correspondence

Biobanks could identify medically actionable fndings relevant for COVID-19 clinical care

To the Editor — DNA biobanks have the Table 1 | Potential COVID-19-related medically actionable genetic conditions potential to provide real-time clinical utility during this COVID-19 pandemic Class of actionable Genetic condition (s) by identifying patients with underlying condition genetic conditions that could result in Conditions associated Long QT syndromes CASQ2, KCNE1, KCNH2a,b, KCNQ1a,b, RYR2a,b, a higher risk for COVID-19-related with an increased and catecholaminergic SCN5Aa,b morbidity or mortality. Medically actionable susceptibility polymorphic VT genetic findings are generally considered to medications G6PD deficiency G6PD to be genetic changes that reveal or commonly used in a,b a,b predict a genetic condition for which managing COVID-19 Malignant hyperthermia CACNA1S , RYR1 preventive measures and/or treatments and respiratory failure susceptibility 1,2 are available . In 2013, the American Conditions that cause Urea cycle disorders ASL, ASS1, CPS1, NAGS, OTCa,b, SLC25A13b, College of Medical Genetics and Genomics reversible metabolic or SLC25A15 (ACMG) recommended the reporting of thrombotic crises that Lysinuric intolerance SLC7A7 medically actionable secondary findings are often induced by b identified during routine clinical exome severe illnesses Fatty acid oxidation disorders ACADM, ACADVL , CPT2, ETFA, ETFB, ETFDH and genome sequencing1, and in 2016 Acute porphyrias CPOX, HMBSb, PPOX the ACMG updated this list to include 59 Adrenal insufficiency disorders AAAS, ABCD1b, AIRE, LHX4, PCSK1, PROP1 for genetic conditions they deemed b b to meet criteria for medical actionability Hereditary thrombophilia PROC , PROS1 , SERPINC1 (i.e., ACMG59)3. Although these ACMG Methylmalonic acidemia MMACHCb, MMADHCb recommendations were not intended to Atypical hemolytic uremic C3, CD46, CFB, CFH, CFI become a definitive statement on genetic syndrome conditions that are or are not medically Conditions that Familial cardiomyopathies ACTC1a,b, DSC2a,b, DSG2a,b, DSPa,b, LMNAa,b, actionable, the ACMG59 list has become cause reversible MYBPC3a,b, MYH7a,b, MYL2a,b, MYL3a,b, a default standard across multiple DNA cardiopulmonary PKP2a,b, PRKAG2a,b, TMEM43a,b, TNNI3a,b, biobanks, in which sequencing has complications that can TNNT2a,b, TPM1a,b, TTN identified that roughly 3% of the population be exacerbated during Cystic fibrosis CFTR harbors a deleterious variant in one of these severe illnesses genes4. While the overall clinical impact of Refsum disease PEX7, PHYH returning unanticipated genomic findings Familial pulmonary BMPR2b is still being studied, early findings in some hypertension categories indicate evidence of its potential Congenital myasthenic CHRNA1, CHRNB1, CHRND, CHRNE, COLQ, 5 impact on improving patient outcomes . syndrome CHAT, GFPT1, MUSK, DOK7, RAPSN

More recently, ongoing efforts from the a b Clinical Genome Resource Actionability ACMG59 actionable gene. Clinical Genome Resource actionable gene. Working Group have highlighted over 150 medically actionable genetic conditions2. will not protect them from developing Brigham Personalized Medicine, Boston, MA, Using the ACMG59 and Clinical Genome COVID-19, it may indicate potential USA. 3Channing Division of Network Medicine, Resource actionability curations as a complexity and allow clinicians to anticipate Department of Medicine, Brigham and Women’s reference, we have identified over 70 genetic and mitigate morbidity or mortality Hospital and Harvard Medical School, Boston, conditions that could be relevant to making associated with their clinical management. MA, USA. 4Broad Institute of Harvard and MIT, clinical decisions for patients who have Academic and national biobanks are Cambridge, MA, USA. developed COVID-19 (Table 1). These well positioned to quickly initiate a clinical ✉e-mail: [email protected] genetic conditions can broadly be split workflow for returning these medically into three main categories: (1) conditions actionable findings, as many have already Published online: 15 June 2020 associated with an increased susceptibility accrued a critical mass of genotyping and https://doi.org/10.1038/s41591-020-0953-x to medications commonly used in managing sequencing data, and many of these biobanks COVID-19 and respiratory failure; (2) already have in place the governance References conditions that cause reversible metabolic infrastructure for returning clinically 1. Green, R. C. et al. Genet. Med. 15, 565–574 (2013). ❐ 2. Webber, E. M. et al. Hum. Mutat. 39, 1677–1685 (2018). or thrombotic crises that are often induced actionable genetic findings to patients. 3. Kalia, S. S. et al. Genet. Med. 19, 249–255 (2017). by severe illnesses such as COVID-19; 4. Natarajan, P. et al. Sci. Transl. Med. 8, 364ra151 (2016). and (3) conditions that cause reversible Andrew B. Stergachis 1,2,3 ✉ , 5. Manickam, K. et al. JAMA Netw. Open 1, e182140 (2018). cardiopulmonary complications that can Scott T. Weiss2,3 and Robert C. Green1,2,4 1 Competing interests be exacerbated during severe illnesses such Division of Genetics, Department of Medicine, R.C.G. receives compensation for advising AIA, Grail, as COVID-19. Although knowledge of a Brigham and Women’s Hospital and Harvard Humanity, UnitedHealthcare, Verily and Wamberg and is a patient’s status for one of these conditions Medical School, Boston, MA, USA. 2Mass General co-founder of and equity holder in Genome Medical.

Nature Medicine | VOL 26 | July 2020 | 990–994 | www.nature.com/naturemedicine 991