Inheritance

Autosomal dominant

Prevalence

Source:

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - Definitive

Clinical Validity Scoring Notes and points

ClinGen Epilepsy GCEP doesn’t provide a good summary, so will need to document molecular mechanism below.

Clinical Validity Points Total

n/a

Clinical Validity Classification

Definitive

Source: ClinGen Epilepsy GCEP

Molecular Mechanism

Loss of function

1. NM_001032221.6(STXBP1):c.1162C>T (p.Arg388Ter) - NMD+ and de novo in patient with hypotonia, gross and diffuse tremor, and global delay. Sat by herself at 18months, walked at 4 years, severe sialorrhea suggestive of some orofacial dyspraxia. First seizure was at 2.75 years old. (PMID: 18703708)

2. NM_003165.6:.1099C>T p.R367* - NMD+, de novo in patient 2 with seizures, abnormal tone, developmental delay >> ID (never acquired hand skills, language) PMID: 31344879

3. NM_003165.6:c.1303G>T p.E435*: de novo in patient 3 with epilepsy at 1 month, hypomyelination, 26384463

Review and natural history study cites LOF (can’t access the supplement) - PMID: 35851549

Penetrance

(list source/PMID)

Age of Onset

(list source/PMID)

Early onset

Severity

Severe

Clinical Features

developmental and epileptic encephalopathy

Epilepsy (tonic-clonic, focal, tonic seizures, epileptic spasms)

Developmental delay, intellectual disability

Autistic features

Behavioral problems

Gait disorders (postural abnormalities, broad-based gait, assymetric posture, dystonia)

Movement disorders - ataxia, dystonia, dyskinesia, tremor, choreoathetosis)

Tone abnormalities (spasticity, hypotonia

35851549, 27905812

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

The STXBP1 gene is associated with autosomal dominant developmental and epileptic encephalopathy, which is characterized by epilepsy, developmental delay, intellectual disability, autistic features, behavioral problems, tone abnormalities (spasticity, hypotonia), and movement disorders (ataxia, dystonia, dyskinesia, tremor, choreoathetosis). The age of onset of seizures is typically in childhood with a median age of onset of 6 weeks (PMID: 26865513, 35851549, 27905812). Pathogenic variants are typically found to be de novo and the molecular mechanism is loss of function (PMID: 18703708, 31344879, 26384463).

Case ID, Curator name, Date, Jira ticket link

Andrea Oza, SP0012515 2016-210-335, 08.19.2024