Array comparative genomic hybridization: results from an adult population with drug-resistant epilepsy and co-morbidities.

The emergence of array comparative genomic hybridization (array CGH) as a diagnostic tool in molecular genetics has facilitated recognition of microdeletions and microduplications as risk factors for both generalised and focal epilepsies. Furthermore, there is evidence that some microdeletions/duplications, such as the 15q13.3 deletion predispose to a range of neuropsychiatric disorders, including intellectual disability (ID), autism, schizophrenia and epilepsy. We hypothesised that array CGH would reveal relevant findings in an adult patient group with epilepsy and complex phenotypes

Genome-wide mapping for clinically relevant predictors of lamotrigine- and phenytoin-induced hypersensitivity reactions.

An association between carbamazepine-induced hypersensitivity and HLA-A*3101 has been reported in populations of both European and Asian descent. We aimed to investigate HLA-A*3101 and other common variants across the genome as markers for cutaneous adverse drug reactions (cADRs) attributed to lamotrigine and phenytoin

Characterisation and validation of insertions and deletions in 173 patient exomes.

Recent advances in genomics technologies have spurred unprecedented efforts in genome and exome re-sequencing aiming to unravel the genetic component of rare and complex disorders. While in rare disorders this allowed the identification of novel causal genes, the missing heritability paradox in complex diseases remains so far elusive. Despite rapid advances of next-generation sequencing, both the technology and the analysis of the data it produces are in its infancy. At present there is abundant knowledge pertaining to the role of rare single nucleotide variants (SNVs) in rare disorders and of common SNVs in common disorders. Although the 1,000 genome project has clearly highlighted the prevalence of rare variants and more complex variants (e.g. insertions, deletions), their role in disease is as yet far from elucidated.We set out to analyse the properties of sequence variants identified in a comprehensive collection of exome re-sequencing studies performed on samples from patients affected by a broad range of complex and rare diseases (N = 173). Given the known potential for Loss of Function (LoF) variants to be false positive, we performed an extensive validation of the common, rare and private LoF variants identified, which indicated that most of the private and rare variants identified were indeed true, while common novel variants had a significantly higher false positive rate. Our results indicated a strong enrichment of very low-frequency insertion/deletion variants, so far under-investigated, which might be difficult to capture with low coverage and imputation approaches and for which most of study designs would be under-powered. These insertions and deletions might play a significant role in disease genetics, contributing specifically to the underlining rare and private variation predicted to be discovered through next generation sequencing

HLA-A*3101 and Carbamazepine-Induced Hypersensitivity Reactions in Europeans.

BACKGROUND: Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations. METHODS: We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions. RESULTS: The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P = 3.5×10-8). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A* 3101 allele (P = 1.1×10-6). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18). CONCLUSIONS: The presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. Copyright © 2011 Massachusetts Medical Society.0info:eu-repo/semantics/publishe