Our research focuses on three inherited human diseases:

Schimke immuno-osseous dysplasia

Spinocerebellar ataxia with neuropathy type 1

a disorder of sterol metabolism regulating behavior and neural development

We have identified the genetic causes of these diseases. Schimke immuno-osseous dysplasia is caused by a defect of organizing DNA within the nucleus. Spinocerebellar ataxia with neuropathy type 1 is caused by a defect in the ability to repair damaged DNA. The disorder of sterol metabolism, which is X-linked, causes brain neuron migration defects and intellectual disability in males but only aggressive behaviour in females.

To understand how these genetic defects cause disease, we are using multiple approaches including biochemistry, cell biology, fruit fly genetics and mouse genetics. Because these disorders cause alterations observed in other human diseases, we are also developing them as models for dissecting the pathophysiology of those diseases.


Mesenteric cysts, lymphatic leak, and cerebral cavernous malformation in a proband with KRIT1 -related disease
American Journal of Medical Genetics Part A
Ashley Moller-Hansen and Stephanie Huynh and Cornelius F. Boerkoel and Hui-Lin Chin
DOI: 10.1002/ajmg.a.62510

An approach to rapid characterization of DMD copy number variants for prenatal risk assessment
American Journal of Medical Genetics Part A
Hui-Lin Chin and Kieran O'Neill and Kristal Louie and Lindsay Brown and Kamilla Schlade-Bartusiak and Patrice Eydoux and Rosemarie Rupps and Ali Farahani and Cornelius F. Boerkoel and Steven J. M. Jones
DOI: 10.1002/ajmg.a.62349

Evaluating patients referred to a medical genetics connective tissue disorder clinic
Molecular Genetics and Metabolism
Brandon Chalazan and Hui-Lin Chin and Nour Gazzaz and Stephanie Huynh and Neal Boerkoel
DOI: 10.1016/s1096-7192(21)00313-9

Single center experience in the application of evidence based medicine to the clinical interpretation of genomic sequence reports
Molecular Genetics and Metabolism
Hui-Lin Chin and Nour Gazzaz and Brandon Chalazan and Ashley Moller-Hansen and Laura Li and Stephanie Huynh and Neal Boerkoel
DOI: 10.1016/s1096-7192(21)00350-4

Ethical considerations in the application of advanced genomic testing for a donor-conceived child
Molecular Genetics and Metabolism
Stephanie Huynh and Alexandra Olmos Perez and Alice Virani and Brandon Chalazan and Nour Gazzaz and Cornelius Boerkoel and Steven Jones and Hui-Lin Chin
DOI: 10.1016/s1096-7192(21)00551-5

Single center experience in clinical whole-exome sequencing
Molecular Genetics and Metabolism
Nour Gazzaz and Stephanie Hyunh and Ashley Moller-Hansen and Brandon Chalazan and Neal Boerkoel and Hui-Lin Chin
DOI: 10.1016/s1096-7192(21)00306-1

Pan-cancer RNA-seq data stratifies tumours by some hallmarks of cancer
Journal of Cellular and Molecular Medicine
F. Graeme Frost and Praveen F. Cherukuri and Samuel Milanovich and Cornelius F. Boerkoel
DOI: 10.1111/jcmm.14746

A Novel AMELX Mutation, Its Phenotypic Features, and Skewed X Inactivation
Journal of Dental Research
X. Duan and S. Yang and H. Zhang and J. Wu and Y. Zhang and D. Ji and L. Tie and C.F. Boerkoel
DOI: 10.1177/0022034519854973

Glycomics in rare diseases: from diagnosis tomechanism
Translational Research
Mariska Davids and Megan S. Kane and Lynne A. Wolfe and Camilo Toro and Cynthia J. Tifft and David Adams and Xueli Li and Mohd A. Raihan and Miao He and William A. Gahl and Cornelius F. Boerkoel and May Christine V. Malicdan
DOI: 10.1016/j.trsl.2018.10.005

Reactive oxygen species stress increases accumulation of tyrosyl-DNA phsosphodiesterase 1 within mitochondria
Scientific Reports
Hok Khim Fam and Kunho Choi and Lauren Fougner and Chinten James Lim and Cornelius F. Boerkoel
DOI: 10.1038/s41598-018-22547-8

FOXP1 haploinsufficiency: Phenotypes beyond behavior and intellectual disability?
American Journal of Medical Genetics Part A
Angela Myers and Christèle du Souich and Connie L. Yang and Lior Borovik and Jill Mwenifumbo and Rosemarie Rupps and CAUSES Study and Anna Lehman and Cornelius F. Boerkoel
DOI: 10.1002/ajmg.a.38462

Pharmacogenomic incidental findings in 308 families: The NIH Undiagnosed Diseases Program experience
Genetics in Medicine
Elizabeth M.J. Lee and Karen Xu and Emma Mosbrook and Amanda Links and Jessica Guzman and David R. Adams and Elise Flynn and Elise Valkanas and Camillo Toro and Cynthia J. Tifft and Cornelius F. Boerkoel and William A. Gahl and Murat Sincan
DOI: 10.1038/gim.2016.47

Chromatin changes inSMARCAL1deficiency: A hypothesis for the gene expression alterations of Schimke immuno-osseous dysplasia
Marie Morimoto and Kunho Choi and Cornelius F. Boerkoel and Kyoung Sang Cho
DOI: 10.1080/19491034.2016.1255835

Congenital Bilateral Retinal Detachment in Two Siblings with Osteoporosis-Pseudoglioma Syndrome
Ophthalmic Genetics
Lotte G. Welinder and Johane M. Robitaille and Rosemarie Rupps and Cornelius F. Boerkoel and Christopher J. Lyons
DOI: 10.3109/13816810.2015.1016240

SMARCAL1 and replication stress
Carol E. Bansbach and Cornelius F. Boerkoel and David Cortez
DOI: 10.4161/nucl.11739

4q12-4q21.21 deletion genotype-phenotype correlation and the absence of piebaldism in presence ofKIThaploinsufficiency
American Journal of Medical Genetics Part A
Parisa Hemati and Christèle du Souich and Cornelius F. Boerkoel
DOI: 10.1002/ajmg.a.36821

Coffin-Siris syndrome: Phenotypic evolution of a novelSMARCA4mutation
American Journal of Medical Genetics Part A
Michael Tzeng and Christèle du Souich and Helen Wing-Hong Cheung and Cornelius F. Boerkoel
DOI: 10.1002/ajmg.a.36533

Elucidating the role of mitochondrial Tdp1 in response to oxidative stress
Hok Khim Fam and Miraj K. Chowdhury and Cheryl Walton and Kunho Choi and Glenda Hendson and Cornelius F. Boerkoel
DOI: 10.1016/j.mito.2013.07.048

TDP1 and PARP1 Deficiency Are Cytotoxic to Rhabdomyosarcoma Cells
Molecular Cancer Research
Hok Khim Fam and Cheryl Walton and Sheetal A. Mitra and Miraj Chowdhury and Nichola Osborne and Kunho Choi and Guobin Sun and Patrick C.W. Wong and Maureen J. O'Sullivan and Gulisa Turashvili and Samuel Aparicio and Timothy J. Triche and Mason Bond and Catherine J. Pallen and Cornelius F. Boerkoel
DOI: 10.1158/1541-7786.mcr-12-0575

The Role of Nuclear Bodies in Gene Expression and Disease
Marie Morimoto and Cornelius Boerkoel
DOI: 10.3390/biology2030976

Gene Clusters, Molecular Evolution and Disease: A Speculation
Advances in Genome Science: Changing Views on Living Organisms
DOI: 10.2174/9781608051298113010008

Mucopolysaccharidosis IIIB (Sanfilippo syndrome type B) masquerading as a behavioral disorder
Molecular Genetics and Metabolism
Jacqueline Brady and Aditi Trehan and Rena Godfrey and Cynthia Tifft and Cornelius Boerkoel and Dennis Landis and Camilo Toro
DOI: 10.1016/j.ymgme.2012.11.042

Kearns-Sayre syndrome presenting as isolated growth failure
Case Reports
C. M. Holloman and L. A. Wolfe and W. A. Gahl and C. F. Boerkoel
DOI: 10.1136/bcr-2012-007272

Late-onset Tay–Sachs disease: A genocopy of spinal muscular atrophy?
Molecular Genetics and Metabolism
Aditi Trehan and Jacqueline Brady and Colleen Wahl and Cornelius Boerkoel and Camilo Toro and Cynthia Tifft
DOI: 10.1016/j.ymgme.2012.11.252

Beckwith-Wiedemann syndrome in sibs discordant for IC2 methylation
American Journal of Medical Genetics Part A
Karen Y. Niederhoffer and Maria Peñaherrera and Denise Pugash and Rosemarie Rupps and Laura Arbour and Francine Tessier and Sanaa Choufani and Chunhua Zhao and Irina Manokhina and Cheryl Shuman and Wendy P. Robinson and Rosanna Weksberg and Cornelius F. Boerkoel
DOI: 10.1002/ajmg.a.35377

Hypothesis: SLC12A3 Polymorphism modifies thiazide hypersensitivity of antenatal Bartter syndrome to thiazide resistance
European Journal of Medical Genetics
Cherry Mammen and Rosemarie Rupps and Peter Trnka and Cornelius F. Boerkoel
DOI: 10.1016/j.ejmg.2011.12.006

VAR-MD: A tool to analyze whole exome-genome variants in small human pedigrees with mendelian inheritance
Human Mutation
Murat Sincan and Dimitre R Simeonov and David Adams and Thomas C. Markello and Tyler M. Pierson and Camilo Toro and William A. Gahl and Cornelius F. Boerkoel
DOI: 10.1002/humu.22034

The NIH Undiagnosed Diseases Program: bonding scientists and clinicians
Disease Models & Mechanisms
William A. Gahl and Cornelius F. Boerkoel and Manfred Boehm
DOI: 10.1242/dmm.009258

Expression profile of NSDHL in human peripheral tissues
Journal of Molecular Histology
Marie Morimoto and Christèle du Souich and Joanne Trinh and Keith W. McLarren and Cornelius F. Boerkoel and Glenda Hendson
DOI: 10.1007/s10735-011-9375-x

Minimal genotype-phenotype correlation for small deletions within distal 1p36
American Journal of Medical Genetics Part A
A. Buck and C. du Souich and Cornelius F. Boerkoel
DOI: 10.1002/ajmg.a.34333

Fetal alcohol syndrome: a phenocopy of spondylocarpotarsal synostosis syndrome?
Clinical Dysmorphology
Jennifer Vassel and Rosemarie Rupps and Deborah Krakow and Narman Puvanachandra and Jane A. Gardiner and Sharon R. Lazeo and Cornelius F. Boerkoel
DOI: 10.1097/mcd.0b013e3283398730

SMARCAL1 and replication stress: An explanation for SIOD?
Carol E. Bansbach and Cornelius F. Boerkoel and David Cortez
DOI: 10.4161/nucl.1.3.11739

Spinocerebellar Ataxia with Axonal Neuropathy
Advances in Experimental Medicine and Biology
Cheryl Walton and Heidrun Interthal and Ryuki Hirano and Mustafa A. M. Salih and Hiroshi Takashima and Cornelius F. Boerkoel
DOI: 10.1007/978-1-4419-6448-9_7

Phenotypic and molecular characterization of a novelDCXdeletion and a review of the literature
Clinical Genetics
A Chou and C Boerkoel and C du Souich and R Rupps
DOI: 10.1111/j.1399-0004.2009.01206.x

Gene Clusters, Molecular Evolution and Disease: A Speculation
Current Genomics
Leah Elizondo and Paymaan Jafar-Nejad and J. Clewing and Cornelius Boerkoel
DOI: 10.2174/138920209787581271

Developmental expression pattern of the cholesterogenic enzyme NSDHL and negative selection of NSDHL-deficient cells in the heterozygous Bpa1H/+ mouse
Molecular Genetics and Metabolism
David Cunningham and Kaitlyn Spychala and Keith W. McLarren and Luis A. Garza and Cornelius F. Boerkoel and Gail E. Herman
DOI: 10.1016/j.ymgme.2009.06.016

Clinical and genetic distinction of Schimke immuno-osseous dysplasia and cartilage-hair hypoplasia
American Journal of Medical Genetics Part A
Alireza Baradaran-Heravi and Christian Thiel and Anita Rauch and Martin Zenker and Cornelius F. Boerkoel and Ilkka Kaitila
DOI: 10.1002/ajmg.a.32406

L Pape and N Kanzelmeyer and A Baradaran-Heravi and C Boerkoel and M Burg and J Ehrich and T Lücke
DOI: 10.1097/01.tp.0000330742.09471.48

Lethal neonatal Menkes' disease with severe vasculopathy and fractures
Acta Paediatrica
RP Jankov and CF Boerkoel and J Hellmann and WL Sirkin and Z Tumer and N Horn and A Feigenbaum
DOI: 10.1111/j.1651-2227.1998.tb00955.x

Gray matter heterotopias and brachytelephalangic chondrodysplasia punctata: A complication of hyperemesis gravidarum induced vitamin K deficiency?
American Journal of Medical Genetics Part A
Nicola Brunetti-Pierri and Jill V. Hunter and Cornelius F. Boerkoel
DOI: 10.1002/ajmg.a.31573

Atrophy of vermis cerebelli in Schimke-immuno-osseous dysplasia
T Lücke and JM Clewing and CF Boerkoel and H Hartmann and AM Das and M Knauth and H Becker and F Donnerstag
DOI: 10.1055/s-2006-953600

A novel 8.5 MB dup(1)(p34.1p34.3) characterized by FISH in a child presenting with congenital heart defect and dysmorphic features
American Journal of Medical Genetics Part A
P.A. Lennon and C.F. Boerkoel and K. Plunkett and S. Soukam and S.W. Cheung and A. Patel
DOI: 10.1002/ajmg.a.31392

Schimke Versus Non-Schimke Chronic Kidney Disease: An Anthropometric Approach
T. Lucke and D. Franke and J. M. Clewing and C. F. Boerkoel and J. H.H. Ehrich and A. M. Das and M. Zivicnjak
DOI: 10.1542/peds.2005-2614

Molecular Mechanisms for CMT1A Duplication and HNPP Deletion
Annals of the New York Academy of Sciences
DOI: 10.1111/j.1749-6632.1999.tb08563.x

Fatal lymphoproliferative disorder in a child with Schimke immuno-osseous dysplasia
American Journal of Medical Genetics
Doris Taha and Cornelius F. Boerkoel and John Williamson Balfe and Mohammed Khalifah and Emily A. Sloan and Maha Barbar and Abdulrazzaq Haider and Hassan Kanaan
DOI: 10.1002/ajmg.a.30356

Chromatin remodeling and human disease
Current Opinion in Genetics & Development
Cheng Huang and Emily A Sloan and Cornelius F Boerkoel
DOI: 10.1016/s0959-437x(03)00054-6

Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg-Hirschsprung disease: Phenotypes linked bySOX10 mutation
Annals of Neurology
Ken Inoue and Konstantin Shilo and Cornelius F. Boerkoel and Carol Crowe and Joram Sawady and James R. Lupski and Dimitri P. Agamanolis
DOI: 10.1002/ana.10404

The genetic convergence of Charcot-Marie-Tooth disease types 1 and 2 and the role of genetics in sporadic neuropathy
Current Neurology and Neuroscience Reports
Cornelius F. Boerkoel and Hiroshi Takashima and James R. Lupski
DOI: 10.1007/s11910-002-0056-8

Screening for mutations in a genetically heterogeneous disorder: DHPLC versus DNA sequence for mutation detection in multiple genes causing Charcot-Marie-Tooth neuropathy
Genetics in Medicine
Hiroshi Takashima and Cornelius F Boerkoel and James R Lupski
DOI: 10.1097/00125817-200109000-00002

EGR2 mutation R359W causes a spectrum of Dejerine-Sottas neuropathy
Cornelius F. Boerkoel and Hiroshi Takashima and Carlos A. Bacino and Donna Daentl and James R. Lupski
DOI: 10.1007/s100480100107

Denaturing high-performance liquid chromatography of the myotubularin-related 2 gene (MTMR2) in unrelated patients with Charcot-Marie-Tooth disease suggests a low frequency of mutation in inherited neuropathy
Alessandra Bolino and Lorne J. Lonie and Michael Zimmer and Cornelius F. Boerkoel and Hiroshi Takashima and Anthony P. Monaco and James R. Lupski
DOI: 10.1007/s100480000101

Alström syndrome: further evidence for linkage to human chromosome 2p13
Human Genetics
G.B. Collin and J.D. Marshall and C.F. Boerkoel and A.V. Levin and R. Weksberg and J. Greenberg and J.L. Michaud and J.K. Naggert and P.M. Nishina
DOI: 10.1007/s004390051133

Frequent monoallelic loss of D13S319 in multiple myeloma patients shown by interphase fluorescence in situ hybridization
H Chang and D Bouman and CF Boerkoel and AK Stewart and JA Squire
DOI: 10.1038/sj.leu.2401208

Schimke immunoosseous dysplasia complicated by moyamoya phenomenon
American Journal of Medical Genetics
Cornelius F. Boerkoel and Malgorzata J.M. Nowaczyk and Susan I. Blaser and Wendy S. Meschino and Rosanna Weksberg
DOI: 10.1002/(sici)1096-8628(19980630)78:23.0.co;2-k

Genetic defects in patients with glycogenosis type II (acid maltase deficiency)
Muscle & Nerve
Nina Raben and Ralph C. Nichols and Cornelius Boerkoel and Paul Plotz
DOI: 10.1002/mus.880181415

Transcriptional interaction between retroviral long terminal repeats (LTRs): mechanism of 5' LTR suppression and 3' LTR promoter activation of c-myc in avian B-cell lymphomas.
Journal of Virology
C F Boerkoel and H J Kung
DOI: 10.1128/jvi.66.8.4814-4823.1992

Systematic over-expression screens for chromosome instability identify conserved dosage chromosome instability genes in yeast and human tumors
Supipi Duffy and Hok Khim Fam and Yikan Wang and Erin B Styles and Jung-Huyn Kim and J. Sidney Ang and Tejomayee Singh and Vladimir Larionov and Sohrab Shah and Brenda Andrews and Cornelius Boerkoel and Phillip Hieter
DOI: 10.1101/038489


Disorders of cognition and behaviour
Many families and patients presenting to the Psychiatric and Medical Genetics Clinics have strong family histories of cognition and behaviour. We have been using multiple tools to map the molecular bases of their disease. Through these studies of individuals and families, we are identifying novel pathways that not only regulate neural development and maintenance, but also regulate human behaviour. Currently we are studying inherited causes of aggressive behaviour, obsessive compulsive disorder and intellectual disability. We have identified a studied pathway of sterol metabolism as a regulator of neural development and aggressive behaviour. To define the function of this pathway and the molecular pathology underlying the disease, we are employing a combination of yeast and murine genetics, cell culture systems and biochemical analyses.

Spinocerebellar ataxia with neuropathy: a developmental role for DNA repair
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) repairs covalent topoisomerase IB-DNA complexes. In yeast, Tdp1 mutations cause double strand breaks through interference of the stalled topoisomerase IB complexes with DNA replication. This would suggest that mutations of Tdp1 predispose mammals to neoplasia or dysfunction of rapidly replicating tissues; however, we have found that deficiency of Tdp1 in humans causes spinocerebeller ataxia with axonal neuropathy (SCAN1), a disease of large terminally differentiated essentially non-dividing neuronal cells. We hypothesize that loss-of-function mutations in TDP1 cause SCAN1 either by interfering with DNA transcription or by inducing apoptosis in post-mitotic neurons rather than by interfering with DNA replication. To define the function of TDP1 and the molecular pathology underlying SCAN1, we are using a combination of Drosophila and murine genetics, and cell culture systems; these studies are being done in collaboration with Dr. Hiroshi Takashima. To date, our analyses suggest a novel biological process that is distinct from the previously described function of Tdp1. Our challenge is to use this process to gain insight into a new pathway for neural development and maintenance.

Schimke immuno-osseous dysplasia: exploration of a novel chromatin remodeling pathway
Presently the research in my laboratory focuses on defining the biologic and biochemical function of SMARCAL1 (swi/snf related, matrix associated, actin dependent regulator of chromatin, subfamily a-like 1), a protein homologous to helicases and the SNF2 family of chromatin remodeling proteins. Mutations in the SMARCAL1 gene cause Schimke immuno-osseous dysplasia (SIOD), an autosomal recessive fatal multisystem human disease. The SMARCAL1 protein has not been studied previously in any organism; therefore, its function and the underlying mechanism by which mutations cause SIOD are unknown. To define the function of SMARCAL1 and the molecular pathology underlying SIOD, we are employing a combination of Drosophila and murine genetics, cell culture systems and biochemical analyses to obtain insight into this novel pathway regulating tissue growth and maintenance.

SIOD is characterized by skeletal dysplasia, progressive renal failure and immunodeficiency. Additional but more variable disease features include atherosclerosis, hypothyroidism, and tooth and pigmentary abnormalities. SIOD is usually fatal within the first two decades of life because of renal failure, systemic infection, bone marrow failure, or cerebral ischemia. Our challenge is to explain molecularly how mutations of SMARCAL1 cause this severe pleiotropic disease, identify potential therapies to treat or ameliorate the disease, and derive insights into general principles of developmental biology and pathophysiology.

Honours & Awards

Clinical Investigator Award, Child & Family Research Institute - 2008

Michael Smith Foundation for Health Research Scholar Award in the Biomedical Sciences - 2008

Chairman’s Prize, United Mitochondrial Disease Foundation - 2010

Research Group Members

Ashley Moller-Hansen, Undergraduate Student