주간건강과질병 제 10 권제 51 호 연구단신, Brief report 미진단희귀질환연구네트워크소개 질병관리본부국립보건연구원생명의과학센터희귀질환과황주연, 안윤진 * * 교신저자 : / Global initiativ

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1 연구단신, Brief report 미진단희귀질환연구네트워크소개 질병관리본부국립보건연구원생명의과학센터희귀질환과황주연, 안윤진 * * 교신저자 : carotene@korea.kr / -9-8 Global initiative for the undiagnosed diseases network Hwang Joo-Yeon, Ahn Younjhin* Division of Rare Diseases, Center for Biomedical Sciences, KNIH, KCDC Undiagnosed diseases ( diagnostic odyssey ) are a global public health issue with long-term medical consequences. In 8, the National Institute of Health (NIH) Undiagnosed Diseases Program (UDP) was established to provide diagnostic criteria for previously unrecognized diseases as well as to obtain insights into novel disease mechanisms and pathways. The UDP project could be important for patients, academic medical centers, the scientific community, and society. In 5, a nationwide Undiagnosed Diseases Network (UDN) was launched. However, the unmet needs of this network remain a significant problem. Given the broad spectrum of unknown or ultra-rare disorders, international collaborations and networks are important to integrate clinical research resources across ethnic populations for a more comprehensive understanding of diagnoses and treatments. To address this issue further, the Undiagnosed Diseases Network International (UDNI) was initiated to build consensus framework of principles, best practices, and governance. Recently, the Korea NIH has made an effort to uncover and identify undiagnosed diseases through a pilot project by developing systematic input system as a gateway. It is high time we pay more attention to the UDNI to accelerate diagnosis, improve recommendations for clinical management, and advance research. We expect to improve diagnostic accuracy through international network participation and data sharing. Keywords: Undiagnosed disease, Clinical-genomic, Undiagnosed diseases program, Undiagnosed diseases network, Undiagnosed diseases network international 들어가는말 현대의첨단의료시스템에도불구하고자신의병명도진단받지못한채고통을겪고있는환자들이있다. 바로미진단희귀질환자이다. 환자수가적고질환에대한정보를접하기어렵기 때문에이들은진단과적절한치료를받지못한상태로난민처럼여러병원을떠돌게되는데, 조사에따르면미국의환자들은 번이상의오진을경험하고, 확진에이르기까지평균.6 년이소요된다. 이러한의료난민 (undiagnosed medical refugee) 으로의진단방랑 (diagnostic odyssey) 이장기화됨에따라환자들의경제적 96

2 의료비부담과더불어사회적소외감, 신체적 / 정신적고통은계속악화되고있는실정이다. 미진단희귀질환자는적절한전문의료진을찾지못하거나, 부적절한검사방법및부정확한검사해석에의한주요원인뿐아니라희귀질환자의임상적양상이복잡 (phenotypic variability) 하거나진단유전체정보 (diagnostic genetic information) 의부재로정확하게진단을받지못하고있는것이현실적인문제이다. 따라서상세불명희귀질환에대한임상-유전체자료를체계적으로축적 기록화하는것이필요하며, 이러한정보를바탕으로미진단환자들의진단과병인파악을위해국가간연구협력을강화하고네트워크기반의임상-유전체정보공유활성화가중요하다. 이글에서는현재진행되고있는미진단자진단지원프로그램및국제희귀질환지원네트워크등연구동향을소개하고자한다. 몸말 지난 8년 5월미국국립보건원 (National Institutes of Health, NIH) 산하국립인간유전체연구소 (National Human Genome Research Institute, NHGRI) 는미진단희귀질환자를돕기위해국가주도의미진단희귀질환진단프로그램 (undiagnosed patients program, UDP) 을시작하였다. UDP의주요목표는진단프로그램을통해미진단환자들의진단확실성을높이고, 질환발병기전및원인에대한새로운지식을축적하고자함이다. UDP 통계를살펴보면, 진단소요기간은최소 주에서최장 년이며, 년간약 만건이상이접수되었다. 검토된신청건 ( 총,95개 ) 가운데 86명의환자들이진단프로그램대상으로확정되어약 9% 의채택률 (acceptance rate) 을보였으며, 이중 % 는소아환자에해당되며, 신경계통표현형이가장높은빈도로 나타났다 (Figure ). Rheumatology 9 Renal 8 Pulmonary Psychiatry Orthopedics Ophthalmology Oncology Total F M Neurology Metabolic Immunology Infectious Disease Hematology 6 Gynecology Gastrointestinal Fibrmyalgia/CFS Endocrine 5 8 Dermatology 5 8 Cardiovascular Allergy Figure. Primary phenotypes of UDP accepted patients 9

환자들의표현형정보는 PhenoTips DB를이용한 Human Phenotype Ontology (HPO) term을기반으로표준화되고있으며, 시료검체로는혈장 (plasma), 혈청 (serum), DNA/ RNA, 소변 (urine), 뇌척수액 (cerebrospinal fluid) 그리고피부생체검사 (skin biopsy) 로부터분리된섬유아세포

3 환자들의표현형정보는 PhenoTips DB를이용한 Human Phenotype Ontology (HPO) term을기반으로표준화되고있으며, 시료검체로는혈장 (plasma), 혈청 (serum), DNA/ RNA, 소변 (urine), 뇌척수액 (cerebrospinal fluid) 그리고피부생체검사 (skin biopsy) 로부터분리된섬유아세포 (fibroblast) 등이분리되어저장된다. 유전체접근방법으로고밀도단일염기다형성어레이 (high-density single nucleotide polymorphism chip), 전장엑솜서열 (whole exome sequencing, WES) 및전장유전체정보 (whole genome sequencing, WGS) 가생산되었으며, 선정된유전변이들 (potentially pathogenic variants) 은생물정보학, 세포및다양한동물모델시스템 (fly, zebrafish, worm or mouse) 을통해기능연구가수행되었다. 그결과는 ) 다인자 (polygenic- /multifactorial) 복합질환 (osteoporosis, nephrolithiasis 및 viral infection) 에대한이해, ) 희귀질환이둘이상겹쳐진경우의해석, ) 새롭게인식된질병기전의이해그리고 ) 정밀의학분야에참조정보로서활용되고있다. 그간의성공적인 UDP경험을바탕으로 5년에미국 NIH는네트워크조정센터 (coordinating center) 와중앙바이오뱅크 (central biorepository) 를비롯하여유전자기능코어, 질환동물모델 (model organisms screening) 코어, 대사체 (metabolomics) 코어, 개의시퀀싱코어로구성된 additional research sites 및 개의 clinical sites로구성된미진단자진단네트워크 (Undiagnosed Disease Network, UDN) 프로젝트를시작하였다 (Figure, Table ). 각임상사이트들에서는연간 5명의환자그리고 NIH는 5명의환자를진단하는것을목표로미진단자진단프로그램을추진하고있으며환자및임상전문의가신청 등록할수있도록온라인환자신청포탈 ( UDN Gate-way ) 을개설하였다 ( way.undiagnosed.hms.harvard.edu). UDN 전반적인데이터흐름을살펴보면, 크게 단계로 ) 환자신청및초기대응, ) 임상사이트로환자이송및데이터전송, ) 평가, ) 리포트및검토단계로분류될수있다. 또한지리적인제한점을감안하여신속하고효율적인데이터관리를위해전문 Figure. UDN locations ( Blue: DNA sequencing cores, Red: clinical sites, Yellow: additional sites. 98

4 Table. Activities of each site in the UDN No Institution Role (Title) Principal Investigator Harvard Medical School Coordinating Center Isaac Kohane, Alexa McCray Harvard Teaching Hospitals (Boston Children s, Brigham & Women s, Massachusetts General s) Clinical Site- (Center for integrated approaches to undiagnosed disease) Joseph Loscalzo Baylor College of Medicine (With Oregon University) Clinical Site- (BMC clinical site) DNA Sequencing Core- Brendan Lee Christine Eng Model Organisms Screening Center Hugo Bellen Duke University Health System (With Columbia University Medical Center) Clinical Site- (Integrated & diverse genomic medicine program) Vandana Shashi, David Goldstein 5 National Institutes of Health Clinical Site- William Gahl, Cynthia Tifft, David Adams 6 Standford Medical Center University of California Los Angeles 8 Vanderbilt University Medical Center Clinical Site-5 (Stanford center for undiagnosed disease) Clinical Site-6 (UCLA clinical site for the investigation of undiagnosed disorders) Clinical Site- Central Biorepository Euan Ashley, Paul Graham Fisher, Jonathan Bernstein Katrina Dipple, Stanley Nelson, Christina Palmer, Eric Vilain John Phillips III, John Nweman, Rizwan Hamid Joy Cogan 9 Battelle Pacific Northwest National Laboratory (With Oregon Health & Science University) Metabolomics Core Thomas Metz, Davis Koeller HudsonAlpha(with Illumina) DNA Sequencing Core- (Clinical genome wide sequencing core for the UDN) Howard Jacob 네트워크를구성하고 personally-identifiable information (PII) 및 personal health information (PHI) 정보등을보안저장 관리하고있다. 아래그림 (Figure ) 의상부 ( ABOVE THE LINE ) 는 Coordinating Center (CC) 책임하에운영되는모든기술적절차나시스템을뜻하며, 하부 ( BELOW THE LINE ) 는각지역의 Clinical Site (CS) 나코어내에서운영되는시스템내용을나타낸다. 예를들면, EMR (Electronic Medical Record), LIMS (Laboratory Information Management Systems), 지역자료관리시스템, 바이오뱅크등이해당된다. UDN의임상-유전체분석절차는각임상사이트에서환자에대한 WES 및 WGS 플랫폼을결정하고수집된검체로부터 DNA를추출하여 QC 정보, 임상및표현형정보를시퀀싱코어로전달하게된다. UDN 가이드라인에따라 WES/WGS 분석과 Sanger sequencing 을이용한변이검증절차후최종결과물을코디네이팅센터로보내고저장 관리, 리포트하는방식으로진행된다 (Figure ). 그럼에도불구하고미진단희귀질환자들의미충족욕구 (unmet needs) 는점차글로벌이슈로확대됨에따라지난 차이탈리아로마 (.9) 및 차헝가리부다페스트 (5.6) 에서개최된두번의국제컨퍼런스를통해미진단국제네트워크 (Undiagnosed Diseases Network International, UDNI) 가형성되었다. 이후 차, 차및 5차 UDNI 국제컨퍼런스가오스트리아빈 (6.), 일본도쿄 (6.) 그리고스웨덴스톡홀름 (.8) 에서개최되었다. 99

5 ABOVE THE LINE Patient applies to DNN via Gateway Patient assigned UUID and UDN ID Patient receives confirmation of application & initial referral to a CS Case Review Committee reviews Applicant Review Forms and Accepts Patient CS uploads subset of data to Gateway CS creates Applicant Review Form in Gateway BELOW THE LINE CS collects medical, phenotypic and possibly sequencing information before and during evaluation CS may contact patient and request medical records CS stores information under appropriate site specific security measures CS stores information under appropriate site specific security measures (i.e. encryption, authentication, look outs etc.) Figure. UDN data flow process Sequencing Cores Prepare data files according to UDN guidelines Send data files to CC Sequence sample according to UDN guidelines Prepare clinical report according to UDN guidelines Send clinical report to CC Sanger confirm variants Coordinating Center Alerts Sequencing Core of sample shipment and available clinical data Notify Sequencing Core of request and new data Store sequence data and reports, notify CS Clinical Sites Request Sanger confirmation, send new data Determine exome or genome sequencing using UDN guidelines Send exome/genome selection, updated phenotype info, and shipping info to CC Prepare and ship DNA from Clinical Site to Sequencing Core Run clinical Site specific analyses Collect blood sample at clinical evaluation or before and ship to Clinical Site Extract DNA and QC at Clinical Site DNA is stared at Clinical Site with other bio-specimens collected during clinical evaluation Notify Clinicians of clinical report Figure. UDN sequencing flow diagram

6 UDNI에는정부기관, 대학, 병원, 연구소등다양한기관들이포함되어있으며, 현재오스트레일리아, 오스트리아, 벨기에, 캐나다, 프랑스, 독일, 헝가리, 인디아, 이스라엘, 이탈리아, 일본, 한국, 스페인, 스리랑카, 스웨덴, 태국, 네덜란드그리고미국이참여하고있으며, 연례국제협력회의를통해프로그램운영현황및진단지원사례등다양한정보를공유하고이를통해새로운질병을찾고질환원인유전자발굴과기전규명에대한연구협력등을논의하고있다. 마지막으로중요한부분이데이터공유인데 NIH Data Sharing Policy 에따라모든임상, 시퀀싱, 실험연구데이터등 UDN data 는협력네트워크내보안절차에따라모든 UDN 연구자에게공유되며, NCBI에서운영하는 dbgap(the database of Genotypes and Phenotypes) 에데이터공개형태 (de-identified) 로가공되어기탁될예정이다. 맺는말. Cynthia Tifft et al. The Ntional Institutes of Health undiagnosed diseases program. Curr Opin Rediatr. ;6(6): Domenica Taruscio et al. Undiagnosed Diseases Network International (UDNI): White paper for global actions to meet patient need. Molecular Genetics and Metabolism. 5;6:-5.. Brownstein CA et al. Data sharing in the undiagnosed diseases network. Hum Mutat. 5;5(): Jessica Guzman et al. The undiagnosed diseases program integrated collaboration system (UDPICS): one program s experience developing custom software to support research for complexdisease families. Children (Basel), 5;():L-5 6. Gareth Baynam et al. The rare and undiagnosed diseases diagnostic service-application of massively parallel sequencing in a state-wide clinical service. Orphanet J Rare Dis. 6;:.. William A. Gahl et al. The NIH Undiagnosed Diseases Program and Network: Applications to modern medicine. Mol Genet Metabol. 6;(): Gareth Baynam et al. Initiating an undiagnosed diseases program in the Western Australian public health system. Orphanet J Rare Dis. ;:8. 그간국가차원의 UDP 운영을위한전담코어센터를비롯하여관리 운영체계가미미하였다. 질병관리본부국립보건연구원은국내미진단자진단지원프로그램의효율적표준모델수립을위해 년미진단자진단지원시범사업을시작하였으며, 향후본격적인미진단자진단지원사업을통해한국 UDP를개발하고지속적으로관리 운영할계획이다. 또한국제미진단희귀질환지원네트워크 (UDNI) 참여와데이터공유기반 (Match Maker Exchange System) 을통해국가위상을제고하고국제협력연구를강화할예정이다. 따라서환자의진단확실성을높이고새로운질병기작에대한이해와연구효율성을극대화함으로써국내희귀질환진단및치료기술개발을위한연구활성화에기여할수있을것이다. 참고문헌. William A. Gahl et al. The NIH Undiagnosed Diseases Program: Insights into rare diseases. Genet Med. ;():5-9.

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1.. Volume 12, Number 1, 6~16, Factors influencing consultation time and waiting time of ambulatory patients in a tertiary teaching hospital Jee-In Hwang College of Nursing Science, Kyung Hee University :