Intellectual disability
Gene: PTRH2

PTRH2 (peptidyl-tRNA hydrolase 2)
EnsemblGeneIds (GRCh38): ENSG00000141378
EnsemblGeneIds (GRCh37): ENSG00000141378
OMIM: 608625, Gene2Phenotype
PTRH2 is in 8 panels

3 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

Comment on phenotypes: OMIM phenotype accessed on 24 October 2025.
Created: 24 Oct 2025, 5:13 p.m. | Last Modified: 24 Oct 2025, 5:13 p.m.

Panel Version: 9.150

Comment on list classification: There is sufficient evidence available for the association of biallelic PTRH2 variants with intellectual disability/ global developmental delay. Hence, this gene can be promoted to green rating in the next GMS update.
Created: 4 Feb 2025, 6:30 p.m. | Last Modified: 4 Feb 2025, 6:30 p.m.

Panel Version: 8.78

Comment on publications: PMID:39176129 and PMID:39766776 papers were identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Created: 4 Feb 2025, 6:27 p.m. | Last Modified: 4 Feb 2025, 6:27 p.m.

Panel Version: 8.76

PMID:39176129 reported two sisters with a homozygous missense likely pathogenic variant in the PTRH2 gene (p.Gln85Arg). They both had moderate intellectual disability.

PMID:39766776 reported the identification of p.Ala90Glyfs*13 variant in homozygous state in two siblings from a family presenting with infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). This variant was previously identified in two siblings reported in PMID:25574476. All four patients presented with global developmental delay and intellectual disability. Survey of all reported cases so far has shown that ID was present in 28/32 cases (87.5%).

This gene has been associated with relevant phenotypes in both OMIM (MIM #616263) and Gene2Phenotype (with 'definitive' rating on the DD panel).
Created: 4 Feb 2025, 6:26 p.m. | Last Modified: 4 Feb 2025, 6:26 p.m.

Panel Version: 8.75

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1, MONDO:8000012

Publications

Created: 4 Feb 2025, 6:26 p.m.
Last Modified: 4 Feb 2025, 6:26 p.m.
Panel version: 9.149

Catherine Snow (Genomics England)

Comment on list classification: Expert review by Konstantinos Varvagiannis on PTRH2.

Hu et al. (2014 - PMID:25574476) reported on 2 sibs born to consanguineous Yazidian-Turkish family, homozygous for a frameshift variant [NM_016077.4(PTRH2):c.269_270delCT (p.Ala90Glyfs)].

Picker-Minh et al (2016 - PMID: 27129381) reported on 5 individuals, from 2 unrelated consanguineous (Tunesian / Saudi-Arabian) pedigrees. These subjects were homozygous for a missense variant [NM_016077.4(PTRH2):c.254A>C (p.Gln85Pro)]. An individual from one of the families, which had 4 affected members, had been identified and reported by Alazami et al. (PMID: 25558065 - 2015).

A summary of the features observed in all 7 cases was provided by Picker-Minh et al (2016 - PMID: 27129381). ID was reported in 6/7 cases, 2/3 families, information was not available for one of the families. It should also be noted that there is large phenotypic variability even among individuals with the same variant.

Sharkia et al. (PMID: 28328138) describe 3 sibs homozygous for the p.Gln85Pro variant. The index patient was reported to have normal intelligence upon formal testing which also appeared to be the case for her 2 sisters.

Therefore as currently there is only evidence for ID from two families and ID is a conflicting phenotype even in the same variant. Classifying PTRH2 as Amber and adding to the "watch-list".
Created: 29 May 2019, 4:28 p.m. | Last Modified: 17 Jul 2019, 2:25 p.m.

Panel Version: 0.201

Created: 29 May 2019, 4:28 p.m.
Last Modified: 17 Jul 2019, 2:25 p.m.
Panel version: Imported from Intellectual disability update May 2019 panel version 0.110

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Biallelic pathogenic variants in PTRH2 cause Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (MIM 616263).

Several affected individuals have been reported to date. ID was a feature in the majority.

Hu et al. (2014 - PMID:25574476) reported on 2 sibs born to consanguineous Yazidian-Turkish family, homozygous for a frameshift variant [NM_016077.4(PTRH2):c.269_270delCT (p.Ala90Glyfs)].

In PMID: 27129381 (2016) the same group reported on 5 additional individuals, from 2 unrelated consanguineous (Tunesian / Saudi-Arabian) pedigrees. These subjects were homozygous for a missense variant [NM_016077.4(PTRH2):c.254A>C (p.Gln85Pro)].

A summary of the features observed in all 7 cases is provided in table 1 of the latter article. ID was a feature in all 6 individuals for whom this information was available (6/7). Phenotypic variability even among individuals with the same variant is underscored.

mRNA studies for both variants have shown similar levels compared to controls, with reduced protein upon Western blot (for both). In Ptrh2-null mouse model a similar to the human phenotype is observed (muscle weakness and wasting, ataxia, cerebelar atrophy, etc.) (PMIDs:25574476 and 28175314).

Alazami et al. (PMID: 25558065 - 2015) report on an additional individual homozygous for the p.Gln85Pro variant. This boy presented with intellectual disability (clinical details provided in the supplement).

Sharkia et al. (PMID: 28328138) describe 3 sibs homozygous for the p.Gln85Pro variant. The index patient was reported to have normal intelligence upon formal testing which also appeared to be the case for her 2 sisters.

Apart from the 2 variants observed in the published patients, 2 further variants have been submitted in ClinVar as likely pathogenic, namely : NM_016077.4(PTRH2):c.253C>T (p.Gln85Ter) and NM_001015509.2(PTRH2):c.114dup (p.Gly39Trpfs).

PTRH2 is not associated with any phenotype in G2P.

This gene is included in gene panels for intellectual disability offered by diagnostic laboratories (incl. Radboudumc).

As a result it can be considered for inclusion in the ID panel as green (or amber).

[As several individuals presented with ataxia, demyelinating sensorimotor neuropathy, sensorineural hearing loss and other possibly relevant phenotypes, consider inclusion in the respective gene panels].
Sources: Literature, Radboud University Medical Center, Nijmegen
Created: 23 Dec 2018, 11:07 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (MIM 616263)

Publications

Variants in this GENE are reported as part of current diagnostic practice

Created: 23 Dec 2018, 11:07 a.m.

Panel version: 2.588

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Amber
Expert Review
Expert Review

Phenotypes

Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263
neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1, MONDO:8000012

Tags

watchlist Q1_25_ promote_green

OMIM

608625

Clinvar variants

Variants in PTRH2

Penetrance

Complete

Publications

Panels with this gene