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    Genetics in Haematology Nov24-1

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    Genetics in Haematology Nov24-1

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    5 views82 pages

    Genetics in Haematology Nov24-1

    Uploaded by

    doctorraihanmd

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    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
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    of 82

    Introduction to Genetics in

    Haematology
    Not Asked in Resource Limitations
    Examination
    NOT detailed /
    in-depth

    Haematology Curriculum,
    Not Haematopathology
    Cytogenetics
    Study of chromosome structure and Karyotyping
    function

    Chromosomal
    Fluorescent In-situ Microarray
    Hybridization Analysis
    (FISH) (CMA)
    Precursor T and B cells undergo rearrangements of their receptors during early
    development by recombining certain variable (V) and joining (J) gene segments,
    with or without diversity (D) segment.

    Random nucleotide insertions happen within the joining regions to further increase
    the sequence diversity
    Hierarchical classification of the International Consensus Classification of AML Blood (2022) 140 (12): 1345–1377.
    ❖ Conventional cytogenetic analysis is mandatory in the
    evaluation of AML.

    ❖ If conventional cytogenetics fails, fluorescence in situ


    hybridization is an alternative to detect specific
    abnormalities like RUNX1::RUNX1T1, CBFB::MYH11,
    KMT2A (MLL), and MECOM (EVI1) gene fusions, or
    myelodysplasia-related chromosome abnormalities, eg,
    loss of chromosome 5q, 7q, or 17p material
    Molecular genetic testing should screen for all the genetic abnormalities that
    define disease and risk categories or that are needed for targeted treatment
    modalities.

    These tests can be performed by commercially available gene panel diagnostics


    or platforms simultaneously testing for mutations and rearrangements.

    When AML with germline predisposition is suspected, a dedicated gene panel


    including known predisposing alleles should be used.
    *Bone marrow or peripheral blood blast count of ≥10% required, except for AML with
    t(9;22)(q34.1;q11.2)/BCR::ABL1 which requires bone marrow or peripheral blood blast
    count of ≥20% due to its overlap with progression of chronic myeloid leukemia,
    BCR::ABL1-positive
    CHIP
    Germline Variant
    Somatic Variant
    What is the significance of the Variant Allele Frequency (VAF)?

    The VAF is the frequency at which the variant is detected in a specimen.

    It is often used as a proxy for disease burden (e.g., a VAF of 50% may suggest a
    germline variant, whereas a VAF of 15% may suggest a neoplastic disease burden of
    30%).

    However, the VAF is affected by many factors including the variance of the assay (often
    as high as +/-15%), sampling, assay design, and cytogenetic changes at the allele
    including amplification or loss of heterozygosity (LOH).

    The VAF should always be interpreted with caution.

    For additional assistance, please contact the laboratory or the molecular professional
    who issued the report.
    Will the assay detect the ABC mutation in gene XYZ?
    Check the assay description - Is gene XYZ included on the panel?

    Is the region including the ABC mutation included on the panel?

    Does the assay detect this type of mutation (e.g., large indels or structural
    variants)?

    For additional assistance, please contact the laboratory or the molecular


    professional who issued the report.
    The report says there are no mutations in gene XYZ.
    Could the assay have missed anything?
    Any given assay has limits on its capabilities.

    There is always a lower limit of detection; moreover, genomic assays do not


    necessarily identify every type of variant with equivalent sensitivity.

    An assay may perform well in identifying single-nucleotide variants (SNVs), less


    well in identifying insertions and deletions (indels), and may not be able to identify
    larger indels at all.

    Negative results must always be interpreted with caution.


    Allele

    One of two or more versions of a genetic sequence at a


    particular region on a chromosome. An individual inherits two
    alleles for each gene, one from each parent.
    compound heterozygosity

    The presence of two different mutated alleles at a particular


    gene locus
    CNV
    A variation in the number of copies of a particular sequence
    of DNA present in the genome of an individual.
    CNVs include insertions, deletions, and duplications of
    segments of DNA. They account for a significant number of
    the genetic variations between individuals.
    CNVs may also be associated with specific traits or
    disorders.
    Also called copy number variant.
    Codon

    A sequence of three consecutive nucleotides in a DNA or


    RNA molecule that codes for a specific amino acid.
    Certain codons signal the start or end of translation.

    These are called start or stop (or termination) codons.


    congenital

    Describes a condition or trait that is present at birth.


    Congenital conditions may be caused by genetic factors,
    non-genetic factors, or a combination of both.
    Cytogenetics

    The study of the structure, function, and


    abnormalities of human chromosomes.
    Double Heterozygosity

    The presence of two different mutated alleles at two separate


    genetic loci.
    Depth of Coverage

    Refers to the number of times a nucleotide is read during


    sequencing.
    A greater depth of coverage can increase confidence in the
    final results.
    Deep coverage aids in differentiating sequencing errors from
    single nucleotide polymorphisms.
    This can be specifically useful when a patient has a
    mosaicism or when a tumor is heterogeneous for a mutation.
    Deletion

    A type of genetic change that involves the absence of a


    segment of DNA.
    It may be as small as a single base but can vary significantly
    in size.
    Epigenetics

    The study of heritable changes that do not affect the DNA


    sequence but influence gene expression.
    Exon

    The sequence of DNA that is present in the final, mature


    messenger RNA transcript.
    Most exons code for amino acids, which link together to form a
    protein.
    Most genes are made up of many exons with introns in between
    them.
    Epigenetic Variant

    A heritable change that does not affect the DNA sequence


    but results in a change in gene expression.
    Examples include promoter methylation and histone
    modifications.
    Also called epigenetic alteration and epimutation.
    FISH
    A technique used to identify the presence of specific
    chromosomes or chromosomal regions through hybridization
    (attachment) of fluorescently-labeled DNA probes to denatured
    chromosomal DNA.
    Examination through a microscope under fluorescent lighting
    detects the presence or absence of the colored hybridized signal,
    hence the presence or absence of the chromosome material.
    Also called fluorescence in situ hybridization.
    Germline

    The cells from which eggs or sperm (i.e., gametes) are


    derived.
    Germline variant

    A variant in a reproductive cell (egg or sperm) that is in the


    DNA of every cell in the offspring's body.
    A variant contained within the germline can be passed from
    parent to offspring and is, therefore, hereditary.
    Also called germline mutation.
    Heterozygous Genotype

    The presence of two different alleles at a particular gene


    locus.
    A heterozygous genotype may include one normal allele and
    one mutated allele or two different mutated alleles
    (compound heterozygote).
    Homozygous Genotype

    The presence of two identical alleles at a particular gene


    locus.

    A homozygous genotype may include two normal alleles or


    two alleles that have the same variant.
    Haploinsufficiency

    The situation that occurs when one copy of a gene is


    inactivated or deleted and the remaining functional copy of
    the gene is not adequate to produce the needed gene product
    to preserve normal function.
    Haplotype

    A set of closely linked genetic markers or DNA variations on a


    chromosome that tend to be inherited together.
    Locus

    The physical location of a specific gene on a chromosome.


    Locus Heterogeneity

    The presence of variants at different gene loci that cause the


    same or similar phenotypic expressions of a disease or
    condition.
    Aneuploidy

    The occurrence of one or more extra or missing


    chromosomes in a cell or organism. Aneuploidy refers to any
    chromosome number that is not an exact multiple of the
    haploid number of chromosomes (which is 23 in humans).
    Copy Number Variant

    A variation in the number of copies of a particular sequence


    of DNA present in the genome of an individual. Copy number
    variants include insertions, deletions, and duplications of
    segments of DNA. They account for a significant number of
    the genetic variations between individuals. Copy number
    variants may also be associated with specific traits or
    disorders. Also called CNV.
    Loss of Heterozygosity
    If there is one normal and one abnormal allele at a particular locus, as might be
    seen in an inherited autosomal dominant cancer susceptibility disorder, loss of the
    normal allele produces a locus with no normal function.

    When the loss of heterozygosity involves the normal allele, it creates a cell that is
    more likely to show malignant growth if the altered gene is a tumor suppressor
    gene.

    Also called LOH.


    Linkage

    The tendency for genes or other segments of DNA to be


    inherited together during meiosis because of their location
    near one another on the same chromosome.

    Finding linked genes can help identify a disease-causing


    gene.
    Linkage Analysis

    A gene-hunting technique that traces patterns of disease in


    high-risk families.

    Linkage analysis attempts to locate a disease-causing gene


    by identifying genetic markers of known chromosomal
    location that are co-inherited with the gene or trait of interest.
    Phenotype

    The observable characteristics or traits in an individual based


    on the expression of their genes.

    The phenotype is determined by the individual's genotype and


    possibly influenced by other factors, such as environmental
    factors or other genetic modifiers.
    PCR
    A common laboratory technique used during molecular genetic
    testing to produce many copies of a specific sequence of DNA .

    PCR allows these DNA sequences to be amplified so there is a


    sufficient quantity of DNA to be analyzed by molecular genetic
    tests.

    Also called polymerase chain reaction.


    Variant

    An alteration in the most common DNA nucleotide sequence.

    The term variant can be used to describe an alteration that


    may be benign, pathogenic, or of unknown significance.

    The term variant is increasingly being used in place of the


    term mutation.

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