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CSTB Gene Curation

CSTB Gene Curation

Owned by Andrea Oza
Last updated: 2024-05-07
4 min read

Gene-disease assertions not curated here (add link or write note): AR developmental and epileptic encephalopathy (Moderate by Epilepsy GCEP. Note - it is not very clear to me why they split the two phenotypes, under the genetic evidence for Unverricht-Lundborg syndrome, it seems there are some comp hets with an SNV and STR expansion. However, I didn’t dig any further.

Disease

Progressive Myoclonic Epilepsy Type 1 (aka Unverricht-Lundborg syndrome)

Disease

Progressive Myoclonic Epilepsy Type 1 (aka Unverricht-Lundborg syndrome)

Inheritance

Autosomal recessive

Prevalence

Orphanet

Medline Plus Genetics

 Worldwide prevalence unknown; Finland prevalence 2-4\/100,000

Source: STRchive

Rapid or full curation?

Rapid
Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

Definitive per Epilepsy GCEP, approved 6/16/2020

Clinical Validity Scoring Notes and points

Variants in the CSTB gene have been reported in more than 55 affected individuals (from 40 families) with autosomal recessive (AR) Unverricht – Lundborg disease (aka EPM1 (Epilepsy, progressive myoclonic)) since 1996 (Pennacchio et al.). Most of affected individuals have repeat expansion variants, which is proved to cause a loss of function of the protein and it suggest homozygous loss of function is the mechanism of Unverricht – Lundborg disease for this gene. This gene-disease relationship is supported by expression study, and animal model study. In summary, CSTB is definitively associated with autosomal recessive Unverricht – Lundborg disease. This has been repeatedly demonstrated in both the research and clinical diagnostic setting, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel by 6/16/2020.

Lumping and Splitting: Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability between three disease entities: (1) Unverricht – Lundborg syndrome(EPM1) (MONDO:0009698), and (2) developmental and epileptic encephalopathy (MONDO:0100062). Therefore, we have split curations for the disease entities, (1) Unverricht – Lundborg syndrome(EPM1) (MONDO:0009698), and (2) developmental and epileptic encephalopathy (MONDO:0100062).

Gene Clinical Validity Standard Operating Procedures (SOP) - SOP8

Source:

Clinical Validity Points Total

 

Source:

Clinical Validity Classification

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Definitive

Source:

Molecular Mechanism

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function (Variant spectrum includes SNVs and STR expansions)

Triplet repeat expansion

 

CCC-CGC-CCC-GCG (dodecamer)

 

STR review:

Suggested cutoff: 4

Penetrance

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

 

Source:

Age of Onset

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Typically 6-15 (PMID: 9012407)

Severity

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

Moderate

Clinical Features

  • Epilepsy: stimulus-sensitive myoclonus, tonic-clonic. Typically well controled by anti-seizure medication

  • Myoclonic jerks (progressive and treatment resistant

  • Ataxia, incoordination, intention tremor, dysarthria

  • Normal cognition, but emotional lability / depression

 

**”Some medications (reports include valproate, N-acetylcysteine, levetiracetam) can result in marked improvement, but phenytoin can worsen neurologic manifestations, and can even increase cerebellar degeneration; Other medications (eg, carbamazepine, oxcarbazepine, tiagabine, vigabatrin, gabapentin, pregabalin) can worsen myoclonus/myoclonic seizures” https://research.nhgri.nih.gov/CGD/view/?t=CSTB&par=general:gene,conditions:manifestation,intervention:All&g=CSTB

Sources: PMID: 20301321, 18325013

HPO Terms

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

 

Gene SOPs & Notes

SHORT TANDEM REPEATS (SEE MOL MECH)

Curation Summary

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

The CSTB gene is associated with autosomal recessive progressive myoclonic epilepsy type 1, also known as Unverricht-Lundborg syndrome. It is characterized by childhood to adolescent onset of epilepsy, myoclonic jerks, ataxia, incoordination, and intention tremor. It is reported that the epilepsy and myoclonic is responsive to valproic acid or levetiracetam, and clonazepam and piracetam are used to treat myoclonus. However, certain medications have been reported to worsen symptoms, including phenytoin, sodium channel blockers (carbamazepine, oxcarbazepine), GABAergic drugs (tiagabine, vigabatrin) as well as gabapentin and pregabalin (PMID: 18325013).

Case ID, Curator name, Date, Jira ticket link

Andrea Oza 05.06.24

 

 

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