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Chief & Senior Investigator

Medical Genomics and Metabolic Genetics Branch


Clinical Genomics Section


B.S. University of California, Riverside, 1979

M.D. University of Illinois College of Medicine, 1983


Dr. Biesecker is a clinical and molecular geneticist and is the chief of the Medical Genomics and Metabolic Genetics Branch at the National Human Genome Research Institute (NHGRI) of the National Institutes of Health. He uses genetic and genomic technologies to study the etiology of inherited disorders. He received his medical training at the University of Illinois, training in pediatrics at the University of Wisconsin, and in clinical and molecular genetics at the University of Michigan. His laboratory has elucidated the etiology and natural history of numerous diseases, including Proteus syndrome, PIK3CA-related overgrowth syndrome, TARP syndrome, oculofaciocardiodental syndrome, Lenz microphthalmia syndrome, McKusick-Kaufman syndrome, Bardet-Biedl syndrome, Pallister-Hall syndrome and Amish microcephaly, and has contributed to the discovery of many others. In addition, he developed the ClinSeq®program, which has consented more than 1,000 subjects for whole-genome sequencing with the interpretation and return of results. He co-directs a Clinical Laboratory Improvement Ammendments (CLIA)-certified molecular diagnostic laboratory within NHGRI.

Dr. Biesecker serves as an editor or board member for four biomedical journals, is an advisor to the Illumina Corporation and was a member of the board of directors for the American Society of Human Genetics. He served on advisory panels for the World Trade Center and Hurricane Katrina victim identification efforts. He was recently elected to the National Academy of Medicine of the National Academy of Sciences and has been elected to be the president of the American Society of Human Genetics for 2019.

Scientific Summary

The Clinical Genomics Section research program focuses on understanding the relationship of genomic variation to health and disease. The laboratory is currently engaged in studies in two main areas: rare disorders of development and overgrowth, and new approaches to hypothesis-generating clinical genomics research. The goals of this research program are to improve the medical care of patients affected by these disorders, provide generalized knowledge about the broad field of genetic disease and better understand basic mechanisms of normal and abnormal human development and physiology.

Sequencing data

The laboratory's rare disease group uses an integrated clinical-molecular approach to heritable disorders, focusing on pleiotropic malformation syndromes and mosaic overgrowth disorders. Over the past 20 years, the laboratory has performed clinical and molecular delineation of a host of disorders, including malformation syndromes, such as Pallister-Hall syndrome, Greig cephalopolysyndactyly syndrome, McKusick-Kaufman syndrome, Lenz microphthalmia syndrome, oculofaciocardiodigital syndrome and others; and overgrowth disorders, including Proteus syndrome, fibroadipose overgrowth syndrome, hemihyperplasia with multiple lipomatosis, CLOVES syndrome and others. Patients with these disorders exhibit various combinations of congenital malformations, overgrowth, birthmarks, intellectual disability, and other structural and functional abnormalities. The Clinical Genomics Section has been recognized as an international leader in finding novel diagnostic and management approaches to these disorders, many of which are extremely rare. To further elucidate the disorders' clinical manifestations, Dr. Biesecker's group takes advantage of the clinical resources available through the Mark O. Hatfield Clinical Research Center on the main NIH campus.

In order to understand the pathobiology of these syndromes, Dr. Biesecker's group initially used positional cloning, and more recently was in the forefront of using massively parallel sequencing to identify the mutated genes. The group also studies genotype-phenotype correlations and uses animal models to investigate the pathogenetic mechanisms of these disorders. Protocols aimed at understanding the disorders listed above, as well as other disorders having similar manifestations, are actively recruiting individuals for study. The patients undergo extensive and sophisticated phenotypic assessments to generate data essential for understanding the range and variability of these rare disorders.

Based on the molecular discoveries in overgrowth disorders, the group is moving actively into therapeutic approaches. Several of these disorders have been found to have mutations in genes that lead to hyperactivation of the AKT/PIK3CA signaling pathway, a pathway that is commonly mutated in cancer. The group takes advantage of small molecule cancer therapeutic agents to develop approaches to treatment. In contrast to congenital malformations, mosaic overgrowth disorders have a substantial component of postnatal progression, which means that patients with these disorders may be responsive to inhibition of this pathway. By studying this pathway in vitro, in animal models, and in patients, Dr. Biesecker's group hopes to lead to treatments to slow, halt, or perhaps even reverse the severe and often debilitating overgrowth caused by these disorders.

The second major area of research is a highly collaborative large-scale medical sequencing project, which aims to develop and explore novel methods for conducting hypothesis-generating clinical genomics research. This project, aptly named ClinSeq®, uses massively parallel sequencing and other genomic interrogation methods as a tool for clinical research. The ClinSeq® study enrolls patients with a range of phenotypes, from healthy through diseased, having initially focused on cardiovascular disease. Patients undergo an initial medical evaluation for cardiovascular phenotypic features. Using massively parallel sequencing, billions of base pairs of sequence are being generated. This study will contribute to our understanding of the relative contributions of rare versus common genetic variants to common disease. Recent studies in the ClinSeq® cohort include discovery of a gene associated with coronary artery calcification using transcriptome sequencing and the use of a simple method for extracting mitochondrial sequence data from nuclear exome sequencing.

The clinical focus of the ClinSeq® initiative has been expanded to include pharmacogenetics, as well as evaluation of genes that cause cancer susceptibility, malignant hyperthermia, and cardiac muscle and rhythm disorders. This project is one of the leading efforts in an exciting new area of research and is establishing new approaches to study design, informed consent and subject participation for clinical genomics research.


Stone D, Slavotinek A, Bouffard GG, Banerjee-Basu S, Baxevanis A, Barr M, Biesecker LG. Mutations in a putative chaperonin cause the McKusick-Kaufman syndrome. Nat Genet, 25:79-82. 2000. [PubMed]

Johnston JJ, Kelley RI, Crawford TO, Morton DH, Agarwala R, Koch T, Schäffer AA, Francomano CA, Biesecker LG. A novel nemaline myopathy in the Amish caused by a mutation in troponin T1. Am J Hum Genet, 67:814-821. 2000. [PubMed]

Slavotinek, AM, Stone EM, Heckenlively JR, Green JS, Heon E, Musarella MA, Parfrey PS, Sheffield V, Biesecker LG. Bardet Biedl syndrome can be caused by mutations in MKKS. Nat Genet, 26:15-16. 2000. [PubMed]

Rosenberg MJ, Agarwala R, Bouffard G, Davis J, Fiermonte G, Hilliard MS, Koch T, Kalikin LM, Makalowska I, Morton DH, Petty EM, Weber JL, Palmieri F, Kelley RI, Schaffer AA, Biesecker LG. Mutant deoxynucleotide carrier is associated with congenital microcephaly. Nat Genet, 32:175-9. 2002. [PubMed]

Ng D, Thakker N, Corcoran CM, Donnai D, Perveen R, Schneider A, Hadley DW, Tifft C, Zhang L, Wilkie AOM, van der Smagt J, Gorlin RJ, Burgess SM, Bardwell VJ, Black GCM, Biesecker LG. Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in the X-linked transcriptional corepressor, BCOR. Nat Genet, 36:411-6. 2004. [PubMed]

Johnston JJ, Olivos-Glander I, Killoran C, Turner J, Peters K, Abbott MH, Aughton DJ, Curry CJ, David A, Dinulos MB, Fox MA, Graham JM, Jr, Grange K, Guttmacher AE, Hannibal M, Henn W, Hennekam RCM, Holmes LB, Hoyme HE, Leppig KA, Lin AE, MacLeod P, Manchester DK, Mazzanti L, McDonald MM, Mendelsohn NJ, Moeschler JB, Moghaddam B, Neri G, Newbury-Ecob R, Pagon RA, Phillips JA, III, Sadler LS, Stoler JM, Tilstra D, Walsh Vockley CM, Zackai EH, Zadeh TM, Brueton L, Black GCM, Biesecker LG. Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister Hall syndromes: Robust phenotype prediction from the type and position of GLI3 mutations. Am J Hum Genet, 76:609-622. 2005. [PubMed]

Lindhurst MJ, Fiermonte G, Song S, Struys E, DeLeonardis F, Schwartzberg PL, Chen A, Castegna A, Verhoeven N, Mathews CK, Palmieri F, Biesecker LG. Knockout of Slc25a19 causes mitochondrial thiamine pyrophosphate depletion, embryonic lethality, CNS malformations, and anemia. Proc Nat Acad Sci USA, 103:15927-15932. 2006. [PubMed]

Biesecker LG, Mullikin JC, Facio FM, Turner C, Cherukuri PF, Blakesley RW, Bouffard GG, Chines PS, Cruz P, Hansen NF, Teer JK, Maskeri B, Young AC; NISC Comparative Sequencing Program, Manolio TA, Wilson AF, Finkel T, Hwang P, Arai A, Remaley AT, Sachdev V, Shamburek R, Cannon RO, Green ED. The ClinSeq Project: Piloting large-scale genome sequencing for research in genomic medicine. Genome Res, 19(9):1665-74. 2009. [PubMed]

Johnston JJ, Teer JK, Cherukuri PF, Hansen NF, Loftus SK; NIH Intramural Sequencing Center, Chong K, Mullikin JC, Biesecker LG. Massively parallel sequencing of exons on the X chromosome identifies RBM10 as the gene that causes a syndromic form of cleft palate. Am J Hum Genet, 86:743-8. 2010. [PubMed]

Teer JK, Bonnycastle LL, Chines PS, Hansen NF, Aoyama N, Swift AJ, Abaan H, Albert TJ, NISC Comparative Sequencing Program, Margulies EH, Green ED, Collins FS, Mullikin JC, Biesecker LG. Systematic comparison of three genomic enrichment methods for massively parallel DNA sequencing. Genome Res, 20:1420-1431. 2010. [PubMed]

Sloan JL, Johnston JJ, Manoli I, Chandler RJ, Krause C, Carrillo-Carrasco N, Chandrasekaran SD, O'Brien K, Hauser NS, Sapp JC, NISC, Barshop BA, Berry S, James PM, Champaigne NL, de Lonlay P, Valayannopoulos V, Geschwind MD, Nyhan WL, Biesecker LG, Venditti CP. Whole exome sequencing identifies mutations in ACSF3 as the cause of combined malonic and methylmalonic aciduria. Nat Genet, 43:883-886. 2011. [PubMed]

Lindhurst MJ, Sapp JC, Teer JK, Johnston JJ, Finn EM, Peters K, Turner J, Cannons JL, Bick D, Blakemore L, Blumhorst C, Brockmann K, Calder P, Cherman N, Deardorff M, Everman DB, Golas G, Greenstein RM, Kato BM, Keppler-Noreuil KM, Kuznetsov SA, Miyamoto RT, Newman K, Ng D, O'Brien K, Rothenberg S, Schwartzentruber DJ, Singhal V, Tirabosco R, Upton J, Wientroub S, Zackai EH, Hoag K, Whitewood-Neal T, Robey PG, Schwartzberg PL, Darling TN, Tosi LL, Mullikin JC for the NISC Comparative Sequencing Program, Biesecker LG. A mosaic cctivating mutation in AKT1 associated with the Proteus syndrome. New Engl J Med, 365:611-619. 2011. [PubMed]

Johnston JJ, Gropman A, Sapp JC, Teer J, Martin J, Brodsky R, Biesecker LG for the NIH Intramural Sequencing Center. The phenotype of a germline mutation in PIGA: The gene somatically mutated in paroxysmal nocturnal hemoglobinuria. Am J Hum Genet,90:295-300. 2012. [PubMed]

Teer JK, Green ED, Mullikin JC, Biesecker LG. VarSifter: Visualizing and analyzing exome-scale sequence variation data on a desktop computer. Bioinformatics, 28:599-600. 2012. [PubMed]

Lindhurst MJ, Parker VER, Payne F, Sapp JC, Rudge S, Harris J, Witkowski AM, Zhang Q, Groeneveld MP, Scott CE, Daly A, Huson SM, Tosi LL, Cunningham ML, Darling TN, Geer J, Gucev Z, Sutton VR, Walters MR, Dixon AK, Helliwell T, O'Rahilly S, Savage DB, Wakelam MJO, Barroso I, Biesecker LG, Semple RK. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA. Nat Genet, 44:928-933. 2012. [PubMed]

Johnston JJ, Rubinstein WS, Facio F, Ng D, Singh L, Teer J, Mullikin J, Biesecker LG. Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. Am J Hum Genet, 91:97-108. 2012. [PubMed]

Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire A, Nussbaum RL, O'Daniel JM, Ormond K, Rehm H, Watson MS, Williams MS, Biesecker LG. ACMG Recommendations for Reporting of Secondary Findings in Clinical Exome and Genome Sequencing. Genet Med, 15:565-574. 2013. [Full Text]

Gonsalves SG, Ng D, Johnston JJ, Teer JK, NISC Comparative Sequencing Program; Mullikin JC, Biesecker LG. A genomic approach to malignant hyperthermia susceptibility. Anesthesiology, 119:1043-1053. 2013. [PubMed]

Johnston J, Lewis K, Ng D, Singh LN, Wynter J, Brewer C, Brooks BP, Brownell I, Candotti F, Gonsalves SG, Hart SP, Kong HH, Rother KI, Sokolic R, Solomon BD, Zein WM, Cooper DN, Stenson PD, Mullikin JC, Biesecker LG. Individualized iterative phenotyping for genome-wide analysis of loss of function mutations. Am J Hum Genet, 96:913-925. 2015. [PubMed]

Johnston JJ, Sanchez-Contreras MY, Keppler-Noreuil K, Sapp J, Crenshaw M, Finch NA, Cormier-Daire V, Rademakers R, Sybert V, Biesecker LG. A point mutation in PDGFRB causes autosomal dominant Penttinen syndrome. Am J Hum Genet, 97:465-474. 2015. [PubMed]

Darnell A, Austin H, Bluemke D, Cannon R, Fischbeck K, Gahl W, Goldman D, Grady C, Greene MH, Holland SM, Chandros Hull S, Porter FD, Resnick D, Rubinstein W, Biesecker LG. A Clinical Service to Support the Return of Secondary Genomic Findings in Human Research. Am J Hum Genet, 98:435-441. 2016. [PubMed]

Johnston JJ, van der Smagt JJ, Rosenfeld JA, Pagnamenta AT, Alswaid A, Baker EH, Blair E, Borck G, Brinkmann J, Craigen Q, Dung VC, Emrick L, Everman DB, van Gassen KL, Gulsuner S, Harr MH, Jain M, Kuechler A, Leppig KA, McDonald-McGinn DM, Ngoc CTB, Peleg A, Roeder ER, Rogers RC, Sapp JC, Schäffer AA, Schanze D, Stewart H, Taylor JC, Verbeek NE, Walkiewicz MA, Zackai EH, Zweier C, Members of the UDN, Zenker M, Lee B, Biesecker LG. Autosomal Recessive Noonan Syndrome Associated with Mutations in LZTR1. Genet Med [In Press]

Clinical Genomics Section Staff

Generic Profile Photo
Stephen G. Gonsalves
  • Graduate Student
  • Clinical Genomics Section
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Celine S. Hong, Ph.D.
  • Postdoctoral Fellow
  • Clinical Genomics Section
Jennifer Johnston
Jennifer Johnston, Ph.D.
  • Staff Scientist
  • Clinical Genomics Section
Kim M. Keppler-Noreuil, M.D.
  • Associate Investigator
  • Medical Genomics and Metabolic Genetics Branch
Katie L. Lewis
Katie L. Lewis
  • Genetic Counselor
  • Clinical Genomics Section
Marjorie Lindhurst, Ph.D.
Marjorie Lindhurst, Ph.D.
  • Research Scientist
  • Clinical Genomics Section
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David Ng, M.D.
  • Staff Clinician
  • Clinical Genomics Section
Julie C. Sapp
Julie C. Sapp
  • Genetic Counselor
  • Clinical Genomics Section

Last updated: November 1, 2017