DanMAC5: a browser of aggregated sequence variants from 8,671 whole genome sequenced Danish individuals.

OBJECTIVES: Allele counts of sequence variants obtained by whole genome sequencing (WGS) often play a central role in interpreting the results of genetic and genomic research. However, such variant counts are not readily available for individuals in the Danish population. Here, we present a dataset with allele counts for sequence variants (single nucleotide variants (SNVs) and indels) identified from WGS of 8,671 (5,418 females) individuals from the Danish population. The data resource is based on WGS data from three independent research projects aimed at assessing genetic risk factors for cardiovascular, psychiatric, and headache disorders. To enable the sharing of information on sequence variation in Danish individuals, we created summarized statistics on allele counts from anonymized data and made them available through the European Genome-phenome Archive (EGA, https://identifiers.org/ega. DATASET: EGAD00001009756 ) and in a dedicated browser, DanMAC5 (available at www.danmac5.dk ). The summary level data and the DanMAC5 browser provide insight into the allelic spectrum of sequence variants segregating in the Danish population, which is important in variant interpretation. DATA DESCRIPTION: Three WGS datasets with an average coverage of 30x were processed independently using the same quality control pipeline. Subsequently, we summarized, filtered, and merged allele counts to create a high-quality summary level dataset of sequence variants.

Impact of Genetic Testing on Therapeutic Decision-Making in Childhood-Onset Epilepsies-a Study in a Tertiary Epilepsy Center.

We assessed the frequency of pediatric monogenic epilepsies and precision therapies at a tertiary epilepsy center. We analyzed medical records of children, born in 2006-2011 and followed at the Danish Epilepsy Center from January to December 2015; 357 patients were identified, of whom 27 without epilepsy and 35 with acquired brain damage were excluded. Of the remaining 295 children, 188 were consented for study inclusion and genetic testing. At inclusion, 86/188 had a preexisting genetic diagnosis and did not undergo further genetic testing. The 102 genetically unsolved patients underwent WES, which identified a (likely) pathogenic variant in eight patients and a highly relevant variant of unknown significance (VUS) in seven additional patients. Single nucleotide polymorphism array was performed in the remaining 87 patients and revealed no (likely) pathogenic copy number variants (CNVs). Patients with a genetic diagnosis had a significantly lower median age at seizure onset and more often had febrile seizures, status epilepticus, or neurodevelopmental impairment compared to those who remained genetically unsolved. Most common epilepsies were focal or multifocal epilepsies and developmental and epileptic encephalopathies (DDEs). Fifty-three patients, with a putative genetic diagnosis, were potentially eligible for precision therapy approaches. Indeed, genetic diagnosis enabled treatment adjustment in 32/53 (60%); 30/32 (93%) patients experienced at least a 50% reduction in seizure burden while only 4/32 (12.5%) became seizure-free. In summary, a genetic diagnosis was achieved in approximately 50% of patients with non-acquired epilepsy enabling precision therapy approaches in half of the patients, a strategy that results in > 50% reduction in seizure burden, in the majority of the treated patients.