Early onset or syndromic epilepsy
Gene: CLPB
Wortmann et al, 2015 - identified a total of 14 rare predicted deleterious alleles in CLPB in 14 individuals from 9 unrelated families. Table 1 - 4/14 patients in 3 families with epilepsy (family 5 - 2 individuals, family 8 and family 9 - 1 individual) - hom and compound het.
Saunders et al, 2015 - biallelic variants identified in 5 children from 4 families - 4/5 children from 3 families had epilepsy.
Kiykim et al, 2016 - patient with novel compound het variants in CLPB - seizures as part of the phenotype.
Pronicka et al, 2017 - 31 patients includes Wortmann et al 2015, Kanabus et al, 2015, Saunders et al 2015 & Kiykim et al 2016 & Capo-Chichi et al 2015 (patients 27-30 all had epilepsy) as well as patients 16, 17, 24, 25 & 31 - previously unreported (all had epilepsy). 17/31 cases with epilepsy - all hom or compound het.
Wortmann et al, 2021 - 6 unrelated probands all with neutopenia and a phenotype dominated by epilepsy, develpmental issues and 3-methylglutaconic aciduria by NGS - identified four diff de novo monoallelic variants in CLPB. Show that the variants disturb refoldase andf to a lesser extent ATPase activity of CLPB in a dominant negative manner.Created: 11 Nov 2022, 2:20 p.m. | Last Modified: 11 Nov 2022, 2:20 p.m.
Panel Version: 2.603
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
25597510; 25597511; 26916670
Updating tags to be Q3_22_expert_review, Q3_22_MOI and Q3_22_rating so that gene is included in the next GMS report (Oct 2022)Created: 5 Oct 2022, 4:54 p.m. | Last Modified: 5 Oct 2022, 4:54 p.m.
Panel Version: 2.597
The rating of this gene has been updated to Green and the mode of inheritance updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.Created: 1 Feb 2023, 9:39 a.m. | Last Modified: 1 Feb 2023, 9:39 a.m.
Panel Version: 3.29
Seizures are only reported in a subset of individuals with a biallelic CLPB defect (at least 9 individuals). However, these can arise early in the disease course and may be intractable in some cases it might of value to review the Amber rating relating to the recessive disease.
On the other hand, Wortmann et al. 2021 (PMID: 34140661) recently published six unrelated individuals with one of four different de novo monoallelic missense variants in CLPB and epilepsy was a prominent clinical feature in 5/6 individuals presented in the study.
This will be flagged for further GMS review to determine the most appropriate MOI and rating on this panel.Created: 15 Nov 2021, 5:34 p.m. | Last Modified: 15 Nov 2021, 5:34 p.m.
Panel Version: 2.465
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Publications
As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Although there are three cases, most patients don't have seizures. Demoted from Green to Amber.Created: 25 Nov 2019, 9:12 p.m. | Last Modified: 25 Nov 2019, 9:12 p.m.
Panel Version: 1.462
Added CLPB to panel based on epilepsy/seizure phenotype on the 'Inborn errors of metabolism' panel. There are multiple (>3) cases of patients with CLPB variants and seizures amongst their 3-MGA phenotype.Created: 21 Oct 2019, 2:18 p.m. | Last Modified: 21 Oct 2019, 2:18 p.m.
Panel Version: 1.370
Tag Q3_22_rating was removed from gene: CLPB. Tag Q3_22_MOI was removed from gene: CLPB. Tag Q3_22_expert_review was removed from gene: CLPB.
Source Expert Review Green was added to CLPB. Source NHS GMS was added to CLPB. Mode of inheritance for gene CLPB was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag Q3_21_MOI was removed from gene: CLPB. Tag Q3_22_MOI tag was added to gene: CLPB.
Tag Q4_21_expert_review was removed from gene: CLPB. Tag Q3_21_MOI tag was added to gene: CLPB. Tag Q3_22_rating tag was added to gene: CLPB. Tag Q3_22_expert_review tag was added to gene: CLPB.
Phenotypes for gene: CLPB were changed from 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271 to 3-methylglutaconic aciduria, type VIIB, autosomal recessive, OMIM:616271; 3-methylglutaconic aciduria, type VIIA, autosomal dominant, OMIM:619835; Neutropenia, severe congenital, 9, autosomal dominant, OMIM:619813
Publications for gene: CLPB were set to 26916670; 25597510; 25597511
Tag Q4_21_expert_review tag was added to gene: CLPB.
Phenotypes for gene: CLPB were changed from Seizures; Generalised epilepsy; 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 616271 to 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, OMIM:616271
Gene: clpb has been classified as Amber List (Moderate Evidence).
gene: CLPB was added gene: CLPB was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Green Mode of inheritance for gene: CLPB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CLPB were set to 26916670; 25597510; 25597511 Phenotypes for gene: CLPB were set to Seizures; Generalised epilepsy; 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 616271