PROJECT SUMMARY Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are associated with widespread epidermal necrosis with the clinical presentation consisting of widespread blisters and bullae and involvement of mucous membranes and the eyes. The mortality of SJS/TEN is up to 50% and long-term physical and mental health morbidity is considerable and understudied. In adults over 80% of SJS/TEN is drug associated, and promising discoveries have associated variation in class I specific major histocompatibility complex alleles such as HLA-B*15:02 and HLA-B*58:01 which are associated with carbamazepine and allopurinol SJS/TEN For most drugs, however, genetic factors driving risk for SJS/TEN are unknown. In the case of allopurinol although HLA- B*58:01 has close to 100% negative predictive value in Southeast Asia only 50-60% of Europeans and Africans who develop allopurinol SJS/TEN carry HLA-B*58:01. Common causes of SJS/TEN in the US include trimethoprim-sulfamethoxazole, allopurinol and aromatic anticonvulsants such as lamotrigine, phenytoin and carbamazepine where the prevalent genetic associations in US populations have yet to be defined which has stalled preventive efforts and implementation. The rarity of SJS/TEN and lack of access to large cohorts of survivors has impaired the ability to define genetic risk factors and long-term morbidity. We will utilize a registry developed by the SJS Foundation (http://sjsupport.org/) to develop a data and DNA biobank of phenotype adjudicated SJS/TEN survivors. Our testable hypothesis is that we will determine genetic risk factors for the most common drugs associated with SJS/TEN and the nature and risk of long-term complications associated with SJS/TEN both of which will have the potential to have significant impact on SJS/TEN prevention and patient outcomes. In Specific Aim 1 we will establish a large cohort of SJS/TEN survivors with an associated DNA biobank. Participants will be recruited through the SJS Foundation website, Facebook page and registry and consented for medical record review and oral DNA collection. Independent adjudication for drug-induced SJS/TEN will determine eligible participants. In Specific Aim 2 we will define long-term mental and physical health complications associated with SJS/TEN and associated risk factors. Validated questionnaires will assess mental and physical health complications cross- sectionally in patients at different time points following SJS/TEN through instruments validated for psychological distress, post-traumatic stress disorder and health-related quality of life. In Specific Aim 3 we will determine HLA and other genetic risk factors associated with drug-induced SJS/TEN. High resolution HLA, ERAP and KIR typing as well as expanded multi-ethnic genotyping array (MegaEx ) will be performed on 1000 patients who have been verified as having drug-induced SJS/TEN by an independent panel of three dermatologists. Controls will be the BioVu reference population of 100,000 with MegaEx typing, imputed HLA/KIR/ERAP typing as well as BioVu drug tolerant controls matched 2:1 on age, sex and race and underlying disease.