Early onset or syndromic epilepsy

Gene: PNPT1

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 3 Mar 2022, 5:34 p.m. | Last Modified: 3 Mar 2022, 5:34 p.m.

Panel Version: 2.491

Comment on list classification: New gene added by Konstantinos Varvagiannis. There is sufficient evidence for this gene to be rated GREEN at the next major review and depending on the policy of inclusion of metabolic genes on this panel (added 'for-review tag).

Created: 7 Dec 2020, 11:04 a.m. | Last Modified: 7 Dec 2020, 11:04 a.m.

Panel Version: 2.230

Green List (high evidence)

Reviewed for the intellectual disability panel. Seizures may be observed in affected individuals (details below). Please consider inclusion with amber / green rating.

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Biallelic PNPT1 pathogenic variants cause Combined oxidative phosphorylation deficiency 13 (MIM 614932). Despite phenotypic variability - common to disorders resulting from mitochondrial dysfunction - DD and ID of relevant severity to the current panel have been reported in several individuals published in the literature. Seizures may also be observed.

Rius et al (2019 - PMID: 31752325) provide an overview of 24 affected individuals (7 new and 17 from previous studies). Neurodevelopmental features are summarized in fig.1 and additional details are provided in the supplement. Based on this review, seizures were present in 7 individuals (of the 18 for whom this information was available).

PNPT1 encodes the mitochondrial polynucleotide phosphorylase, involved in the import of nuclear-encoded RNA to mitochondria. Loss of its activity has been shown to result in combined respiratory chain deficiency. However, as discussed by Rius et al and previous articles as well, OXPHOS studies in affected individuals may be normal or suggestive of only mild impairment due to tissue specificity and different assay methods used (eg. spectrophotometric vs dipstick activity assays). The same applies to lactate which was normal or mildly elevated in some affected individuals.

Missense, pLoF function variants as well as a synonymous one leading to aberrant splicing (NM_033109.4:c.1818T>G) have been reported.
Sources: Literature

Created: 28 Nov 2019, 6:18 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Combined oxidative phosphorylation deficiency 13, MIM 614932

Publications

• 31752325