%0 Journal Article %J Epilepsia %D 2020 %T Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort. %A Rochtus, Anne %A Olson, Heather E %A Smith, Lacey %A Keith, Louisa G %A El Achkar, Christelle %A Taylor, Alan %A Mahida, Sonal %A Park, Meredith %A Kelly, McKenna %A Shain, Catherine %A Rockowitz, Shira %A Rosen Sheidley, Beth %A Poduri, Annapurna %K Adolescent %K Adult %K Age of Onset %K Brain Diseases %K Child %K Child, Preschool %K Chromosomes, Human %K Cohort Studies %K Epilepsy %K Epilepsy, Generalized %K Exome %K Female %K Genetic Testing %K Genetic Variation %K Humans %K Infant %K Male %K Microarray Analysis %K Phenotype %K Whole Exome Sequencing %K Young Adult %X

OBJECTIVE: We evaluated the yield of systematic analysis and/or reanalysis of whole exome sequencing (WES) data from a cohort of well-phenotyped pediatric patients with epilepsy and suspected but previously undetermined genetic etiology.

METHODS: We identified and phenotyped 125 participants with pediatric epilepsy. Etiology was unexplained at the time of enrollment despite clinical testing, which included chromosomal microarray (57 patients), epilepsy gene panel (n = 48), both (n = 28), or WES (n = 8). Clinical epilepsy diagnoses included developmental and epileptic encephalopathy (DEE), febrile infection-related epilepsy syndrome, Rasmussen encephalitis, and other focal and generalized epilepsies. We analyzed WES data and compared the yield in participants with and without prior clinical genetic testing.

RESULTS: Overall, we identified pathogenic or likely pathogenic variants in 40% (50/125) of our study participants. Nine patients with DEE had genetic variants in recently published genes that had not been recognized as epilepsy-related at the time of clinical testing (FGF12, GABBR1, GABBR2, ITPA, KAT6A, PTPN23, RHOBTB2, SATB2), and eight patients had genetic variants in candidate epilepsy genes (CAMTA1, FAT3, GABRA6, HUWE1, PTCHD1). Ninety participants had concomitant or subsequent clinical genetic testing, which was ultimately explanatory for 26% (23/90). Of the 67 participants whose molecular diagnoses were "unsolved" through clinical genetic testing, we identified pathogenic or likely pathogenic variants in 17 (25%).

SIGNIFICANCE: Our data argue for early consideration of WES with iterative reanalysis for patients with epilepsy, particularly those with DEE or epilepsy with intellectual disability. Rigorous analysis of WES data of well-phenotyped patients with epilepsy leads to a broader understanding of gene-specific phenotypic spectra as well as candidate disease gene identification. We illustrate the dynamic nature of genetic diagnosis over time, with analysis and in some cases reanalysis of exome data leading to the identification of disease-associated variants among participants with previously nondiagnostic results from a variety of clinical testing strategies.

%B Epilepsia %V 61 %P 249-258 %8 2020 02 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/31957018?dopt=Abstract %R 10.1111/epi.16427 %0 Journal Article %J Elife %D 2017 %T Genetic identification of a common collagen disease in puerto ricans via identity-by-descent mapping in a health system. %A Belbin, Gillian Morven %A Odgis, Jacqueline %A Sorokin, Elena P %A Yee, Muh-Ching %A Kohli, Sumita %A Glicksberg, Benjamin S %A Gignoux, Christopher R %A Wojcik, Genevieve L %A Van Vleck, Tielman %A Jeff, Janina M %A Linderman, Michael %A Schurmann, Claudia %A Ruderfer, Douglas %A Cai, Xiaoqiang %A Merkelson, Amanda %A Justice, Anne E %A Young, Kristin L %A Graff, Misa %A North, Kari E %A Peters, Ulrike %A James, Regina %A Hindorff, Lucia %A Kornreich, Ruth %A Edelmann, Lisa %A Gottesman, Omri %A Stahl, Eli Ea %A Cho, Judy H %A Loos, Ruth Jf %A Bottinger, Erwin P %A Nadkarni, Girish N %A Abul-Husn, Noura S %A Kenny, Eimear E %K Adolescent %K Adult %K Aged %K Child %K Collagen Diseases %K Female %K Fibrillar Collagens %K Genotype %K Heterozygote %K Hispanic Americans %K Homozygote %K Humans %K Male %K Middle Aged %K Molecular Epidemiology %K Multigene Family %K Musculoskeletal Diseases %K New York City %K Pedigree %K Whole Genome Sequencing %K Young Adult %X

Achieving confidence in the causality of a disease locus is a complex task that often requires supporting data from both statistical genetics and clinical genomics. Here we describe a combined approach to identify and characterize a genetic disorder that leverages distantly related patients in a health system and population-scale mapping. We utilize genomic data to uncover components of distant pedigrees, in the absence of recorded pedigree information, in the multi-ethnic Bio biobank in New York City. By linking to medical records, we discover a locus associated with both elevated genetic relatedness and extreme short stature. We link the gene, , with a little-known genetic disease, previously thought to be rare and recessive. We demonstrate that disease manifests in both heterozygotes and homozygotes, indicating a common collagen disorder impacting up to 2% of individuals of Puerto Rican ancestry, leading to a better understanding of the continuum of complex and Mendelian disease.

%B Elife %V 6 %8 2017 09 12 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/28895531?dopt=Abstract %R 10.7554/eLife.25060