Transcript MDx Standards for IHTSDO

Published Standards for
Molecular Laboratories
Alexis B. Carter, MD, FCAP
Director of Pathology Informatics
Diplomate, American Board of Pathology, Molecular Genetic Pathology
Department of Pathology and Laboratory Medicine
Member, Center for Comprehensive Informatics
Financial Disclosures
U.S. Requirement
• None in the last three years
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Objectives
• Discuss international and some U.S. published
standards for molecular pathology
• Provide fodder for discussion on standards for
incorporation of molecular pathology terms into
SNOMED CT
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SNOMED CT
• SNOMED CT aims to improve patient care
through the development of systems to
accurately record health care encounters
• Molecular information is increasingly a part of
health care encounters
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Inclusions
• Published standards discussed will include
– U.S. standards
– International standards
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Definition
“Molecular Pathology” includes…
Nucleic acid techniques (PCR, etc.)
Chromosome analysis (Karyotyping)
Fluorescence in situ hybridization (FISH) (and other ISH)
Human Leukocyte Antigen (HLA) molecular testing
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International Standards
• Nomenclature of gene names (HUGO)
• Nomenclature for sequence variations (HGVS)
• Nomenclature for factors of the HLA System (IMGT)
• International System for Human Cytogenetic
Nomenclature 2009 (ISCN)
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U.S. Standards
• Standards for categorizing sequence variations
(ACMG)
• Report content standards (AMP, CAP)
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Gaps in Standards
• Standard names for molecular methods
• Others?
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HUGO
• Human Gene Nomenclature Committee (HGNC)
– Guidelines first published 1979
– Updates 1987, 1995, 1997, 2002
– Includes
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Gene symbols, names, families and associated clinical disorders
Homologies with other species
How to name genes identified by sequence only
How to reference gene rearrangements and recombinations
– Refers nomenclature of associated enzymes and proteins to
Nomenclature Committee of the International Union of
Biochemistry and Molecular Biology
(http://ca.expasy.org/enzyme)
Wain HM, et al. Genomics. 2002;79(4):464-470.
Wain HM, et al. Nucleic Acids Res. 2002;30(1):169-171.
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HGVS
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Human Genome Variation Society
http://www.hgvs.org/mutnomen/
Recommendations for nomenclature of sequence variations
Example: Cystic Fibrosis
Historical
Delta F508
HGVS Nucleotide
HGVS Amino Acid
c.1521-1523delCTT p.Phe508del
den Dunnen JT, et al. Hum Mutat. 2000;15(1):7-12.
Ogino S, et al. J Mol Diagn. 2007;9(1):1-6.
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HGVS
• Gets rid of ambiguity surrounding nomenclature
– Example of historical terminology: C36G
– What does this mean?
• Is this cytosine to guanine at nucleotide 36?
• Is this DNA or RNA? Protein?
• Is this Cysteine to Glycine at amino acid 36?
• Unfortunately, not used much in medical literature
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HLA Molecular Nomenclature
• IMGT/HLA database
– http://imgt.cines.fr/
– Official sequences for the WHO Nomenclature
Committee For Factors of the HLA System
– Part of the international ImMunoGeneTics project
(IMGT)
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HLA Molecular Nomenclature
• http://hla.alleles.org/nomenclature/nomencla
ture_2009.html
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ISCN 2009
• International System for Human Cytogenetic
Nomenclature
– Chromosome analysis (karyotyping)
– In situ hybridization (ISH)
• Specifically fluorescence in situ hybridization (FISH)
– Comparative Genomic Hybridization (CGH)
– Chromosome painting
– Are introducing microarray nomenclature and
nomenclature for Multiple Ligation-Dependent Probe
Amplification (MLPA)
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ISCN 2009
• Multiple versions denoted by year of
publication
• Most recent is 2009
Shaffer LG et al., eds. ISCN (2009): An International System for Human
Cytogenetic Nomenclature. S. Karger: Basel 2009.
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ACMG
• American College of Medical Genetics
• http://www.acmg.net
• Recommendations on reporting of sequence
variations
• Updated 2008
Richards CS, et al. Genet Med. 2008;10(4):294-300.
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ACMG
• Recommendations on reporting of sequence variations
1. Sequence variation is previously reported and is a recognized cause of the
disorder
2. Sequence variation is previously unreported and is of the type which is
expected to cause the disorder
3. Sequence variation is previously unreported and is of the type which may or
may not be causative of the disorder
4. Sequence variation is previously unreported and is probably not causative of
disease
5. Sequence variation is previously reported and is a recognized neutral variant
6. Sequence variation is not known or expected to be causative of disease, but is
found to be associated with a clinical presentation
Richards CS, et al. Genet Med. 2008;10(4):294-300.
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Reporting – Standards
Gulley ML, et al. Arch Pathol Lab Med. 2007;131(6):852-863.
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Reporting Standards
• Recommends use of HUGO-approved gene
nomenclature
• Has some standards for approved use of
method abbreviations
– Q-PCR  Quantitative PCR
– RT-PCR  Real-time PCR
• NOT reverse transcriptase PCR
• Recommends use of ACMG categories
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Reporting Standards
• Has a number of other recommendations on
nomenclature of genetic variation
– Use of RefSeq through the National Library of
Medicine in the U.S.A.
• http://www.ncbi.nlm.nih.gov/RefSeq
– Use of Mutnomen HGVS nomenclature
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Other Reporting Standards
• British Clinical Molecular Genetics Society
(http://www.cmgs.org)
• Organisation for Economic Cooperation and
Development (http://www.oecd.org)
• Clinical and Laboratory Standards Institute
(http://www.clsi.org)
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Gaps
Nomenclature of Molecular Methods
• Plethora of result types
• Terminology can be confusing
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Quantitative and qualitative
Homozygous, heterozygous, heteroplasmic, wild type
Multiplex assays generate multiple results (CF testing)
Deletion studies
Epigenetic results
High-throughput testing (microarrays)
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Questions?
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