Likely inborn error of metabolism

Gene: PTPMT1

I feel this should be green for mitochondrial disorders on the following basis

"As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype."

The paper shows 2 variants in unrelated families, expression of the WT protein in patient cells rescues the mitochondrial morphology, families have abnormal cardiolipin metabolism on blood spot - nhs accredited test, the zebrafish knock out recapitulates cardiolipin ratios and microcephaly seen in most of the patients.

Created: 7 May 2026, 1:52 p.m. | Last Modified: 7 May 2026, 1:52 p.m.

Panel Version: 10.1

I don't know

Comment on list classification: Following discussion with the Genomics England Clinical Team (William Macken and Helen Brittain) it was decided that it may be possible to classify this gene as green given the reasonably extensive functional work (further outlined below); however, inclusion should first be reviewed by the GMS expert team. As the phenotype is nonspecific, only tagging for promotion on more phenotypically broad panels.
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Functional evidence (PMID: 39279645):

All patient fibroblasts showed decreased PTPMT1 protein expression. Cardiolipin content was decreased in one case but normal in another unrelated individual. Mitochondria in fibroblasts from 2 cases (distantly related) displayed fragmentation and abnormal shape - rescued using expression of WT PTPMT1.

A ptpmt1 knockout zebrafish model showed abnormalities in head and body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency.

Created: 26 Jun 2026, 2:03 p.m. | Last Modified: 26 Jun 2026, 2:03 p.m.

Panel Version: 10.11

Comment on phenotypes: This gene now has a phenotype in OMIM (Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199) - accessed on 26-06-2026

Created: 26 Jun 2026, 1:50 p.m. | Last Modified: 26 Jun 2026, 1:50 p.m.

Panel Version: 10.10

New gene-disease association. Currently not associated with any phenotype in OMIM or G2P.

PMID:39279645 (2025) - 6 individuals from 3 unrelated families identified with biallelic variants in this gene. All patients presented with a complex, neonatal/infantile onset neurological and neurodevelopmental syndrome, however there was variability in the overall clinical presentation between families. Features include developmental delay, microcephaly, facial dysmorphism, epilepsy, spasticity, cerebellar ataxia and nystagmus, sensorineural hearing loss, optic atrophy and bulbar dysfunction. Brain MRI revealed a variable combination of corpus callosum thinning, cerebellar atrophy and white matter changes.

Patient from Family 1 harboured a homozygous missense variant (c.65A>C) while Family 2 and 3 carried the same homozygous variant (c.255G>C) and were shown to share some common ancestry using DNA microarray analysis.

Knockout zebrafish model displayed abnormalities in body size, developmental alterations, decreased total cardiolipin levels and OXPHOS deficiency.

Overall can be classified as Amber on the basis that two families were shown to be distantly related and no specific features were observed universally across all cases (GDD was mild in 5/6 individuals so outside the scope of the ID panel).
Sources: Literature

Created: 12 Mar 2025, 3:59 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with ataxia and brain abnormalities, OMIM:621199

Publications

• 39279645