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Intellectual disability v9.351 PTPN1 Ida Ertmanska Tag Q1_26_expert_review tag was added to gene: PTPN1.
Intellectual disability v9.351 PTPN1 Ida Ertmanska changed review comment from: Comment on list classification: There are 11 unrelated individuals reported with heterozygous PTPN1 variants, presenting with loss of previously acquired skills, spasticity/dystonia, cerebral atrophy, and white matter changes. There is a high degree of non-penetrance, as 9/12 reported patients have inherited the PTPN1 variants from their asymptomatic parents. Hence, this gene is recommended for Green with expert review to determine if the non-penetrance is in scope of testing.; to: Comment on list classification: There are 11 unrelated individuals reported with heterozygous PTPN1 variants, presenting in childhood with loss of previously acquired skills, spasticity/dystonia, cerebral atrophy, and white matter changes. There is a high degree of non-penetrance, as 9/12 reported patients have inherited the PTPN1 variants from their asymptomatic parents. Hence, this gene is recommended for Green with expert review to determine if the non-penetrance is in scope of testing.
Intellectual disability v9.351 PTPN1 Ida Ertmanska commented on gene: PTPN1: Comment on list classification: There are 11 unrelated individuals reported with heterozygous PTPN1 variants, presenting with loss of previously acquired skills, spasticity/dystonia, cerebral atrophy, and white matter changes. There is a high degree of non-penetrance, as 9/12 reported patients have inherited the PTPN1 variants from their asymptomatic parents. Hence, this gene is recommended for Green with expert review to determine if the non-penetrance is in scope of testing.
Intellectual disability v9.351 PTPN1 Ida Ertmanska Tag Q1_26_promote_green tag was added to gene: PTPN1.
Intellectual disability v9.351 PTPN1 Ida Ertmanska edited their review of gene: PTPN1: Changed rating: GREEN
Intellectual disability v9.351 PTPN1 Ida Ertmanska Phenotypes for gene: PTPN1 were changed from Encephalopathy, HP:0001298 to Encephalopathy, HP:0001298; dystonia, early-onset, and/or spastic paraplegia, MONDO:0859215
Intellectual disability v9.350 PTPN1 Ida Ertmanska edited their review of gene: PTPN1: Changed phenotypes to: Encephalopathy, HP:0001298, dystonia, early-onset, and/or spastic paraplegia, MONDO:0859215
Intellectual disability v9.350 PTPN1 Ida Ertmanska edited their review of gene: PTPN1: Changed publications to: 10066179, 39986310; Changed phenotypes to: Encephalopathy, HP:0001298
Intellectual disability v9.350 PTPN1 Ida Ertmanska Phenotypes for gene: PTPN1 were changed from to Encephalopathy, HP:0001298
Intellectual disability v9.349 PTPN1 Ida Ertmanska Publications for gene: PTPN1 were set to 39986310
Intellectual disability v9.348 PTPN1 Ida Ertmanska Classified gene: PTPN1 as Amber List (moderate evidence)
Intellectual disability v9.348 PTPN1 Ida Ertmanska Gene: ptpn1 has been classified as Amber List (Moderate Evidence).
Intellectual disability v9.347 PTPN1 Ida Ertmanska changed review comment from: PMID: 39986310 Zhu et al., 2025
Reported heterozygous PTPN1 variants in 12 patients from 11 families. 2/10 were canonical splice variants, 2 were missense variants, and 6 were STOP-gain. 3 cases were de novo, 9 individuals inherited the variant from an asymptomatic parent. Sequencing method: WES + Sanger.

Phenotype: 12/12 individuals experienced subacute loss of skills (age range 15 months to 8 years) after initial normal development in 11 of 12 (one patient had mild motor delay); weakness (12/12), spasticity (initially manifesting as a hemiparesis in seven patients and then becoming bilateral) +/- dystonia, bulbar involvement (dysphagia and/or dysphasia) in 11/12 patients; absence of seizures. In 4/12 patients, fever and raised liver enzymes were noted around the time of presentation.
Some patients demonstrated stabilisation / recovery of neurological function in the absence of treatment, while in others the disease appeared to respond to immune suppression.

PTPN1 is associated with {Insulin resistance, susceptibility to}, MIM:1258539 in OMIM. It is not associated with disease in ClinGen or Gene2Phenotype (resources accessed 24 Mar 2026).
Probability of loss-of-function intolerance (pLI) score = 1.00 (predicted to be highly intolerant to LoF).
Sources: Literature; to: PMID: 39986310 Zhu et al., 2025
Reported heterozygous PTPN1 variants in 12 patients from 11 families. 2/10 were canonical splice variants, 2 were missense variants, and 6 were STOP-gain. 3 cases were de novo, 9 individuals inherited the variant from an asymptomatic parent. Sequencing method: WES + Sanger.

Phenotype: 12/12 individuals experienced subacute loss of skills (age range 15 months to 8 years) after initial normal development in 11 of 12 (one patient had mild motor delay); weakness (12/12), spasticity (initially manifesting as a hemiparesis in seven patients and then becoming bilateral) +/- dystonia, bulbar involvement (dysphagia and/or dysphasia) in 11/12 patients; absence of seizures. In 4/12 patients, fever and raised liver enzymes were noted around the time of presentation.

Brain MRI findings: Cerebral atrophy (9/12 patients), non-specific white matter changes (8/12), intracranial calcification (2/12). In 8 cases, the brain abnormalities resolved.Some patients demonstrated stabilisation / recovery of neurological function in the absence of treatment, while in others the disease appeared to respond to immune suppression.

Functional evidence: PMID: 10066179 Elchebly et al., 1999 - Ptpn1 knock-out (KO) mice are both viable and healthy, demonstrating enhanced insulin sensitivity and resistance to metabolic syndrome.

PTPN1 is associated with {Insulin resistance, susceptibility to}, MIM:1258539 in OMIM. It is not associated with disease in ClinGen or Gene2Phenotype (resources accessed 24 Mar 2026).
Probability of loss-of-function intolerance (pLI) score = 1.00 (predicted to be highly intolerant to LoF).
Sources: Literature
Intellectual disability v9.347 PTPN1 Ida Ertmanska gene: PTPN1 was added
gene: PTPN1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PTPN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PTPN1 were set to 39986310
Review for gene: PTPN1 was set to AMBER
Added comment: PMID: 39986310 Zhu et al., 2025
Reported heterozygous PTPN1 variants in 12 patients from 11 families. 2/10 were canonical splice variants, 2 were missense variants, and 6 were STOP-gain. 3 cases were de novo, 9 individuals inherited the variant from an asymptomatic parent. Sequencing method: WES + Sanger.

Phenotype: 12/12 individuals experienced subacute loss of skills (age range 15 months to 8 years) after initial normal development in 11 of 12 (one patient had mild motor delay); weakness (12/12), spasticity (initially manifesting as a hemiparesis in seven patients and then becoming bilateral) +/- dystonia, bulbar involvement (dysphagia and/or dysphasia) in 11/12 patients; absence of seizures. In 4/12 patients, fever and raised liver enzymes were noted around the time of presentation.
Some patients demonstrated stabilisation / recovery of neurological function in the absence of treatment, while in others the disease appeared to respond to immune suppression.

PTPN1 is associated with {Insulin resistance, susceptibility to}, MIM:1258539 in OMIM. It is not associated with disease in ClinGen or Gene2Phenotype (resources accessed 24 Mar 2026).
Probability of loss-of-function intolerance (pLI) score = 1.00 (predicted to be highly intolerant to LoF).
Sources: Literature
Intellectual disability v2.468 PTPN11 Louise Daugherty Source Victorian Clinical Genetics Services was added to PTPN11.
Intellectual disability PTPN11 BRIDGE consortium edited their review of PTPN11
Intellectual disability PTPN11 BRIDGE consortium edited their review of PTPN11
Intellectual disability PTPN11 BRIDGE consortium reviewed PTPN11