Intellectual disability
Gene: PNPT1

PNPT1 (polyribonucleotide nucleotidyltransferase 1)
EnsemblGeneIds (GRCh38): ENSG00000138035
EnsemblGeneIds (GRCh37): ENSG00000138035
OMIM: 610316, Gene2Phenotype
PNPT1 is in 17 panels

7 reviews

Sarah Leigh (Genomics England Curator)

The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.

Panel Version: 3.1510

Created: 9 Mar 2022, 3:40 p.m.
Last Modified: 9 Mar 2022, 3:40 p.m.
Panel version: 3.1510

Arina Puzriakova (Genomics England Curator)

Comment on list classification: GDD/ID is a prominent feature of the disease presentation and there are sufficient unrelated cases (>3) presenting with relevant severity to this panel. This is a possible route for diagnostic testing and so there may be value in classifying as Green - PNPT1 will be flagged for review at the next GMS panel update (added 'for-review' tag)
Created: 7 Dec 2020, 10:53 a.m. | Last Modified: 7 Dec 2020, 10:53 a.m.

Panel Version: 3.608

Created: 7 Dec 2020, 10:53 a.m.
Last Modified: 7 Dec 2020, 10:53 a.m.
Panel version: 3.608

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Multi-system disorder but DD/ID is a prominent feature, we have rated this gene Green.
Created: 13 Feb 2020, 6:15 a.m. | Last Modified: 13 Feb 2020, 6:15 a.m.

Panel Version: 3.1

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Combined oxidative phosphorylation deficiency 13, MIM#614932

Created: 13 Feb 2020, 6:15 a.m.
Last Modified: 13 Feb 2020, 6:15 a.m.
Panel version: 3.1

Rebecca Foulger (Genomics England curator)

As summarised by Konstantinos Varvagiannis: PMID:31752325 (Rius et al., 2019) summarise 17 patients from the literature plus 7 new patients with biallelic PNPT1 variants (24 patients total). There is wide phenotypic variability. Most patients presented within the first year of life, and most common presenting phenotypes were tone abnormalities, feeding difficulties, and hearing loss. Neurodevelopmental abnormalities were seen in 17 patients, and the authors note that the most common neurodevelopmental abnormalities were severe DD and regression. Supplementary table 1 provides more phenotype details, including global developmental delay, regression and ID. Although there are sufficient cases, have kept rating as Amber for now because of the large spectrum of phenotypes, and ID is unlikely to be the presenting phenotype.
Created: 28 Nov 2019, 10:08 p.m. | Last Modified: 28 Nov 2019, 10:08 p.m.

Panel Version: 2.1131

Created: 28 Nov 2019, 10:08 p.m.
Last Modified: 28 Nov 2019, 10:08 p.m.
Panel version: 2.1131

Konstantinos Varvagiannis (Other)

Green List (high evidence)

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.

Overall, this gene might be considered for upgrade to green rating.
Created: 28 Nov 2019, 6:12 a.m. | Last Modified: 28 Nov 2019, 6:18 a.m.

Panel Version: 2.1129

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

31752325

Created: 28 Nov 2019, 6:12 a.m.
Last Modified: 28 Nov 2019, 6:18 a.m.
Panel version: 2.1129

BRIDGE consortium (NIHRBR-RD)

Green List (high evidence)

This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_20141118_conf;in_ddg2p_20141118_conf;in_ddg2p_201507;in_ddg2p_201507_conf;in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf . Main mutation mechanism : Loss of function; All missense/in frame
Created: 27 Jul 2017, 8:04 p.m.

Evidences key, gene present in following gene lists and main mutation mechanism : ddg2p_20141118; ddg2p_20141118_conf; ddg2p_201507; ddg2p_201507_conf; neuro_20160418_strict; Loss of function; All missense/in frame. This is a pertinent gene from the BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene comes from the SPEED_NEURO_v3.0_20170404 gene list. The following experts from the BRIDGE consortium NIHRBR-RD contributed to this panel: - Professor F. Lucy Raymond, Cambridge Institute for Medical Research, University of Cambridge - Manju Kurian, Paediatric neurologist, Great Ormond Street Hosptial - Keren Carss, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Alba Sanchis-Juan, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Marie Erwood NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Louise Daugherty, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust
Created: 19 Jul 2017, 1:08 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

25529582

Created: 2 Aug 2017, 9:41 p.m.

Panel version: 1.354

Louise Daugherty (Genomics England Curator)

Comment on list classification: This gene is from an expert list and needs further assessment by the Genomics England curation team to assess inclusion and pertinence to this panel.
Created: 20 Jul 2017, 1:19 p.m.

Created: 20 Jul 2017, 1:19 p.m.

Panel version: 1.227

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Green

Phenotypes

Combined oxidative phosphorylation deficiency 13, OMIM:614932
Combined oxidative phosphorylation defect type 13, MONDO:0013977

OMIM

610316

Clinvar variants

Variants in PNPT1

Penetrance

Complete

Publications

31752325

Panels with this gene