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Intellectual disability v9.150 PTRH2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 24 October 2025.
Intellectual disability v9.150 PTRH2 Achchuthan Shanmugasundram Phenotypes for gene: PTRH2 were changed from Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263 to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263; neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1, MONDO:8000012
Intellectual disability v9.149 PTRH2 Achchuthan Shanmugasundram edited their review of gene: PTRH2: Changed phenotypes to: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263, neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1, MONDO:8000012
Intellectual disability v8.78 PTRH2 Achchuthan Shanmugasundram Classified gene: PTRH2 as Amber List (moderate evidence)
Intellectual disability v8.78 PTRH2 Achchuthan Shanmugasundram Added comment: 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.
Intellectual disability v8.78 PTRH2 Achchuthan Shanmugasundram Gene: ptrh2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v8.77 PTRH2 Achchuthan Shanmugasundram Phenotypes for gene: PTRH2 were changed from Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, 616263; Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (MIM 616263) to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263
Intellectual disability v8.76 PTRH2 Achchuthan Shanmugasundram Tag Q1_25_ promote_green tag was added to gene: PTRH2.
Intellectual disability v8.76 PTRH2 Achchuthan Shanmugasundram edited their review of gene: PTRH2: Changed phenotypes to: Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263
Intellectual disability v8.76 PTRH2 Achchuthan Shanmugasundram Added comment: 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.
Intellectual disability v8.76 PTRH2 Achchuthan Shanmugasundram Publications for gene: PTRH2 were set to 25574476; 28175314; 28328138; 25558065; 27129381
Intellectual disability v8.75 PTRH2 Achchuthan Shanmugasundram reviewed gene: PTRH2: Rating: GREEN; Mode of pathogenicity: None; Publications: 39176129, 39766776; Phenotypes: infantile-onset multisystem neurologic, endocrine, and pancreatic disease, OMIM:616263; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.981 PTRH2 Catherine Snow Tag watchlist tag was added to gene: PTRH2.
Intellectual disability v2.978 PTRH2 Catherine Snow Source Expert Review was added to PTRH2.
Source Expert Review Amber was added to PTRH2.
Added phenotypes Infantile-onset multisystem neurologic, endocrine, and pancreatic disease, 616263 for gene: PTRH2
Publications for gene PTRH2 were changed from 25574476; 27129381; 25558065; 28328138; 28175314 to 25574476; 28175314; 28328138; 25558065; 27129381
Rating Changed from No List (delete) to Amber List (moderate evidence)
Intellectual disability v2.588 PTRH2 Konstantinos Varvagiannis gene: PTRH2 was added
gene: PTRH2 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: PTRH2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTRH2 were set to 25574476; 27129381; 25558065; 28328138; 28175314
Phenotypes for gene: PTRH2 were set to Infantile-onset multisystem neurologic, endocrine, and pancreatic disease (MIM 616263)
Penetrance for gene: PTRH2 were set to Complete
Review for gene: PTRH2 was set to GREEN
gene: PTRH2 was marked as current diagnostic
Added comment: 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