Early onset or syndromic epilepsy

Gene: NTRK2

Green List (high evidence)

AD EIEE 58 - onset of refractory seizures in first few days or months of life. Hamdan et al, 2017 - 4 unrelated children - seizures were generalised infantile spasms, focal or of multiple types and were difficult to control. All had a de novo het missense variant Y434C. No functional work done.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epileptic encephalopathy, early infantile, 617830; Obesity, hyperphagia, and developmental delay 613886

Publications

• 29100083

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Comment on list classification: Updated rating from Grey to Green: Added and reviewed Green by Konstantinos Varvagiannis. Although probable rating in DD-G2P for 'Epilepsy and ID', there are sufficient unrelated cases (>3) of patients with NTRK2 variants and seizures from PMID:29100083 and PMID:15494731 (2 variants) for both EE and obesity/hyperphagia phenotypes.

Created: 11 Dec 2018, 11:25 a.m.

In 4 unrelated patients with early infantile epileptic encephalopathy-58 (MIM:617830), Hamdan et al. (PMID:29100083, 2017) identified a de novo heterozygous transition (c.1301A-G, NM_006180.4, Tyr434Cys) in the NTRK2 gene.

Patient in Yeo et al (PMID:15494731) with obesity and hyperphagia had a history of absence seizures in second and third years of life only.

Created: 11 Dec 2018, 11:21 a.m.

Green List (high evidence)

Heterozygous pathogenic variants in NTRK2 cause Epileptic encephalopathy, early infantile, 58 (EIEE58 - MIM 617830) or Obesity, hyperphagia, and developmental delay (MIM 613886).

Seizures can be noted in individuals falling into either diagnosis [eg. observed in the individuals with obesity and hyperphagia as in PMIDs: 15494731 and 29100083 (individual with Thr720Ile)].

Concerning EIEE58 Tyr434Cys appears to be a recurrent variant that has been observed in 4 unrelated individuals (summary in table 2 from PMID: 29100083).

NTRK2 is a probable DD gene in G2P associated with epilepsy and ID.

As a result, this gene can be considered for inclusion in this panel as green.
Sources: Literature

Created: 10 Dec 2018, 5:31 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Epileptic encephalopathy, early infantile, 58 (MIM 617830); Obesity, hyperphagia, and developmental delay (MIM 613886)

Publications

• 29100083
• 15494731