THE ROLE OF NEXT GENERATION SEQUENCING IN CLINICAL PRACTICE Prof. HATEM EL-SHANTI

NUCLEIC ACID STRUCTURE Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

DNA PROCESSING TRANSCRIPTION TRANSLATION Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

GENE STRUCTURE Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

DNA SEQUENCING Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

NEXT GENERATION SEQUENCING Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

BIOINFORMATIC TECHNOLOGY Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

BURDEN OF MENDELIAN DISORDERS Birth defects include genetic disorders that are present at birth, such as metabolic disorders, as well as, congenital anomalies [>7,000] About 6% of total births world-wide are born with a major birth defect of genetic etiology Birth defects are commonly lethal Survivors have a life-long disability About half of those born with a major birth defect will die before their 5th birthday About half of those born with a major birth defect who survive their 5th birthday will be disabled for life Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

CONVENTIONAL UNIVARIATE GENETIC TESTING Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

COMPREHENSIVE GENETIC TESTING Gene or disease panels Target (exons within genes and splice sites) enrichment PCR based or Microarray based Genes with one or overlapping phenotypes Whole exome sequencing Target (all possible exons and splice sites) enrichment Phenotype driven analyses Whole genome sequencing Random shearing of the genome Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

NGS AND MENDELIAN DISEASE Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

NGS AND GENE DISCOVERY Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

CLINICAL APPLICATIONS Gene or disease panels Duchenne/Becker muscular dystrophy Hearing loss Neurodegenerative diseases / leukoencephalopathy Early-onset neuromuscular diseases Retinopathies Whole exome sequencing Mental retardation syndromes Autism Spectrum Disorder (ASD) Undetermined phenotype Whole genome sequencing Non-invasive prenatal diagnosis Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

BENEFITS Potential for reducing mortality and morbidity Genetic counseling Use of investigational drugs Improving quality of life Psychosocial benefits Narrowing the differential diagnosis Increased understanding of disease mechanisms Improved variant database Population-based screening Lower average cost Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

Variants of unknown clinical significance DRAWBACKS Variants of unknown clinical significance Incidental and unsolicited findings Informational privacy and family relations Commercial applications Psychosocial drawbacks Insufficient bioinformatic tools Insufficient ethnic databases Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

LABORATORY AND CLINICAL STANDARDS Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

FIVE-TIER TERMINOLOGY SYSTEM PATHOGENIC LIKELY PATHOGENIC UNCERTAIN CLINICAL SIGNIFICANCE LIKELY BENIGN BENIGN Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

NT5E mutations and arterial calcifications GENOMIC MEDICINE The influencing or basing the clinical care of a patient on the knowledge of the specific genomic variants the patient has Whole Exome Sequencing in a child with intractable inflammatory bowel disease NT5E mutations and arterial calcifications Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

PERSONALIZED MEDICINE Advances the use of genomic medicine while shifting health care from being reactive to being predictive and preventive Integrates unique clinico-pathological, genetic, genomic and environmental information to create an optimized care plan Utilizes the molecular knowledge of common diseases to enhance prevention during wellness and begin therapy early Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

INTEGRATION INTO CLINICAL PRACTICE Advance in genomic and computational technologies led to an exponential accumulation of genomic data Exposure of the gaps in the infrastructure needed for the implementation of genomic data into clinical practice Paucity of standardization into clinical tests Physicians are unprepared to deliver the information Deficiency in genetics knowledge amongst the average health-care provider Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018

THANK YOU FOR YOUR ATTENTION Laboratory Medicine: Current Aspects and Future Prospects 6/5/2018