“Mechanisms and assays
       for rare
  genomic disorders”

                     Cristina Skrypnyk
                  Univ...
Wolf Hirschhorn      OMIM 194190   1/5 0000    del (4p)(16.3)

Williams-Beuren      OMIM 194050   1/20 000    del (7)(q 11...
Charcot-Marie-Tooth type 1A
  Pelizaeus-Merzbacher
        Parkinson
        Alzheimer
          Autism
  Beckwith Wiedema...
Genomic Disorders

      genetic diseases that
          result from DNA
          rearrangements
      (deletion, duplic...
Genomic Disorders
   Mechanisms mediated by genomic architecture

-   non-allelic homologous recombination(NAHR)
-   non-...
Genomic Disorders
   non-allelic homologous
    recombination(NAHR)

    - produced between two low-copy repeats
     (LC...
Genomic Disorders
   Due to their high degree of sequence identity, can
    sometimes be aligned in meiosis or mitosis, t...
Genomic Disorders

   When the two LCRs are
    located on the same
    chromosome and in
    direct orientation, NAHR
  ...
Genomic Disorders

   When they are on the
    same chromosome but in
    opposite orientation, NAHR
    results in inver...
Genomic Disorders
   Interchromosomal and interchromatid NAHR
    between LCRs in direct orientation result in
    recipr...
Syndrome                OMIM              Rearrangement                     Size         Genes         LCRs
              ...
(Stankiewicz and Lupski, 2002)
LCRs 22q11.21
(Shaikh TH. 2000).
Genomic Disorders
Diagnostic methods for the detection               and
  characterization of DNA rearrangements

   flu...
FL1 gene in Smith-Magenis critical region in 17p11.2 - FITC (green), LIS1 in 17p13.3 - Texas Red.
Both 17s are identified ...
N   5
                                          S   q
                                          D   3
                    ...
Blake C et all
Discovery of a previously unrecognized microdeletion syndrome of 16p11.2–p12.2
Nature Genetics 39, 1071 - 1...
THANK YOU!
   The clinical implementation of such advanced
    techniques     is    revolutionizing  clinical
    cytogen...
THANK YOU!
Genomic Disorders
Genomic Disorders
Genomic Disorders
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Genomic Disorders

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Genomic Disorders

  1. 1. “Mechanisms and assays for rare genomic disorders” Cristina Skrypnyk University of Oradea, Faculty of Medicine and Pharmacy, Genetics Department
  2. 2. Wolf Hirschhorn OMIM 194190 1/5 0000 del (4p)(16.3) Williams-Beuren OMIM 194050 1/20 000 del (7)(q 11.23) Langer-Giedion del (8)(q 24.11-q 24.13) WAGRO OMIM 194072 1/60 000 del (11)(p 13) Prader-Willi OMIM 76270 1/20 000 del (15)(q11.2-q 13)pat Angelman OMIM 105830 1/20 000 del (15)(q11.2-q 13)mat Rubinstein-Taybi OMIM 180849 1/125 000 del (16)(p 13.3) Smith-Magenis OMIM 182290 1/25 000 del (17)(p 11.2) Miller-Dieker del (17)(p 13.3) Alagille OMIM 118450 1/70 000 del (20)(p12.1-p11.23) Displasia Di George OMIM 188400 1/ 4000 del (22)(q11.21-q 11.23) Velo-cardio-facial del (10)(p13) Kallmann del(X)(p 22.3)
  3. 3. Charcot-Marie-Tooth type 1A Pelizaeus-Merzbacher Parkinson Alzheimer Autism Beckwith Wiedemann Cat eye Russel Silver Neurofibromatosis type 1 and many other....
  4. 4. Genomic Disorders  genetic diseases that result from DNA rearrangements (deletion, duplication, inversion, insertion) from kb to Mb, covering clusters of different genes -CNVs- (Lupski et al.1998, Stankiewicz et al. 2002, Lupski et al. 2003, Waltz et al. 2004).
  5. 5. Genomic Disorders  Mechanisms mediated by genomic architecture - non-allelic homologous recombination(NAHR) - non-homologous end-joining (NHEJ) - Fork Stalling and Template Switching models (FoSTeS)
  6. 6. Genomic Disorders  non-allelic homologous recombination(NAHR) - produced between two low-copy repeats (LCRs, also called segmental duplications, SD) - LCRs are region-specific DNA blocks of 10 to 300(kb) in size and of > 95% to 97% similarity to each other
  7. 7. Genomic Disorders  Due to their high degree of sequence identity, can sometimes be aligned in meiosis or mitosis, the 'misalignment' and the subsequent crossover between them can result in genomic rearrangements in progeny cells  The non-allelic copies act as the substrates of the homologous recombination and they are responsible for the observed breakpoint clustering.
  8. 8. Genomic Disorders  When the two LCRs are located on the same chromosome and in direct orientation, NAHR between them causes duplication and/or deletion.
  9. 9. Genomic Disorders  When they are on the same chromosome but in opposite orientation, NAHR results in inversion of the fragment flanked by them.
  10. 10. Genomic Disorders  Interchromosomal and interchromatid NAHR between LCRs in direct orientation result in reciprocal duplication and deletion, whereas intrachromatid NAHR only creates deletion.
  11. 11. Syndrome OMIM Rearrangement Size Genes LCRs (Mb) I II III IV Wolf Hirschhorn del(4)(p Williams Beuren 194050 del (7)(q11.23q11.23) 1,6 ELN, 330 1,6 98 C IMK1 CYLN2 WAGR 194072 del(11)(p12p14) PAX6, WTI Prader Willi 176270 del(15)(q11.2q13) pat 4 SNRNP, 500 3,5 C NDN, P Angelmann 105830 del(15)(q11.2q13)mat 4 UBE3A, 500 3,5 C P Rubinstein Taybi 180849 del(16)(p13.3p13.3) CBP Smith-Magenis 182290 del(17)(p11.2p11.2) 5 RAII 250 5 98 C Alagille 118450 del(20)(p12.2p12.2) JAGI Di George/ VCFS 188400 del(22)(q11.2q11.2) 3 TBXI 225 3 97 C 400 98 HNPP 162500 del(17)(p12p12) 1,5 PMP22 24 1,5 C Ichtyosis X 308100 del(X)(p22.3p22.3) 1,9 STS 1,9 LCRs- I-size kb; II-distance Mb; III -homology %; IV- orientation type: C-complex ( Lupski et al. 1998, Emanuel et al. 2001, Shaffer et al. 2000, Stankiewicz et. al. 2002, Waltz et al. 2004)
  12. 12. (Stankiewicz and Lupski, 2002)
  13. 13. LCRs 22q11.21 (Shaikh TH. 2000).
  14. 14. Genomic Disorders Diagnostic methods for the detection and characterization of DNA rearrangements  fluorescence in situ hybridization (FISH)  pulsed-field gel electrophoresis (PFGE)  in silico analyses  multiplex ligation-dependent probe amplification (MLPA)  array comparative genomic hybridization (aCGH)
  15. 15. FL1 gene in Smith-Magenis critical region in 17p11.2 - FITC (green), LIS1 in 17p13.3 - Texas Red. Both 17s are identified by the red LIS1signal. Deletion of the green FLI signal is seen in one 17.
  16. 16. N 5 S q D 3 1 5 Sotos critical region - NSD1 (reed), in 5q35. Both 17s are identified by the centromere green signal. Deletion of the reedNSDN1 signal is seen in one 5q.
  17. 17. Blake C et all Discovery of a previously unrecognized microdeletion syndrome of 16p11.2–p12.2 Nature Genetics 39, 1071 - 1073 (2007)
  18. 18. THANK YOU!  The clinical implementation of such advanced techniques is revolutionizing clinical cytogenetics, improving the understanding of genomic disorders and helping the doctors to offer a better genetics approach for the patients and their families.
  19. 19. THANK YOU!

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