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Essay Plan

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. Essay Plan. Definition of a Contiguous Gene Deletion

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Essay Plan

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  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 Mar;21(3):188-95. • Baldini A. 279-84.Dissecting contiguous gene defects: TBX1. Curr Opin Genet Dev. 2005 Jun;15(3) • Morris CA, Mervis CB. Williams syndrome and related disorders. Annu Rev Genomics Hum Genet. 2000;1:461-84.

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