase of the outer mitochondrial membrane) protein-import complex and cause a distinctive mitochondrial bioenergetic uncoupling phenotype rather than classical oxidative-phosphorylation failure.

Key identifiers: | Resource | Identifier | Notes | |---|---|---| | OMIM (phenotype) | #620601 | "Garg-Mishra progeroid syndrome (GMPGS)" | | OMIM (gene) | 607980* | TOMM7 | | HGNC | 21648 (TOMM7) | Locus 7p15.3 | | Chromosome location | 7p15.3 (GRCh38: chr7:22,812,628–22,822,849, minus strand) | | | MONDO | Not confirmed available — searches for a dedicated GMPGS MONDO term did not resolve a live record as of Sept 2026; the user-supplied MONDO:0957953 could not be independently verified against Monarch Initiative and should be confirmed before use in curation | flag for verification | | KEGG DISEASE | H02768** (Japanese: Garg-Mishra 早老症候群) | Classified under 先天奇形 (congenital malformation); cross-referenced to ICD-11 LD2B "syndrome with premature aging appearance as a major feature" | | GeneReviews / Orphanet | No dedicated chapter identified | Condition is too newly named/characterized (named Jan 2025) to have an established chapter | | ICD-11 | LD2B (via KEGG mapping) — "Syndrome with premature aging appearance as a major feature" | not independently confirmed on WHO ICD-11 browser |

Synonyms / alternative names: Garg-Mishra progeroid syndrome; GMPGS; TOMM7-associated autosomal recessive progeroid syndrome; TOMM7-related progeroid syndrome / short stature syndrome.

Data provenance. All currently available clinical information derives from a small number of individual patient case reports (n=3 published probands, plus 2 deceased affected siblings referenced within those reports) — there is no aggregated disease-level registry, cohort study, or epidemiological database entry for this condition given its very recent description.

Sources: OMIM #620601; OMIM *607980; KEGG DISEASE H02768; MalaCards: Garg-Mishra Progeroid Syndrome; UT Southwestern CT Plus

2. Etiology

Disease causal factor: GMPGS is a monogenic, autosomal recessive mitochondrial disorder. There is no reported environmental, infectious, or multifactorial contribution — all reported cases are attributable to biallelic (homozygous, in all reported cases so far) hypomorphic missense (or, for the allelic-but-distinct Leigh syndrome phenotype, a splice-site null) variant in TOMM7.

Genetic risk factors (causal variants): 1. c.86C>T (p.Pro29Leu / P29L) — the index (founder-region) variant reported by Garg et al. (2022, J Clin Invest, PMID 36282599) in a 21-year-old male of Chinese ancestry, and independently confirmed in a second, unrelated 2-year-old Han Chinese boy (American Journal of Case Reports, PMID 41460760). Minor allele frequency in population databases: 0.000048, observed only in East Asian subpopulations (Korean, Japanese) in gnomAD-type reference panels — consistent with a rare, possibly regional founder allele. GERP++ = 6.07; CADD = 34 (highly deleterious in silico prediction). 2. c.73T>C (p.Trp25Arg / W25R) — reported by Young, Batkovskyte, Kitamura et al. (2023, HGG Advances, PMID 36299998) in a Japanese boy with non-consanguineous parents; homozygous in the proband, heterozygous (carrier, unaffected) in both parents. 3. A distinct, more severe biallelic canonical splice-site variant, c.153-2A>C (intron 2), reported by Yeole et al. (2025, AJMG Part A, PMID 39333057) in a consanguineous Indian family, causes aberrant splicing/frameshift and a lethal Leigh-syndrome phenotype rather than GMPGS — see the Genotype–Phenotype note below.

Population/founder considerations: All GMPGS-causing missense alleles reported to date arise in East Asian probands (Chinese, Han Chinese, Japanese); P29L is essentially private to East Asian gnomAD subpopulations. No consanguinity was reported in the JCI index family or the HGG Advances family (W25R), but both are homozygous — suggesting either founder-allele co-inheritance or a mutational hotspot. The AJCR second case (Han Chinese boy, P29L) is explicitly noted to have consanguineous parents.

Protective factors: None reported; no data available on modifier alleles or protective variants for this ultra-rare condition.

Gene-environment interactions: None reported in the literature to date; the phenotype in every case is explained by the genotype alone, with no environmental co-factor implicated.

Genotype–phenotype correlation (critical mechanistic point): TOMM7 displays striking allelic heterogeneity with a severity gradient tied to variant type: - Hypomorphic missense variants disrupting the TOMM7–TOMM40/TOMM22 transmembrane interaction (P29L, W25R) → partial loss of TOM-complex assembly, producing the comparatively milder, chronic GMPGS phenotype (survivable into adulthood in the mildest case). - A canonical splice/null variant (c.153-2A>C) causing frameshift/loss of functional protein → near-complete loss of function, producing a severe, early-lethal Leigh syndrome phenotype (mitochondrial encephalopathy, lactic acidosis, death in infancy) rather than the progeroid GMPGS presentation.

This is analogous to other TOM/TIM-complex and mitochondrial-import disorders where allele "dosage" of residual function determines whether the phenotype is a chronic growth/metabolic syndrome versus an acute, fatal encephalopathy.

Sources: JCI 156864; HGG Advances PMC9589026; AJMG Part A / Yeole et al. PMC7617585 summary; AJCR abstract #950967

3. Phenotypes

Phenotype data are pooled across the three reported GMPGS probands (JCI index case, HGG Advances case, AJCR case); frequencies below are qualitative given the extremely small n.

Phenotype category Feature Reported in Suggested HPO term
Growth (postnatal) Severe postnatal growth retardation / proportionate short stature (height/weight <3rd percentile; Z-scores as low as −5.4 for height, −3.6 for weight at 15 months in the severe case) 3/3 HP:0008897 (Postnatal growth retardation); HP:0004322 (Short stature)
Growth Relative macrocephaly JCI case HP:0004482 (Relative macrocephaly)
Craniofacial Triangular facies, broad forehead JCI case HP:0000322 / HP:0000341
Craniofacial Severe mandibular hypoplasia (micrognathia), dental crowding JCI, AJCR cases HP:0000347 (Micrognathia)
Craniofacial Prominent nasal bridge, bulbous nose JCI case HP:0000426 / HP:0000414
Craniofacial Underdeveloped facial bones, large neurocranium, open anterior fontanel (severe case) HGG Advances case HP:0000238 (Wide fontanel)
Ophthalmologic High hyperopia (up to +10.75 D) JCI case HP:0000540 (Hyperopia)
Ophthalmologic Microphthalmia (bilateral, axial length 16.8 mm) JCI case (& news coverage) HP:0000568 (Microphthalmia)
Ophthalmologic Pendular nystagmus; poor visual acuity (3/60) JCI, HGG Advances cases HP:0012043 (Pendular nystagmus)
Ophthalmologic Macular scarring AJCR case HP:0007754-like (macular scar; exact HPO TBD)
Body composition Partial lipodystrophy / loss of subcutaneous fat, "marked muscularity" 3/3 HP:0009125 (Lipodystrophy); HP:0009381 (Partial lipodystrophy — verify exact term)
Body composition Café-au-lait spots, coarse eyebrows, sparse hair/frontal hair recession JCI case HP:0000957 (Cafe-au-lait spot)
Neurodevelopmental Developmental delay / learning disability 2–3/3 HP:0001263 (Global developmental delay)
Neurologic Muscular hypotonia, "frog-leg posture," poor head control HGG Advances (severe case) HP:0001252 (Hypotonia)
Skeletal Narrow thorax, broad hands, small nails; flattened vertebrae, gracile long bones (severe case) HGG Advances case HP:0005440 / HP:0001156 / HP:0004325
Skeletal No significant bone-age delay (mild case) JCI case —
Hepatic Microvesicular hepatic steatosis (at autopsy) HGG Advances (severe, fatal case) HP:0001397 (Hepatic steatosis)
Laboratory Elevated serum LDH; mildly elevated alkaline phosphatase; mildly increased WBC HGG Advances, JCI cases —
Cardiac Mild mitral regurgitation; mild LV dilation (no structural defect) JCI case HP:0031653 / HP:0001635
Lifespan Shortened lifespan — one affected sibling of the index case died at age 10 during a febrile illness with respiratory symptoms; the HGG Advances proband died at 2.7 years of pneumonia/respiratory failure 2/3 cases (severe end of spectrum) HP:0001522 (Death in childhood)

Onset/progression: Growth failure is evident from early childhood (postnatal, not congenital — normal birth weight/length reported in both detailed cases), becoming apparent by approximately age 6 in the mildest reported case and much earlier (by 15 months) in the severe HGG Advances case. Severity appears variant/allele-dependent rather than strictly progressive in the surviving index patient, who at age 21 was described as "doing well" with no Parkinsonism or neurological decline.

Quality of life: Not formally assessed with standardized instruments (no EQ-5D/SF-36 data reported); qualitatively, the index patient (age 21) retained verbal communication ability despite significant learning disability, while the more severely affected infant/toddler cases had substantial early mortality.

Sources: JCI 156864; HGG Advances PMC9589026; AJCR abstract; UT Southwestern CT Plus

4. Genetic/Molecular Information

Causal gene: TOMM7 (HGNC:21648; OMIM *607980), 7p15.3, encoding a 55-amino-acid, ~6.2 kDa outer-mitochondrial-membrane protein.

Reported pathogenic variants (all recessive, biallelic):

Variant (cDNA) Protein Zygosity Classification Case PMID
c.86C>T p.Pro29Leu (P29L) Homozygous Pathogenic (hypomorphic) JCI index case (21yo, Chinese ancestry); AJCR case (2yo, Han Chinese, consanguineous) 36282599; 41460760
c.73T>C p.Trp25Arg (W25R) Homozygous Pathogenic (hypomorphic) HGG Advances case (Japanese boy) 36299998
c.153-2A>C splice site, intron 2 → frameshift Homozygous Pathogenic (near-null/loss-of-function) Yeole et al. Leigh syndrome siblings (consanguineous Indian family) — distinct phenotype, not GMPGS 39333057

Allele frequency: P29L MAF ≈ 0.000048, restricted to East Asian gnomAD subpopulations (no homozygotes reported in population databases, consistent with disease causation). No population-frequency data reported for W25R.

Variant type/class: All GMPGS-causing alleles reported to date are missense variants situated in/near the transmembrane α-helical domain of TOMM7, at residues (P29, W25/adjacent R24) predicted to mediate physical interaction with the core TOM-complex proteins TOMM40 and TOMM22. Both P29 and the region around W25 are highly evolutionarily conserved across mammals.

Functional consequence: Partial loss of function (hypomorphic) — mutant TOMM7 protein still localizes normally to the mitochondrial outer membrane (not a trafficking defect) but shows decreased physical interaction with TOMM40/TOMM22, reducing TOM core-complex assembly/stability. This is explicitly distinguished from the complete loss-of-function/null allele (c.153-2A>C), which instead produces a severe Leigh-syndrome phenotype — establishing a dose-dependent genotype–phenotype relationship (see Section 2).

Somatic vs. germline: All variants are germline (inherited, biallelic, present in unaffected heterozygous carrier parents).

Modifier genes: None identified/reported.

Epigenetic information: None reported for this condition.

Chromosomal abnormalities: None — this is a single-gene point-variant disorder; a ~1 Mb region of homozygosity on chromosome 7 encompassing TOMM7 was noted in the index proband, consistent with identity-by-descent inheritance rather than a distinct structural chromosomal lesion.

Suggested ontology terms: HGNC:21648 (TOMM7); GO:0006626 (protein targeting to mitochondrion); GO:0045040 (protein insertion into mitochondrial outer membrane) — as background gene-function terms for pathograph molecular-function/process nodes.

Sources: JCI 156864; OMIM *607980; HGG Advances PMC9589026; GeneCards TOMM7 (via search)

5. Environmental Information

No environmental, lifestyle, or infectious contributing factors are reported for GMPGS — it is a purely monogenic disorder. The HGG Advances proband's terminal event (pneumonia/respiratory failure) and the JCI index case's sibling's terminal febrile illness appear to be complications of underlying disease vulnerability (possibly reduced physiologic reserve from the mitochondrial/metabolic defect) rather than independent causal environmental/infectious agents — no specific pathogen was identified as causal to the syndrome itself.

6. Mechanism / Pathophysiology

Ordered Causal Chain (index/mild phenotype — P29L/W25R hypomorphic alleles)

  1. Biallelic hypomorphic missense variant in TOMM7 (P29L or W25R, in the transmembrane helix) leads to reduced physical/structural interaction between mutant TOMM7 and the TOM core-channel proteins TOMM40 and TOMM22.
  2. Reduced TOMM7–TOMM40/TOMM22 interaction results in decreased assembly/stability of the TOM (translocase of outer mitochondrial membrane) preprotein-import complex, while overall mitochondrial protein localization of TOMM7 itself remains normal (i.e., this is an assembly/stability defect, not a mislocalization defect) — inferred from proteomic and cell-biology data in the JCI report.
  3. Altered TOM-complex composition leads to a shift in the mitochondrial proteome: of 587 mitochondrial proteins assayed, 91 were differentially expressed — with upregulation of electron-transport-chain/ATP-production proteins (ATP5A, UQCRC2, SDHB, NDUFB8, TFAM) and downregulation of phospholipid-metabolism pathway proteins.
  4. This proteomic shift results in a bioenergetic phenotype of elevated basal and maximal mitochondrial oxygen consumption in patient fibroblasts and in knock-in mouse models — but, critically, without impairment of electron-transport-chain function (normal responses to ETC inhibitors) — indicating a dissociation ("uncoupling") between mitochondrial oxidation and ATP synthesis rather than classical OXPHOS chain failure (demonstrated mechanistically in the HGG Advances mouse studies).
  5. This uncoupling/hypermetabolic state is proposed to lead to (a) downregulated phospholipid metabolism contributing to lipodystrophy (reduced adipocyte size, hepatic lipid accumulation), and (b) a chronic energy-demand mismatch in high-growth tissues, manifesting as growth-plate chondrocyte proliferation defects → short stature/dwarfism, and secondarily contributing to the craniofacial (mandibular hypoplasia) and ophthalmologic phenotypes, although the precise tissue-selective mechanisms linking the bioenergetic defect to eye/facial dysmorphology remain inferred rather than directly demonstrated.
  6. Systemic markers of mitochondrial stress (elevated Gdf15, Fgf21, phospho-AMPK) are seen in mouse models, consistent with a chronic mitochondrial-integrated-stress-response state driving the growth-failure phenotype.
  7. Branch point — allele severity determines outcome: where the residual TOM-complex function is more severely disrupted (near-null splice variant, c.153-2A>C) rather than merely reduced (hypomorphic missense), the pathway instead leads to severe, early oxidative-phosphorylation failure with lactic acidosis and CNS injury (Leigh syndrome), rather than the chronic growth/lipodystrophy phenotype of GMPGS — i.e., the same initiating lesion class (TOM-complex dysfunction) bifurcates into two clinically distinct downstream outcomes depending on the magnitude of residual TOMM7 function.

Detail by category

  • Molecular pathways: Mitochondrial protein import (TOM/TIM machinery); downstream effects on oxidative phosphorylation (ETC complexes I–V) and ATP-synthase coupling; phospholipid metabolism pathway (downregulated).
  • Cellular processes: Protein translocation across the mitochondrial outer membrane (GO:0006626 protein targeting to mitochondrion); mitochondrial respiration/oxidative phosphorylation; Parkin-dependent mitophagy — notably shown to remain intact despite TOMM7 P29L, indicating TOMM7's role in mitophagy (via PINK1 stabilization/VDAC2 interaction, per broader TOM-complex literature) is at least partially separable from its role in core TOM-channel assembly.
  • Protein dysfunction: Not misfolding/aggregation — rather, a structural interaction defect (reduced binding to TOMM40/TOMM22) that impairs complex assembly while preserving normal subcellular localization of the mutant protein.
  • Metabolic changes: Increased basal/maximal cellular oxygen consumption (hypermetabolic mitochondrial phenotype); dissociation of oxygen consumption from ATP synthesis (proposed complex-V/F0-F1 coupling defect, mechanism not fully resolved); reduced adipocyte size; hepatic microvesicular steatosis in the severe case.
  • Tissue damage mechanisms: Chronic bioenergetic/hypermetabolic stress in energy-demanding tissues (growth plate cartilage, adipose tissue, liver) rather than acute oxidative/ischemic injury.
  • Molecular profiling: Proteomics performed on patient fibroblasts (mitochondrial proteome, 587 proteins assayed, 91 differentially expressed, P<0.05) — the only "omics" dataset reported for this condition to date; no transcriptomic, metabolomic, or single-cell datasets identified.

Suggested GO terms: GO:0006626 (protein targeting to mitochondrion), GO:0045040 (protein insertion into mitochondrial outer membrane), GO:0008637 (apoptotic mitochondrial changes — if relevant to downstream cell stress, not directly demonstrated), GO:0006119 (oxidative phosphorylation). Suggested CL terms: CL:0000138 (chondrocyte, growth-plate relevance), CL:0000136 (adipocyte), CL:0000182 (hepatocyte), CL:0000057 (fibroblast, the primary cell type studied).

Sources: JCI 156864; HGG Advances PMC9589026

7. Anatomical Structures Affected

Organ level: - Primary: skeletal system (growth plates → short stature), craniofacial skeleton (mandible), eyes (globe size, refraction, retina/macula), adipose tissue (lipodystrophy) - Secondary: liver (steatosis in severe case), cardiovascular system (mild valvular/chamber changes), central nervous system (developmental delay; note the distinct, more severe TOM-complex-null allele causes primary CNS/basal-ganglia injury in Leigh syndrome) - Body systems: musculoskeletal, ophthalmologic, endocrine/metabolic, hepatic, mild cardiovascular

Tissue/cell level: - Growth-plate chondrocytes (reduced proliferation/density — shown in mouse models) - Adipocytes (reduced size, lipoatrophy) - Hepatocytes (microvesicular steatosis) - Dermal fibroblasts (primary cell type used for functional/bioenergetic studies)

Subcellular level: - Mitochondrial outer membrane (site of the primary molecular lesion — TOM complex) - Mitochondrial matrix/inner membrane secondarily affected via proteome shift (ETC/ATP-synthase proteins)

Suggested UBERON terms: UBERON:0002544 (growth plate cartilage), UBERON:0001013 (adipose tissue), UBERON:0002107 (liver), UBERON:0001676 (mandible), UBERON:0000970 (eye). Suggested GO Cellular Component terms: GO:0005741 (mitochondrial outer membrane), GO:0001401 (SAM complex — related import machinery), GO:0005743 (mitochondrial inner membrane, secondary).

Lateralization: Bilateral in all reported ophthalmologic and skeletal findings (no asymmetric/unilateral findings reported).

8. Temporal Development

  • Onset: Not congenital in the classic sense — both detailed cases report normal birth weight/length, with growth failure emerging postnatally: by ~15 months in the severe case, by ~age 6 in the mildest (index) case. Onset pattern is insidious/progressive rather than acute.
  • Progression: Variable and allele-dependent. In the mildest reported allele (P29L, index case), the patient survived to at least age 21 with a relatively stable, non-progressive course (no Parkinsonism, no neurological decline noted). In the W25R case, progression was more rapid, with death at 2.7 years from respiratory failure. Corresponding mouse models show an analogous severity gradient: knock-in (missense) mice show delayed-onset emaciation/death at 9–10 weeks, while null mice die earlier (3–4 weeks), and compound heterozygotes show intermediate severity (6–7 weeks) — directly demonstrating an allele-dose-dependent progression rate.
  • Disease course pattern: Chronic, non-relapsing in survivors; for the most severely affected patients, disease is ultimately fatal in early childhood (respiratory failure/pneumonia as terminal events).
  • Critical periods: Growth-plate/skeletal growth period (infancy through adolescence) appears to be a particular window of vulnerability given the mouse growth-plate findings and the human growth-failure timing.
  • Remission: None reported; no spontaneous or treatment-induced remission described (see growth hormone treatment response in Section 12, which produced partial, not curative, benefit).

9. Inheritance and Population

Epidemiology: No formal prevalence or incidence figures exist. Given only 3 published probands (plus 2 deceased affected siblings referenced within reports) as of this report, GMPGS is among the rarest characterized Mendelian disorders — likely prevalence far below 1/1,000,000 (ultra-rare/"cases in literature" tier).

Inheritance pattern: Autosomal recessive (AR), confirmed in all reported families by parental heterozygosity and proband homozygosity.

Penetrance: Appears complete for the homozygous genotype (all homozygotes reported to date are affected), though sample size is far too small for a robust penetrance estimate.

Expressivity: Markedly variable — ranging from a relatively mild, survivable-to-adulthood phenotype (P29L index case) to a severe, early-fatal phenotype (W25R case) — driven at least partly by allelic effect (see Section 2/6), though environmental/genetic-background modifiers cannot be excluded given the small sample.

Genetic anticipation: Not applicable/not reported (not a repeat-expansion disorder).

Germline mosaicism: Not reported.

Founder effects: The P29L allele's restriction to East Asian gnomAD subpopulations (Korean, Japanese) at MAF 0.000048, and its independent identification in two unrelated Chinese-ancestry probands, suggests a possible regional founder or recurrent mutational hotspot, though formal haplotype analysis was not described in available abstracts.

Consanguinity: Explicitly reported in the AJCR (P29L, Han Chinese) proband's family; not reported as present in the JCI index family or the Japanese (W25R) family, both of which nonetheless carry homozygous variants (compatible with founder-allele inheritance rather than recent consanguinity).

Carrier frequency: Not directly reported; inferable as very low given the rarity of the homozygous MAF (0.000048) reported for P29L.

Population demographics: All reported probands are of East Asian ancestry (Chinese [including one described as "Malaysian" in a news account, likely of Chinese ethnicity], Han Chinese, Japanese). No cases reported in other ancestries for the GMPGS phenotype specifically (the Indian-family Leigh-syndrome allele is a distinct, non-GMPGS phenotype).

Sex ratio: All reported affected probands described in detail are male (JCI index case, HGG Advances case, AJCR case); the one detailed affected female relative (the JCI index patient's deceased sister) suggests the disorder is not X-linked and both sexes can be affected, consistent with autosomal recessive inheritance, though the currently published detailed cases happen to be predominantly male probands — likely a small-sample artifact rather than a true sex bias.

Age distribution: Reported ages at diagnosis/description range from infancy (severe case, died 2.7 yrs) to early adulthood (21 years, index case) to early childhood (2-year-old, AJCR case).

Sources: JCI 156864; HGG Advances PMC9589026; AJCR abstract

10. Diagnostics

Clinical tests reported/used across cases: - Laboratory: Largely non-diagnostic/normal routine chemistries; mild alkaline phosphatase elevation; elevated LDH and mild leukocytosis in the severe case; normal IGF-1, growth hormone axis, lipids, and glucose in the index case (i.e., not a classical GH-deficiency or lipid/metabolic-panel-diagnosable disorder by standard endocrine labs). - Imaging: Brain MRI — normal structurally in the index case; skeletal survey — no significant bone-age delay in the index case but flattened vertebrae/gracile long bones in the severe case. Ophthalmologic exam — critical for diagnosis given the characteristic hyperopia/microphthalmia/nystagmus triad. - Cardiac evaluation: Echocardiography identified mild valvular/chamber findings (not primary diagnostic criteria but part of the phenotypic workup). - Autopsy/histopathology: In the fatal HGG Advances case, autopsy demonstrated microvesicular hepatic steatosis and reduced adipocyte size — a key pathological correlate of the lipodystrophy phenotype.

Genetic testing: - Diagnosis is by molecular genetic testing (exome sequencing) in all reported cases — GMPGS was discovered via exome sequencing revealing the homozygous TOMM7 variant, with Sanger confirmation and parental carrier testing. - No gene panel specific to GMPGS/TOMM7 could be identified (condition too newly described); it would currently be identified incidentally on WES/WGS or via mitochondrial-disease gene panels that happen to include TOMM7 (note: the UK Genomics England PanelApp does list TOMM7 under "Mitochondrial disorders" and "Likely inborn error of metabolism" panels, per search results). - Homozygosity mapping was used in the index case (identifying the ~1 Mb region of homozygosity spanning TOMM7 on chromosome 7) supporting causality.

Differential diagnosis: Given the phenotypic overlap, the differential includes other progeroid syndromes (Hutchinson-Gilford Progeria Syndrome/LMNA; mandibuloacral dysplasia; Wiedemann-Rautenstrauch syndrome; atypical progeroid syndrome due to LMNA), other primordial dwarfism syndromes, and other partial lipodystrophy syndromes (e.g., due to LMNA, PPARG, or other genes within Dr. Garg's broader lipodystrophy research portfolio). Distinguishing features favoring GMPGS: the combination of severe mandibular hypoplasia + high hyperopia/microphthalmia + partial lipodystrophy + biallelic (not dominant) inheritance pattern, and normal LMNA/known progeria-gene sequencing.

Screening: No population or newborn screening program exists for this ultra-rare condition.

11. Outcome/Prognosis

  • Survival/mortality: Highly variable by allele. The mildest reported allele (P29L) is compatible with survival into early adulthood (index proband alive and "doing well" at age 21); however, even within P29L-carrying families, one affected sibling died at age 10 during a febrile illness. The W25R allele proband died at 2.7 years (respiratory failure/pneumonia). No formal survival curves or life-expectancy statistics exist given the tiny cohort size.
  • Morbidity: Growth failure, ophthalmologic impairment (poor visual acuity, 3/60 in the index case), developmental delay/learning disability, and (in the fatal case) progressive multi-organ involvement (skeletal, hepatic, respiratory) constitute the principal morbidity burden.
  • Complications: Respiratory infection/failure appears to be a recurring terminal complication in the more severely affected patients, possibly reflecting reduced physiological/metabolic reserve.
  • Quality-of-life measures: No standardized QoL instrument data reported.
  • Prognostic factors: The specific causal variant (degree of residual TOM-complex function) appears to be the dominant prognostic factor identified to date, corroborated by parallel severity gradients in corresponding mouse models (knock-in vs. null vs. compound-heterozygous alleles).

12. Treatment

Pharmacotherapy: - Recombinant human growth hormone (rhGH) — the only specific therapeutic intervention reported to date. A 2-year-old Han Chinese boy (P29L, homozygous) with growth stagnation was started on long-acting recombinant human growth hormone at 31 months of age; after 10 months of treatment, length increased by 3.8 cm, corresponding to a change in height SDS of −0.34 (i.e., a partial, modest positive response, not normalization of growth). This is reported as a "novel therapeutic insight," suggesting rhGH may have some utility despite the patient's growth-hormone axis being biochemically normal (i.e., this is not classical GH-deficiency treatment, but an empirical trial given growth failure). - Suggested NCIT term: NCIT:C1502 (Somatropin) or a generic pharmacotherapy term with therapeutic_agent bound to the specific rhGH product if disclosed.

Surgical/interventional: None reported.

Supportive/rehabilitative care: - Ophthalmologic correction (refractive correction for high hyperopia) — implied standard-of-care management, not explicitly detailed as a trial outcome. - Developmental/educational support implied for learning disability, not detailed.

Experimental treatments: No registered clinical trials (ClinicalTrials.gov) were identified specific to GMPGS or TOMM7-related disease — consistent with the extreme rarity and recency of characterization. No targeted/precision mitochondrial therapeutics (e.g., mitochondrial-targeted antioxidants, uncoupling-agent-modulating drugs) have been reported/trialed.

Treatment strategy notes: Because the underlying mechanism (bioenergetic uncoupling with preserved ETC function) differs from classical OXPHOS-deficiency mitochondrial diseases, standard mitochondrial-disease supplement "cocktails" (CoQ10, riboflavin, etc., typically aimed at ETC support) have no reported evidence base for this specific uncoupling mechanism — this is a notable gap and area for future therapeutic research explicitly framed as such by Garg and Mishra in institutional coverage of the discovery.

Suggested NCIT treatment terms for KB curation: NCIT:C15986 (Pharmacotherapy) as treatment_term, with therapeutic_agent bound to somatropin/rhGH (verify exact CHEBI/NCIT code before binding); NCIT:C15302 (Physical Therapy)/NCIT:C15747 (Supportive Care) as general supportive-care placeholders pending more specific sourced treatments.

Sources: AJCR abstract #950967

13. Prevention

No primary, secondary, or tertiary prevention strategies are reported or applicable beyond genetic counseling for at-risk (carrier) families, given the autosomal recessive inheritance pattern and the demonstrated East Asian founder-allele association for P29L. No newborn screening, carrier screening program, immunization strategy, or public-health intervention exists for this condition given its extreme rarity and recent characterization. Prenatal diagnosis/preimplantation genetic testing would in principle be technically feasible for known familial variants (as for any characterized AR single-gene disorder) but no reports of this being performed for GMPGS were identified.

14. Other Species / Natural Disease

No naturally occurring GMPGS-like disease has been reported in non-human species (no OMIA entries or veterinary case reports identified). All animal data derive from engineered (not naturally occurring) mouse models — see Section 15. TOMM7 orthologs are highly conserved across mammals (the causal human residues, P29 and the W25/R24 region, are "completely conserved among mammals and other species" per the JCI report), consistent with the gene's fundamental, evolutionarily constrained role in mitochondrial biogenesis. No zoonotic or cross-species transmission relevance applies, as this is a non-infectious monogenic disorder.

15. Model Organisms

Genetically engineered mouse models (both reported in the HGG Advances study, Young et al. 2023) constitute the only model-organism data available:

  1. Knock-in (R/R) mouse — carries the identical W25R missense variant found in the human proband.
  2. Phenotype: relatively normal growth until 7–8 weeks of age, then rapidly progressive emaciation and sudden death around 9–10 weeks.
  3. Growth-plate shortening with reduced chondrocyte proliferation (recapitulates human growth-plate/short-stature phenotype).
  4. Hepatic lipid accumulation and reduced adipocyte size (recapitulates human lipodystrophy/hepatic steatosis).

  5. Elevated OCR (oxygen consumption rate) and ECAR (extracellular acidification rate), upregulated phospho-AMPK, elevated Gdf15/Fgf21 — recapitulating the human bioenergetic-uncoupling signature.

  6. Null (deletion, D/D) mouse — a 184 bp genomic deletion spanning the first exon–intron boundary of Tomm7, expected to be a functional null.

  7. More severe phenotype: early postnatal growth failure and death at 3–4 weeks (i.e., more severe than the missense knock-in, directly modeling the allelic-severity gradient seen in humans, where the near-null splice variant causes lethal Leigh syndrome rather than GMPGS).
  8. Similar but more pronounced skeletal/metabolic changes versus the knock-in model.

  9. "Most prominent gross phenotype in these mouse models is lipoatrophy."

  10. Compound heterozygous (R/D) mice — intermediate phenotype severity, death at 6–7 weeks — providing an allelic-series dose-response model directly relevant to understanding human genotype–phenotype correlations.

Phenotype recapitulation assessment: The mouse models recapitulate the core human triad of growth failure, lipodystrophy/lipoatrophy, and the bioenergetic-uncoupling mitochondrial signature (elevated respiration without ETC-inhibitor-response abnormality) with good fidelity. They do not directly model the human craniofacial dysmorphism (mandibular hypoplasia) or the specific ophthalmologic phenotype (hyperopia/microphthalmia/nystagmus) in the reporting available — these organ-specific human features have not been explicitly assessed/reported in the mouse studies, representing a translational gap between model and human phenotype (relevant to a HUMAN_MODEL_MISMATCH-style annotation if curated in dismech).

Model limitations: Complete lethality in the null model by 3–4 weeks limits long-term phenotypic characterization; the models have not yet been used to test therapeutic interventions (e.g., rhGH, metabolic modulators) as far as current literature indicates.

Research applications: These models are well suited to further mechanistic dissection of the TOM-complex assembly defect, the proton-gradient/ATP-synthase coupling abnormality, and potential pharmacologic correction of the mitochondrial uncoupling phenotype — an active area flagged for future research by the discovering investigators.

Resources: MGI:1913419 (Tomm7 mouse gene entry, Mouse Genome Informatics).

Sources: HGG Advances PMC9589026; MGI:1913419

Curation Notes / Caveats for dismech KB Population

  1. MONDO ID unverified. The user-supplied MONDO:0957953 could not be confirmed against a live Monarch Initiative record during this research session; before creating a kb/disorders/ entry, run the standard dismech term-lookup workflow to confirm or correct this identifier (or record it as NOT_YET_DOCUMENTED/absent per the ontology-term-contract rule against writing unverified CURIEs from memory).
  2. Very small evidence base. With only 3 detailed published probands (Garg et al. 2022 JCI PMID 36282599; Young et al. 2023 HGG Advances PMID 36299998; and the 2025 AJCR case PMID 41460760) plus 2 deceased affected relatives referenced within those reports, essentially every phenotype/prevalence/prognosis claim in this report should be treated as CASES_IN_LITERATURE-tier (Orphanet prevalence-class convention) rather than a population-level statistic.
  3. Allelic heterogeneity is the single most important mechanistic fact — do not conflate the GMPGS-causing hypomorphic missense alleles (P29L, W25R) with the distinct, non-GMPGS, lethal Leigh-syndrome-causing null/splice allele (c.153-2A>C, Yeole et al. 2025) when building the pathograph; they represent different downstream disease entities from the same gene and should likely be modeled as separate causal branches or even separate KB considerations (GMPGS vs. TOMM7-Leigh syndrome) per the dismech lump/split conventions.
  4. All PMIDs above should be independently re-verified and exact-quote-snippeted against references_cache/ per the dismech-references skill before use in an actual KB entry — this report's quotes were extracted via web-fetch/summarization tools rather than direct PMID abstract fetches for several sources (PubMed itself returned cookie-wall/403 errors during this session), so a just fetch-reference PMID:<id> pass is required before any snippet from this report is used as curated evidence.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 8
Resolved 8
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 8
On topic 7
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 48
Resolved 44
Unresolved (possible confabulation) 1
Obsolete 1
Unverifiable 2
Terms whose name was checked 31
Terms named correctly 19
Terms named as a different term 8
Terms whose name is worth a second look 4

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0000238 (1 mention) - the report calls it "Wide fontanel"; HP calls it Hydrocephalus
  • GO:0008637 (1 mention) - the report calls it "apoptotic mitochondrial changes — if relevant to downstream cell stress, not directly demonstrated"; GO calls it apoptotic mitochondrial changes
  • CL:0000138 (1 mention) - the report calls it "chondrocyte, growth-plate relevance"; CL calls it chondrocyte
  • CL:0000057 (1 mention) - the report calls it "fibroblast, the primary cell type studied"; CL calls it fibroblast
  • UBERON:0002544 (1 mention) - the report calls it "growth plate cartilage"; UBERON calls it digit
  • UBERON:0001676 (1 mention) - the report calls it "mandible"; UBERON calls it occipital bone
  • GO:0001401 (1 mention) - the report calls it "SAM complex — related import machinery"; GO calls it SAM complex
  • NCIT:C1502 (1 mention) - the report calls it "Somatropin"; NCIT calls it Fiber

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0005440 (1 mention) - HP does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0006626 (obsolete protein targeting to mitochondrion) (3 mentions) - replaced by GO:0070585

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0000540 (1 mention) - the report calls it "Hyperopia"; HP calls it Hypermetropia, and lists "Hyperopia" among its other names
  • HP:0001522 (1 mention) - the report calls it "Death in childhood"; HP calls it Death in infancy, and lists "Death in early childhood" among its other names
  • GO:0006626 (3 mentions) - the report calls it "protein targeting to mitochondrion"; GO calls it obsolete protein targeting to mitochondrion, and lists "protein targeting to mitochondria" among its other names
  • GO:0005743 (1 mention) - the report calls it "mitochondrial inner membrane, secondary"; GO calls it mitochondrial inner membrane

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • MGI:1913419 - called "Tomm7* mouse gene entry, Mouse Genome Informatics", "Tomm7 Mouse Gene Detail"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: MGI.