Canavan disease

Contact details Introduction Regional Genetics Service Canavan disease (CD) (MIM 271900) is an autosomal recessive , Levels 4-6, Barclay House characterised clinically by , and developmental delay. 37 Queen Square Pathogenic variants in the ASPA gene affect the function of the London, WC1N 3BH protein, demonstrated biochemically by an increase of N-acetyl-L-aspartic acid (NAA) T +44 (0) 20 7762 6888 in the urine. CD has an incidence of around 1/6500 – 1/13500 in the Ashkenazi F +44 (0) 20 7813 8578 Jewish population (approximately 1/40 individuals are carriers), and around 1/100000 in individuals of non-Ashkenazi Jewish ancestry. Pathogenic variants in the ASPA gene are the only known cause of CD. ASPA has 6 coding exons and family specific Samples required variants are found throughout the gene. Three common variants account for 98% of  5ml venous blood in plastic EDTA pathogenic variants in the Ashkenazi Jewish population, and a single common variant bottles (>1ml from neonates) accounts for approximately 30-60% of pathogenic variants in the non-Ashkenazi  A completed DNA request card Jewish population. should accompany all samples

Patient details Referrals To facilitate accurate testing and  Confirmation of diagnosis in individuals clinically suspected of having CD. reporting please provide patient demographic details (full name, date of  Investigation of the molecular defect in individuals with an increased NAA birth, address and ethnic origin), details concentration of any relevant family history and full  Carrier testing in adult relatives of confirmed (genetic) CD patients contact details for the referring clinician  Carrier testing in individuals at increased risk (above the population risk) of having an affected pregnancy, for example a family history of CD, a partner shown to be a carrier or first cousin partnerships within the Ashkenazi Jewish population.

Prenatal testing Prenatal testing is available for couples in whom pathogenic variants have been identified.

Service offered Analysis of of the ASPA gene by next generation sequencing (Agilent SureSelect and Illumina NextSeq). A minimum coverage of 30 reads is required to call a variant. In- house validation attributes a minimum sensitivity of 97.5% (with 95% confidence) for regions covered >30x. This assay is not validated to detect large deletions / duplications. Detection of large deletions/duplications in the ASPA gene is carried out using MLPA. All clinically relevant variants are confirmed by Sanger sequence analysis. Known benign polymorphisms and sequence variants which are unlikely to be pathogenic are not reported. Testing for previously identified pathogenic variants is available to other family members.

Target reporting time 8 weeks for a full screen in an index case (next generation sequencing and MLPA). 4 weeks for familial testing. Please note this service does not currently have UKAS accreditation.

Version 10