Explain the term contiguous gene deletion syndrome. Use examples to explain the phenotypic effects of such deletions (excluding imprinted genes). Outline the methods available for identifying contiguous gene deletions. - PowerPoint PPT Presentation

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Explain the term contiguous gene deletion syndrome. Use examples to explain the phenotypic effects of such deletions (excluding imprinted genes). Outline the methods available for identifying contiguous gene deletions.

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Title: Explain the term contiguous gene deletion syndrome. Use examples to explain the phenotypic effects of such deletions (excluding imprinted genes). Outline the methods available for identifying contiguous gene deletions.


1
Explain the term contiguous gene deletion
syndrome.Use examples to explain the phenotypic
effects of such deletions (excluding imprinted
genes).Outline the methods available for
identifying contiguous gene deletions.
2
Essay Plan
  • Definition of a Contiguous Gene Deletion
  • Features of the Deletions
  • Examples of X linked Contiguous Gene Deletions
  • Detailed Examples and the phenotypic effects
  • Identification of Contiguous Gene Deletions
  • The limitations of such techniques

3
Definition
  • A contiguous gene deletion syndrome is caused by
    a microdeletion that spans two or more genes
    tandemly positioned along a chromosome.
  • Contiguous gene deletion syndromes result from
    deletions of small amounts of chromosomal
    material containing a few genes that are
    functionally unrelated but are linked by location
    on the chromosome.
  • As a result the phenotype observed is the result
    of a loss of the contiguous genes involved.

4
Features of the Syndromes
  • The microdeletion involved is often too small to
    be visualized using conventional cytogenetic
    techniques so detection often requires
    fluorescent in situ hybridization (FISH) or
    another high resolution technique.
  • In some cases, specific features of the syndrome
    can vary in different patients with the same
    syndrome as the phenotype can depend on the
    breakpoints of the deletion and which genes are
    deleted.

5
Features of the Syndromes
  • Some of the syndromes are due to a common
    deletion size in the majority of cases
  • e.g. William syndrome has a 1.6Mb deletion in
    most patients
  • Some are due to deletion of variable sizes which
    can affect the phenotype
  • e.g. Wolf Hirshhorn Syndrome
  • A lot of the best characterised deletion
    syndromes have developmental delay as a major
    feature.

6
Examples of Contiguous Gene Deletion Syndromes
  • Examples of syndromes that can be due to
    deletions of contiguous genes include
  • William Syndrome
  • WAGR
  • Miller Dieker
  • Di George/VCFS
  • Langer-Gideon,
  • Prader Willi Syndrome/Angelman Syndrome
  • Wolf Hirschorn
  • 1p deletion syndrome.

7
X linked Contiguous gene deletions
  • In males, X-chromosome microdeletions produce
    well-defined contiguous gene syndromes that show
    the features of several different X-linked
    mendelian diseases.
  • e.g. Boy BB' who suffered from Duchenne muscular
    dystrophy, chronic granulomatous disease and
    retinitis pigmentosa, together with mental
    retardation.
  • He had a chromosomal deletion in Xp21
  • helped to map disease genes for DMD and chronic
    granulomatous disease.
  • Deletions of the tip of Xp are seen in another
    set of contiguous gene syndromes.
  • Successively larger deletions remove more genes
    and add more diseases to the syndrome
  • Kallman disease and STS deficiency have been
    reported to be frequently deleted together.

8
22q11.2 deletion syndrome
  • 22q11.2 deletion syndrome, also known as
    Velocardiofacial Syndrome or DiGeorge Syndrome
  • Microdeletion of chromosome 22 accounts for more
    than 90 of cases and most deletions are de novo,
    with 10 or less inherited from an affected
    parent.
  • This region contains about 45 genes, but some of
    these genes have not been well characterized.
  • A small percentage of affected individuals have
    shorter deletions in the same region.

9
Symptoms and Cause
  • Symptoms can include
  • Congenital heart disease
  • Cleft palate,
  • characteristic facial features including
    hypertelorism,
  • learning difficulties,
  • hypocalcemia (which can result in seizures),
  • a decrease in blood platelets (thrombocytopenia),
    feeding problems, renal anomalies, hearing loss,
    growth hormone deficiency, autoimmune disorders
    and skeletal abnormalities.
  • The most common deletion (3 Mb), is seen in about
    90 of patients and occurs between the two most
    distant low copy number repeats (LCRs).

10
Genes Involved and Phenotype
  • The COMT and TBX1 genes are deleted in the
    22q11.2 deletion syndrome.
  • The TBX1 gene codes for a protein called T-box 1.
    The T-box 1 protein appears to be necessary for
    craniofacial development development, heart
    development, structures in the ear, and glands
    such as the thymus and parathyroid.
  • Using a knockout model TBX1 has been shown to be
    the dominant gene contributing to the cardiac
    phenotype.
  • Catechol-O-methyltransferase helps maintain
    appropriate levels of neurotransmitters in the
    brain.
  • It is thought that depletion of this enzyme in
    the brain may be responsible for the increased
    risk of behavioral problems and mental illness
    associated with 22q11.2 deletion syndrome.

11
William Syndrome
  • The clinical manifestations of William Syndrome
    include
  • a distinctive facial appearance (elfin face),
  • cardiovascular anomalies (specifically
    supravalvular aortic stenosis (SVAS)
  • hypercalcemia,
  • characteristic neurodevelopmental and behavioral
    profile.
  • Williams syndrome is caused by a deletion of
    chromosome 7q11.23
  • The deleted region includes more than 25 genes,
    many of which have been linked to the phenotypes
    seen in the syndrome
  • The Williams critical region is flanked by low
    copy repeats that predispose to nonallelic
    homologous recombination. WS is due to a 1.6Mb
    deletion in most patients (95).

12
Genes Involved
  • The main gene involved in the syndrome is the
    Elastin gene (ELN).
  • The ELN gene product is the structural protein
    elastin, a major component of elastic fibers
    found in many tissues.
  • Deletion of ELN is responsible for the connective
    tissue abnormalities, including the
    cardiovascular disease in WS.
  • LIMK1 (lim kinase 1) is likely to be a component
    of an intracellular signaling pathway and may be
    involved in brain development.
  • LIMK1 hemizygosity is implicated in the impaired
    visuospatial constructive cognition of Williams
    syndrome.
  • CYLN2 is strongly expressed in the brain,
  • it is believed postulated to be involved in
    cerebellar and neurological abnormalities in WS.

13
WAGR
  • WAGR syndrome is a rare genetic syndrome in which
    affected individuals are predisposed to develop
  • Wilms tumor (nephroblastoma),
  • Aniridia (absence of the iris),
  • Genitourinary anomalies
  • mental Retardation.
  • WAGR syndrome is caused by either submicroscopic
    or cytogenetically visible deletions involving
    varying amounts of 11p that include band 11p13.

14
Genes Involved
  • The two genes know to play a role in WAGR are
    PAX6 and WT1.
  • WT1 encodes a zinc finger transcription factor
    that is critical to normal development of the
    kidneys and gonads.
  • The loss of WT1 produces genitourinary and renal
    abnormalities and predisposes the patient to
    Wilms tumor.
  • The PAX6 gene encodes the PAX6 protein, which is
    a transcription factor, believed to act as the
    major controller of ocular development during
    embryogenesis.
  • Deletion of one PAX6 gene causes aniridia through
    halpoinsufficiency.
  • PAX6 also plays a role in CNS development and may
    be responsible for the mental retardation seen in
    WAGR patients.

15
Miller Dieker
  • Miller-Dieker Syndrome (MDS) is a contiguous gene
    deletion syndrome of chromosome 17p13.3,
    characterised by classical lissencephaly (aka
    lissencephaly type 1) and distinct facial
    features.
  • Lissencephaly (smmoth brain) leads to severe
    mental retardation, significant developmental
    problems, and seizures. Death tends to occur in
    infancy and childhood.
  • The cause of MDS is due to haploinsufficiency of
    several genes on chromosome 17p13.3.
  • Lissencephaly is caused by mutations in the LIS1
    gene or by deletion (of part) of this gene.
  • Facial dysmorphism and other anomalies in
    Miller-Dieker patients appear to be the
    consequence of deletion of additional genes
    distal, one of which may be the 14-3-3 epsilon
    gene.

16
Neurofibromatosis type 1 (NF1)
  • Neurofibromatosis type 1 (NF1) is a common
    autosomal dominant disorder characterised by
    neurofibromas, café-au-lait spots, freckles, bone
    deformities, learning disabilities, macrocephaly,
    short stature and predisposition to developing
    tumors such as myeloid malignancies, gliomas and
    pheochromocytomas. eople.
  • The disease is caused by mutations of the tumour
    suppressor gene NF1 which may be either single
    nucleotide substitutions or large genomic
    deletions.
  • Approximately 5-20 of patients with deletions of
    the entire gene and at least 11 contiguous genes,
    typically have a more severe presentation than
    those with intragenic mutations.

17
Methods for Identification
  • Conventional G-banded cytogenetic analysis can
    often be used for some of the larger deletions
  • e.g. In the 1p terminal deletion syndrome and
    Wolf Hirschorn syndrome
  • In many cases, the deletions involved are beyond
    the resolution of a light microscope so much
    higher resolution methods may be required for
    detection.
  • Detection often requires fluorescent in situ
    hybridization (FISH).

18
FISH Analysis
  • There are now many commercially available FISH
    probes available for analysis of these disorders.
  • e.g. TUPLE1 and N25 probes can be used to detect
    22q11.2 deletions.
  • probes for the 7q11.23 elastin gene should be
    performed in patients in whom Williams syndrome
    is suspected.
  • However in cases of the disorder with variable
    deletion sizes such as 22q11.2,
  • FISH analysis may not be sensitive enough to
    detect very small deletions
  • it is difficult to accurately characterize the
    extent of the large deletions using this
    technique.

19
MLPA
  • Now many of the disorders mentioned above are
    included in the MLPA developmental delay screen
  • MLPA kits containing probes for many of the genes
    in the syndrome critical region have been
    developed and can quickly and accurately detect
    deletions within the critical region.
  • In the Mental Retardation MLPA kits, probes are
    available from many of the syndromes so many of
    the syndromes can be tested for simultaneously.
  • This is a quicker and cheaper method than FISH,
    and for those with a positive result, FISH probes
    can be used to confirm the result.

20
Array CGH
  • Another diagnostic approaches is array CGH which
    can be used to detect very small deletions.
  • Now high-density CGH array analysis is being used
    more and more with the clinical cytogenetic
    laboratories and research labs.
  • It is more sensitive than FISH analysis for
    deletion detection and provides clinically useful
    results on the extent of the deletion.

21
Array CGH
  • High-resolution genomic arrays are becoming
    increasingly important in diagnosing cases of
    developmental delay of unknown genetic etiology
  • They suggest that contiguous genomic alterations
    are the underlying pathogenic cause of a
    significant number of cases of developmental
    delay.
  • Recording the deletions found on such databases
    as DECIPHER means that more rare contiguous gene
    deletions are being identified and characterised.
  • Doing a PubMed search for contiguous gene
    deletion brings up hundreds of results.

22
References
  • www.genereviews.org
  • Strachan and Read
  • www.mlpa.com
  • Elsea SH, Girirajan S. Smith-Magenis syndrome.
    Eur J Hum Genet. 2008 16(4)412-21.
  • Bergemann AD, Cole F, Hirschhorn K. The etiology
    of Wolf-Hirschhorn syndrome.Trends Genet. 2005
    Mar21(3)188-95.
  • Baldini A. 279-84.Dissecting contiguous gene
    defects TBX1. Curr Opin Genet Dev. 2005
    Jun15(3)
  • Morris CA, Mervis CB. Williams syndrome and
    related disorders. Annu Rev Genomics Hum Genet.
    20001461-84.
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