Intellectual disabilityGene: CYP27A1
Advice from clinical team "the phenotypic relevance is borderline. I would opt for amber in view of the small number of cases of school age, or earlier, intellectual impairment. This phenotype is the mainstay of this panel, but not clearly the common presentation for this disorder. Therefore I would prefer to opt to await further cases with a relevant phenotype before reviewing this".
CYP27A1 will therefore remain Amber on the panel and the watchlist tag been added.
Created: 29 Jul 2019, 2:29 p.m. | Last Modified: 29 Jul 2019, 2:29 p.m.
Panel Version: 2.991
Identified by an external reviewer but still unsure whether it should be promoted to green on the ID panel, it is green on a number of other panels. Most recently reviewed on the epilepsy panel https://panelapp.genomicsengland.co.uk/panels/402/. The most recent publication PMID: 29484516 describes a literature search on the disease where 35% are reported to have cognitive decline and age of diagnosis is from birth to 67yrs. The paper also identifies a further five cases, with limited case histories and sequencing was performed only on 2 individuals one homozygous and the other compound hetrozygous, no other sequence or trio data provided. Of the 5 identified cases 3 had cognitive difficulty at school age or earlier, results were not available for two of the individuals. Unsure if phenotype is relevant as variable age of onset.
Created: 23 Jul 2019, 3:42 p.m. | Last Modified: 23 Jul 2019, 3:42 p.m.
Panel Version: 2.970
1. A 2014 literature review of CTX cases by Mignarri et al identified two earlier cohorts that reported an association with intellectual disability (Verrips et al and Pilo de la Fuente et al) and that data was presented along with their own cohort. This showed intellectual disability associated with CTX in 48-61% of cases (Mignarri (60%) 33/55 (6.5+/- 3.1 years), Verrips (61%) 33/54, Pilo de la Fuente, (48%) 12/25) 1
2. In 2018, Wong et al published the results of another literature review which identified 91 publications and 194 cases which was presented along with their own case series of 5 patient. This quote from the results section shows that CTX patients have 46.4% (90/194) had cognitive decline and 35% had baseline cognitive problems. 2
‘Of these 194 CTX patients, 116 (59.8%) had CST (corticospinal tract) abnormalities, 114 (58.8%) had ataxia, 90 (46.4%) had cognitive decline, 74 (38.1%) had gait difficulty, 41 (21.1%) had sensory loss, 37 (19.1%) had seizure, 36 (18.6%) had speech changes, 34 (17.5%) had psychiatric changes, and 19 (9.8%) had parkinsonism;68 (35.0%) had baseline cognitive problems.’
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 cognitive decline may develop throughout life with relatively high probability and weighted later in life.
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, 2:56 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Cerebrotendinous Xanthomatosis (CTX), 213700; intellectaul disability including childhood & adult onset
Variants in this gene cause Cerebrotendinous xanthomatosis - this includes progressive neurologic dysfunction. Mental retardation is included within the phenotype synopsis in OMIM - I am unsure whether this should be included on the ID panel and need to confirm with the clinical team, as it doesn't seem that mental retardation is a feature in all patients. Green in several other panels for this phenotype, therefore enough evidence if it is suitable for this panel.
Created: 27 Oct 2017, 2:46 p.m.
Cerebrotendinous xanthomatosis 213700
This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_movement_disorder_list . Main mutation mechanism : NA
Created: 27 Jul 2017, 5:29 p.m.
Evidences key, gene present in following gene lists and main mutation mechanism : manju_list; Nijmegen_ID_candidates; neuro_20160418_strict; NA. This is a pertinent gene from the BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene comes from the SPEED_NEURO_v3.0_20170404 gene list. The following experts from the BRIDGE consortium NIHRBR-RD contributed to this panel: - Professor F. Lucy Raymond, Cambridge Institute for Medical Research, University of Cambridge - Manju Kurian, Paediatric neurologist, Great Ormond Street Hosptial - Keren Carss, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Alba Sanchis-Juan, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Marie Erwood NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Louise Daugherty, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust
Created: 19 Jul 2017, 12:16 p.m.
Mode of inheritance
Comment on list classification: This gene is from an expert list and needs further assessment by the Genomics England curation team to access inclusion and pertinence to this panel.
Created: 19 Jul 2017, 5:10 p.m.
Tag watchlist tag was added to gene: CYP27A1.
Publications for gene: CYP27A1 were set to 24442603; 29484516
Publications for gene: CYP27A1 were set to
Source Victorian Clinical Genetics Services was added to CYP27A1.
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
This gene has been classified as Amber List (Moderate Evidence).
CYP27A1 was created by BRIDGE
CYP27A1 was added to Intellectual disabilitypanel. Sources: BRIDGE study SPEED NEURO Tier1 Gene