CCMG General Knowledge Study Guide

The purpose of the General Examination is to evaluate key competencies in areas of human genetics that are required for practice in all
CCMG specialities (Cytogenetics, Molecular Genetics, Clinical or Laboratory Biochemical Genetics or Clinical Genetics). In comparison, the
Specialty Examination for each discipline evaluates areas of competence unique to each Specialty.

The General Knowledge Study Guide was developed to define the scope and depth of study for trainees. It is a tool to assist trainees in their
studies and in preparation for the General Examination. Thompson and Thompson 8th edition is the primary reference. However, some
topics may not be covered in T&T and therefore it should not be considered the only reference for review.

A “Genetic Conditions List” accompanies the General Knowledge Study Guide. This list may change over time and is not exhaustive. These
Genetic conditions were selected for one or more of the following reasons:
• they are commonly encountered in practice
• they illustrate key concepts in human genetics
• they illustrate the knowledge and skills required to collaborate and communicate between laboratory genetic disciplines and / or
within the health care community.

Topic Objectives Specific knowledge and skills

By the end of training, all Trainees will be able to:

1. Human genome Understand general a. Describe the organization of the human genome, including coding and non-coding
structure and concepts related to regions
function the human genome b. Describe the chromosomal structure of the human genome
and chromosome c. Describe the organization and structure of genes (exons, introns, promoter
structure and regions, enhancers, silencers, etc.)
function d. Describe the structure of DNA, how it is replicated and maintained (DNA repair
mechanisms)
e. Explain basic gene expression: transcription through to translation, gene regulation

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 (including splicing, tissue specificity, non-coding RNAs), post-translational modifications
f. Describe the stages of cell division and medical relevance of mitosis and meiosis
g. Describe human gametogenesis and fertilization and the transmission of genomic
material
2. Gene Understand general a. Single-Gene Inheritance
Inheritance concepts of i. Describe Mendel’s laws of inheritance
a. Single-gene ii. Describe the basic principles of autosomal dominant, autosomal recessive and X-linked
inheritance inheritance
b. Mitochondrial iii. Give examples of conditions where genotype correlates with phenotypic severity
inheritance iv. Understand the concepts of penetrance, expressivity and anticipation
c. Non-mendelian v. Demonstrate the ability to analyze pedigrees for inheritance patterns
inheritance vi. Describe the effect of genetic and environmental modifiers on single-gene
d. Complex disorders
inheritance b. Mitochondrial Inheritance
e. Epigenetics i. Describe the structure and inheritance of the mitochondrial genome and gene
expression
ii. Understand the basis for clinical heterogeneity in mitochondrial DNA defects
iii. Describe the role of nuclear and mitochondrial genes in mitochondrial disease
iv. Describe general features of mitochondrial disorders (multi-systemic, etc.)
v. Recognize maternal inheritance from pedigree information.
c. Non-mendelian inheritance
i. Describe common non-Mendelian inheritance and their etiologies, including
uniparental disomy, imprinting, mosaicism, unstable triplet repeats, pseudoautosomal
inheritance, etc.
ii. Describe the implications of non-Mendelian inheritance on genetic diagnostic
testing
iii. Describe the implications of non-Mendelian inheritance for clinical genetics, including
pedigree analysis and counselling
d. Complex inheritance
i. Describe qualitative and quantitative traits; provide examples
ii. Define the concepts of multifactorial inheritance, including liability model,

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 threshold effects, epistasis, heritability and concordance
iii. Describe evidence for a genetic contribution to complex traits and common
disorders
iv. Contrast the relative recurrence risks for multifactorial inheritance with single gene
disorders and describe factors that affect risk (such as degree of relationship, sex,
severity)
e. Epigenetics
i. Explain how epigenetic factors influence gene expression and phenotype
3. Population Understand concepts a. Describe the key concepts of human genetic variation in populations, including the role
Genetics of human population of ethnicity and population isolates in human variation
genetics and b. Describe the Hardy-Weinberg equilibrium
principles of c. Demonstrate the ability to use the Hardy-Weinberg equilibrium to assess allele and
personalized genotype frequency
medicine d. Understand the concepts of population screening and when appropriate to offer screening
e. Describe the concept of drug responsiveness risks and benefits based upon genotype
4. Significance of Understand general a. Describe different types of gene mutations (missense, nonsense, frameshift, splicing)
Genetic Variants concepts of the and their effect on transcription, translation and protein function
pathogenicity of b. Understand the significance of different types of gene variants (e.g. haploinsufficiency,
genetic variation dominant-negative, etc.)
c. Understand the concept of hypomorphic versus pseudo-deficient alleles, and approaches to
determine their clinical significance
5. Genetic Understand key a. Describe the concepts of counseling: non-directive, awareness of values and biases
Counseling and concepts in genetic b. Describe appropriate indications for referral for genetic counseling
Risk Assessment counseling and risk c. Demonstrate the ability to modify a priori risk by one conditional factor (basic
assessment Bayesian analysis)
d. Demonstrate the ability to calculate odds ratios
e. Understand basic test performance characteristics: sensitivity, specificity, positive predictive
and negative predictive value
6. Cytogenetics Understand general a. Describe the general principles of cytogenetic methods for chromosome analysis,
Concepts principles of human including karyotyping, FISH and genomic copy number assessment
cytogenetics as b. Describe appropriate indications for cytogenetic testing, including microarray analysis

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 applied to human c. Distinguish between common cytogenetic variants and pathogenic
health rearrangements, including copy number changes
d. Describe the general concepts of autosomal and sex chromosomal abnormalities
(aneuploidy, translocations, etc.)
e. Describe the meiotic segregation of rearranged chromosomes and the effects of
recombination events
f. Describe the etiology of chromosome abnormalities (e.g. non-disjunction, breakage and
repair, non-homologous recombination, uniparental disomy, copy-neutral loss of
heterozygosity)
g. Understand the uses and limitations of cytogenetic tests, including the limits of detection of
mosaicism
h. Understand the effect of mosaicism on phenotype
i. Understand the use of basic ISCN nomenclature
7. Molecular Understand general a. Understand the basic principles of the polymerase chain reaction
Genetics principles of b. Understand the basic concepts of nucleic acid sequencing, including Sanger and
Concepts molecular biology as massively parallel sequencing
applied to human c. Understand the basic principles of molecular techniques that can be used to detect copy
health number changes or large repeats, including qPCR, QF-PCR, MLPA, TP-PCR, whole genome
sequencing and their limitations
d. Understand the basic principles of nucleic acid hybridization assays (e.g. Southern
blot, Northern blot)
e. Understand the basic principles and applications of linkage analysis
f. Understand the basic concepts of targeted sequence variant analysis versus scanning assays
(for unknown sequence variants)
g. Understand the limitations associated with molecular methods (allele drop-out, primer
binding site polymorphisms, large deletions, etc.)
h. Describe the concept of sample identity testing and its use as an adjunct method to
establish the relationship between samples (i.e. maternal cell contamination, sample
identity matching)
i. Describe sequence variants using appropriate nomenclature (i.e. HGVS)
8. Biochemical Understand general a. Describe the different categories of proteins in a cell (structural, enzymes, transport,

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 Genetics principles of receptor proteins etc.), their modes of action and means of regulation
Concepts biochemical genetics b. Describe the biochemical consequences of a primary enzyme block in a metabolic
as applied to human pathway and the way clinical and pathological signs may be produced
health c. Understand the principles of newborn screening
d. Understand the deleterious effects of toxic metabolites on the fetus (e.g. maternal PKU)
e. Understand the unique concepts of testing for human mitochondrial disorders (e.g. nuclear
vs. mitochondrial DNA, heteroplasmy)
9. Clinical Genetics Understand broad a. Describe the methods of assessment of phenotypic variations, syndrome identification
Concepts categories of genetic and diagnosis, including generally accessible computer diagnostic aids (e.g. OMIM)
conditions and their b. Be familiar with disorders in the following categories (see attached Genetic Conditions
methods of list):
assessment i. Cancer Genetics
ii. Clinical Genetics
• Dysmorphology, including birth defects
• Developmental Genetics
• Cardiac Genetics
• Hematology
• Disorders of sexual development
iii. Complex Inheritance
iv. Cytogenetics
• Chromosome Instability
• Microdeletion Syndromes
v. Metabolics
vi. Molecular Genetics
• Imprinting
• Methylation
• Repeat Expansion
vii. Neurogenetics
c. Describe and understand the distinction between genetic screening and genetic testing
d. Describe and understand the distinction between genetic testing for the purpose of
diagnosis and predictive testing to assess risk for predisposition to monogenic or complex

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 genetic diseases as well as their applications and limitations.
10. Cancer Understand general a. Define the concepts of inherited predisposition to cancer, oncogene activation, tumor
Genetics principles of human suppressor inactivation, alteration of cell cycle control and DNA repair genes
cancer cytogenetics b. Explain and contrast inherited versus somatic mutations
and molecular c. Describe the relevance of cytogenetic and molecular analysis to cancer diagnosis, prognosis
pathology and monitoring (e.g. gene expression, recurrent rearrangement, recurrent pathogenic
variants)
11. Developmental Understand key steps a. Understand the key concepts in developmental biology as it relates to normal and
Genetics and in human abnormal human morphogenesis
Birth Defects development b. Understand the concepts of morphogenesis, differentiation, pluripotency,
specification, determination, embryonic induction, competency and signal
transduction.
c. Describe the role of epigenetics in gene expression and human embryogenesis
d. Describe the processes involved in early embryogenesis: fertilization to
gastrulation
e. Describe the major embryonic cell lineages and the distribution in the fetus and extra-
embryonic tissues as they relate to prenatal diagnostic sampling
f. Describe the principle of teratogenesis and understand the impact of teratogen exposure
(e.g. infection, alcohol, medications) and maternal disease (e.g. maternal PKU) on fetal
development
12. Prenatal Understand a. Describe the principles of and approaches to prenatal screening
Diagnosis principles of prenatal b. Describe the principles of and approaches to prenatal diagnosis as compared to postnatal
screening, prenatal diagnosis
diagnosis and related c. Describe the general principles of biochemical, molecular and cytogenetic testing on
methodologies prenatal samples
d. Describe the advantages and disadvantages of amniocentesis and chorionic villus
sampling
e. Describe the genetic factors that contribute to recurrent pregnancy loss

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13. Ethics Understand ethical a. Define the principles of biomedical ethics
and social issues as b. Understand the ethical dilemmas arising in medical genetics
they relate to i. Prenatal genetic testing
Genetics ii. Genetic testing for predisposition disorders
iii. Genetic testing of asymptomatic children
iv. Incidental and secondary findings
v. Newborn screening
vi. Biobanking
c. Describe informed consent and its role in genetic testing
d. Describe privacy and confidentiality principles as it relates to general practice
i. Family members
ii. Database searches
iii. Communication with health care providers
iv. Duty to warn
v. Use of genetic information by employers and insurers
e. Understand the eugenic and dysgenic effects of medical genetics

Core Reference:
• Nussbaum, McInnes and Willard. Thompson & Thompson Genetics in Medicine, 8th Edition 2016.

Optional Resources:
• Rimoin, Pyeritz and Korf. Emery and Rimoin’s Essential Medical Genetics, 1st Edition, 2013.
• Firth and Hurst. Oxford Desk Reference: Clinical Genetics and Genomics, 2nd Edition 2017.
• Gardner, Sutherland and Shaffer. Chromosome Abnormalities and Genetic Counseling, 4th Edition 2011.
• Jorde, Carey and Bamshad. Medical Genetics 5th Edition 2016.
• Leonard. Molecular Pathology in Clinical Practice 2nd Edition 2016.
• Strachan and Read. Human Molecular Genetics 4th Edition 2010.
• Saudubray, Baumgartner and Walter. Inborn Metabolic Diseases- Diagnosis and Treatment, 6th Edition 2016.
• GeneReviews, www.genetests.org

CCMG General Knowledge Study Guide

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