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Genetic epilepsy syndromes

Gene: CYP27A1

Amber List (moderate evidence)

CYP27A1 (cytochrome P450 family 27 subfamily A member 1)
EnsemblGeneIds (GRCh38): ENSG00000135929
EnsemblGeneIds (GRCh37): ENSG00000135929
OMIM: 606530, Gene2Phenotype
CYP27A1 is in 28 panels

4 reviews

Tracy Lester (Genetics laboratory, Oxford UK)

I don't know

AR cerebrotendinous xanthomatosis - no mention of seizure/epilepsy as a feature on OMIM. Szlago et al, 2008 - 2 Argentinian siblings with a novel mutation in this gene - febrile seizures reported follwed by photosensitive epileptic syndrome.
Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.
Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cerebrotendinous xanthomatosis, 213700

Publications

Rebecca Foulger (Genomics England curator)

I don't know

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. Prominent phenotype is dystonia/ataxia. Demoted from Green to Amber.
Created: 25 Nov 2019, 8:48 p.m. | Last Modified: 26 Nov 2019, 4:08 p.m.
Panel Version: 1.475
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: Amber.
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: Upgraded rating from Red to Green based on external review by Philip Dawson. Although seizures are not a consistent feature of CTX patients, there are plenty of cases in the literature of seizures reported in CTX cohorts and individual cases (e.g. PMIDs 29484516 and 22336472) to support inclusion on this panel.
Created: 9 Jul 2019, 10:53 a.m. | Last Modified: 9 Jul 2019, 10:53 a.m.
Panel Version: 1.133
PMID:22336472. Koyama et al. 2012. An 18 year old Japanese female with a history of epileptic seizures amongst her phenotypes. She had compound heterozygous variants in CYP27A1: maternally-inherited V413D and paternally-inherited R474W. The variants were not present in Japanese controls.
Created: 9 Jul 2019, 10:41 a.m. | Last Modified: 9 Jul 2019, 10:41 a.m.
Panel Version: 1.132
PMID:24442603. Mignarri et al 2014. In their CTX cohort of 55 patients, 18 were reported with epilepsy (33%). They report 14/54 (26%) and 8/25 (32%) of epilepsy cases in previous cohorts.
Created: 9 Jul 2019, 10:40 a.m. | Last Modified: 9 Jul 2019, 10:40 a.m.
Panel Version: 1.132
PMID:29484516. Wong et al 2018 evaluated 5 cases of cerebrotendinous xanthomatosis (CTX) patients. CTX is an autosomal recessive condition caused by variants in CYP27A1. Seizures reported in 1/5 cases at 24 years old. They also analysed 194 cases from the literature and reported seizures in 37/194 cases (19%).
Created: 9 Jul 2019, 10:40 a.m. | Last Modified: 9 Jul 2019, 10:44 a.m.
Panel Version: 1.132
PMID:18227423. Szlago et al., 2008 report 2 Argentinian siblings with novel compound het CYP27A1 variants: 11_12insTGGGCTGCGC and T395C. Both patients had photosensitive epilepsy. Patient 2 had febrile seizures preceeding the epilepsy. Samples were taken from the parents and a sibling, though full segregation is not discussed. This is the original case discussed by Sarah Leigh.
Created: 9 Jul 2019, 10:40 a.m. | Last Modified: 9 Jul 2019, 10:40 a.m.
Panel Version: 1.132

Philip Dawson (Leadiant Biosciences)

Green List (high evidence)

1. A 2014 literature review of CTX cases by Mignarri et al identified two earlier cohorts that reported an association with epilepsy (Verrips et al and Pilo de la Fuente et al) and that data was presented along with their own cohort. This showed epilepsy associated with CTX in 26-33% of cases (Mignarri, 18/55 (33%), Verrips, 8/25 (32%), Pilo de la Fuente, 14/54 (26%)) 1
2. In 2018, Wong et al published the results of a PubMed literature review which identified 91 publications and 194 cases which was presented along with their own case series of 5 patients. 37 of the 194 (19.1%) had seizures. They also calculated Cumulative Incidence Function (CIF) for each CTX symptom which gives an indication of the likelihood of a particular symptom having developed at any given age (best- & worst-case scenario) based on a subset of cases where age of symptom onset was available; this shows that epilepsy may develop in both children and adults.
References
1. Mignarri et al, A suspicion index for early diagnosis and treatment of cerebrotendinous xanthomatosis. J Inherit Metab Dis (2014) 37:421-429
2. Wong et al, Natural history of neurological abnormalities in cerebrotendinous xanthomatosis. J Inherit Metab Dis. 2018 Jul;41(4):647-656
Created: 18 Apr 2019, 3 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cerebrotendinous xanthomatosis, 213700, Epilepsy, including childhood onset.

Publications

Sarah Leigh (Genomics England Curator)

Red List (low evidence)

Not associated with phenotype in OMIM or in Gen2Phen. At least one variant in a single case in which seizures are a phenotypic feature.
Sources: Literature
Created: 11 Dec 2018, 3:57 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cerebrotendinous xanthomatosis 213700

Publications

History Filter Activity

25 Nov 2019, Gel status: 2

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: cyp27a1 has been classified as Amber List (Moderate Evidence).

24 Oct 2019, Gel status: 3

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: CYP27A1 were set to 18227423; 22336472; 24442603; 29484516

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source Wessex and West Midlands GLH was added to CYP27A1.

6 Aug 2019, Gel status: 3

Added New Source

Rebecca Foulger (Genomics England curator)

Source NHS GMS was added to CYP27A1.

9 Jul 2019, Gel status: 3

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: CYP27A1 were changed from Cerebrotendinous xanthomatosis 213700 to Cerebrotendinous xanthomatosis, 213700; seizures; photosensitive epilepsy

9 Jul 2019, Gel status: 3

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: CYP27A1 were set to 18227423

9 Jul 2019, Gel status: 3

Entity classified by Genomics England curator

Rebecca Foulger (Genomics England curator)

Gene: cyp27a1 has been classified as Green List (High Evidence).

11 Dec 2018, Gel status: 1

Panel promoted to version 1.0

Sarah Leigh (Genomics England Curator)

Sarah Leigh: Not associated with phenotype

11 Dec 2018, Gel status: 1

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Sarah Leigh (Genomics England Curator)

gene: CYP27A1 was added gene: CYP27A1 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: CYP27A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CYP27A1 were set to 18227423 Phenotypes for gene: CYP27A1 were set to Cerebrotendinous xanthomatosis 213700 Review for gene: CYP27A1 was set to RED