Practice Guidelines for Molecular Diagnosis of Fragile strongXstrong.pdfVIP

Practice Guidelines for Molecular Diagnosis of Fragile X Syndrome 1 2 Prepared and edited by James Macpherson and Abid Sharif following a CMGS Workshop held on 10th July 2012. 1. Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, Wiltshire, SP2 8BJ, U.K. 2. East Midlands Regional Molecular Genetics Service, Nottingham University Hospitals NHS Trust, City Hospital Campus, Nottingham, NG5 1PB, U.K. Guidelines updated by the Association for Clinical Genetic Science (formally Clinical Molecular Genetics Society and Association of Clinical Cytogenetics) approved November 2014. 1. NOMENCLATURE and GENE IDs OMIM Condition Gene name Gene map locus 309550 Fragile X Syndrome FMR1 Xq27.3 309548 FRAXE FMR2 Xq28 2. DESCRIPTION OF DISEASE 2.1 Fragile X Syndrome Fragile X Syndrome is thought to be the commonest single-gene cause of learning disability features in humans with an estimated prevalence of 1 in 4000- 1 in 6000 males, where it causes moderate to severe intellectual and social impairment together with syndromic features 1 including large ears and head, long face and macroorchidism . A fragile site (FRAXA) is expressible at the gene locus at Xq27.3, typically in 2-40 % of blood cells in affected males. The pathogenic mutation in most cases is a large expansion (‘full mutation’) in a CGG repeat tract in the first untranslated exon of the gene FMR1, which normally encodes the RNA-binding protein FMRP. Full mutations (from approximately 200 repeats