Microdeletii Cluj

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Microdeletii Cluj

  1. 1. Conf. dr. Eusebiu Vlad Gorduza1, Asist. dr. Cristina Skrypnyk2 1 Medical Genetics Department, “Gr. T. Popa” University of Medicine and Pharmacy Iaşi; 2 Medical Genetics Department, Faculty of Medicine, University of Oradea
  2. 2. Background  Mic d le n s ro e a re re e d b p ro e tio ynd m s re p s nte y lurim lfo a a rm tive s ro e g ne te b the a s nc o s m c m s m l re io ynd m s e ra d y b e e f o e hro o o a g n tha c nta 10 0g ne t o in -10 e s  The es ro e w red s rib d a r a p a n o p m ta ha e s ynd m s e e c e fte p lic tio f ro e p s c m s m l b nd tha re uc d the lim o re o hro o o a a ing t d e it f s lutio to 3 n -5 Mb .  The FISH te hniq re re e a s e ific to l in d g s o c ue p s nts pc o ia no tic f m ro e tio s ro e b c us p vid d a p tho e ic d le n ynd m s e a e ro e a g nic c nne tio o c n b tw ee en s m o e p vio ly re us w ll-re o nize e cg d plurim lfo a s ro e a s e ificm ro e tio . a rm tive ynd m s nd p c ic d le ns
  3. 3. Background C g ne s p yto e tic te s “ Dark Ages’(b fo 19 2) ’ e re 5  no o c m s m s= 4 . . f hro o o e 8  Hyp to uea e–fro 19 2 o niq g m 5  no o c m s m s= 4 . . f hro o o e 6  Tris m a e–fro 19 9 o ic g m 5.  Le une–2 tris m ↔ Do n s ro e je 1 o y w ynd m  Ba inga e–a r 19 nd g fte 70  Mo c r a e–a r 19 5 le ula g fte 8
  4. 4. Without banding With banding 1950 1970 FISH 1990
  5. 5. Evolution of cytogenetic techniques Control Signals Region-Specific Signal Metaphase Pro(meta)phase FISH 1 band – 10 Mb 1 band – 3-5 Resolution – some kb Mb
  6. 6. Background Molecular technique to detection of chromosomal abnormalities F fluo s e e re c nc I in S situ H hybridization Molecular technique to localize the gene’s sequences
  7. 7. THE USE OF FISH TECHNIQUE Cells in division Cells in interphase •Identify the chromosomal microdeletion or •identify of aneuploidies; microduplication; •Identify specific chromosomal •Identify the translocations anomalies •Identify the marker chromosomes; •Identify the ring chromosomes; •Identify the centromers of dicentric chromosomes; •Identify gene’s fusions prenatal diagnostic; tumoral cytogenetics constitutional and tumoral cytogenetics
  8. 8. Syndromes with chromosomal microdeletion Wolf-Hirschhorn syndrome(4p-). Cri-du-chat syndrome(5p-). Williams syndrome(7q11.23). Retinoblastoma (13q14). Prader-Willi/Angelman syndrome(15q11.2-13). Miller-Dieker syndrome(17q11.23). Smith-Magenis syndrome(17p13.3). DiGeorge/ Velo-cardio-facial/ CATCH-22/ Shprintzen syndrome (22q11.2). Kallman syndrome(Xp22.3).
  9. 9. WILLIAMS SYNDROME • 1/20.000 newborn • Microdeletion 7q11.2 → absence of elastine gene (CHD) and LIMK1 gene (mental retardation) • Short stature • Moderate mental retardation + cognitive deficit (“cocktail party”); • Hypercalcemia; • Elfin facies • CHD- 53-85%, – Supravalvular AS – Supravalvular PS – Peripheral pulmonary stenosis
  10. 10. WILLIAMS SYNDROME Crs. 7
  11. 11. WILLIAMS SYNDROME GENETICS  The m jo a rity of css a ae re de novo 7q11.23 m ro e tio ic d le n;  The m ro e tio ha m te l o p te l o in a is ic d le n s a rna r a rna rig nd p d e b a une ua c s ing ve in a re io ric in ro uc d y q l ro s -o r g n h re e p titiveDNA s q nc s e ue e ;  The c m o re io d le d s a 1,4 Mb a c nta o m n g n e te p ns nd o ins 14 g ne (the m a g ne a ELN – e s s g ne e s e n e s re la ta e e ; LIMK1 - Limkina e1); s  In 9 % o c s s the d g s is e ta lis d b FISH 9 f ae ia no tic s b he y a lys tha ind a a7q na is t ic te 11.2 m ro e tio 3 ic d le n
  12. 12. Williams Syndrome– microdeletion 7q abnormal 7 chromosome normal 7 chromosome
  13. 13. WILLIAMS SYNDROME GENETIC COUNSELING  Theris o p re tha ha ac k f a nts t ve hild w W m s ro e ith illia s ynd m to ha a the a c d c ve no r ffe te hild is ve lo → p na l ry w re ta d g s im o nt; ia no is p rta  The ris o a a c d ind ua to tra m the d e s is k f n ffe te ivid l ns it is a e 5 % (them ro e tio istra m d in a s m l d m nt 0 ic d le n ns itte uto o a o ina p tte → im o ep na l d g s ; a rn) p s re ta ia no is
  14. 14. Velo-cardio-facial Syndrome  DiGe rg s r., C o ed ATC 2 s r. H 2d  1/2 0 - 1/4 0 ne b rn .5 0 .0 0 w o  Mic d le n 22q11.2 (8 %) o d le n 22q11.2 (2 %) ro e tio 0 r e tio 0 c linic:  Fa ia c l d m rp m – lo ys o his ng b a no e hyp rte ris , ro d s, e lo m m ro na , lo s t p s rio ro te e rs ic g thia w e o te ry ta d a  P la c ft → s e c d ultie a te le p e h iffic s  Hyp c lc m o a e ia  Thym a p ra ic nd a thyro hyp p s id o la ia  C rd c d fe ts - 75 o p tie ha C a ia e c % f a nts ve HD (Inte te a rtic rrup d o a h a m lie , C rc no a s AT, Is la d a rtic a h a m lie , TOF, o te o rc no a s C no ntric r VSD) o ve ula  Le rninga b ha ra d o e a nd e vio l is rd rs
  15. 15. Frequency of 22q11 Deletions in CHD Defect % Deleted Interrupted Aortic Arch 50 – 89% Truncus Arteriosus 34 – 41% Tetralogy of Fallot 8 – 35% Aortic Arch Anomalies 24% Ventricular Septal 10% Defects Double Outlet Right <5% Ventricle Transposition of the <1% Great Arteries
  16. 16. VCF syndrome
  17. 17. Velo-cardio-facial syndrome GENETICS  15 o c s s ha % f ae ve a vis le d le n ib e tio d te te b hig s lutio ka typ ; e c d y h-re o n ryo e  8 % o c s s ha 0 f ae ve a m ro e tio ic d le n id ntifie b FISH → c ntig us g ne e d y o o e s ro e ynd m ;  5 o p tie ha a g ne m tio o ha % f a nt ve e uta n r ve aw ngd g s ; ro ia no is  Thec m s m l d le n e o p s 3 Mb hro o o a e tio nc m a s a c m ris s~10 g ne nd o p e 0 e s
  18. 18. abnormal 22 chromosome normal 22 chromosome
  19. 19. Velo-cardio-facial syndrome PATHOGENESIS  Mo hyp the is re o s :  A d ve m nta a no a e lp e l b rm lity o third a fo f nd urth p ryng a p uc s w ha el o he ith a n a no a b rm l m ra n o ne l c s ne ns → ig tio f ura re t uro a no a s o he rt, thym , p ra b rm litie f a us a thyro id g nd ; la s  Ea d ve p e l a m ly o thee b nic rly e lo m nta no a f m ryo va c ture → s c nd ry d ve p e l s ula eo a e lo m nta s q nc s e ue e
  20. 20. Velo-cardio-facial syndrome DIAGNOSIS HIGH RESOLUTION KARYOTYPE ABNORMAL De novo 22q11.2 deletion NORMAL Unbalanced translocation Karyotype in both parents FISH Microdeletion NORMAL FISH in both Molecular tests parents Reconsidering the clinical diagnosis
  21. 21. VELO-CARDIO-FACIAL SYNDROME GENETIC COUNSELING  Theris o p re tha ha ac k f a nts t ve hild w VC s ro e ith F ynd m toha a the a c dc ve no r ffe te hildis:  In thec s o ade novo c m s m l d le n < 1%; ae f hro o o a e tio  In thec s o ade novo c m s m l m ro e tio < 1%; ae f hro o o a ic d le n  In thec s o ade novo unb la e tra lo a n < 1%; ae f a nc d ns c tio  In the c s o a inhe d unb la e tra lo a n – 5 0 ae f n rite a nc d ns c tio -2 % d p nd o c m s m sa p re l o in; e e ing f hro o o e nd a nta rig  In thec s o a inhe d c m s m l m ro e tio –5 % - ae f n rite hro o o a ic d le n 0 the m ro e tio is tra m d in a a s m l d m nt ic d le n ns itte n uto o a o ina p tte a rn
  22. 22. PRADER-WILLI SYNDROME  1/10 0 -1/2 .0 0n.b .0 0 0 0 .  m ro e tio e tio 15 11-q ic d le n/d le n q 13 C linic l: a  Ma r c ria jo rite :  Infantilec ntra hyp to ; e l o nia  Infantilefe d p b m / fa e ing ro le s iluretothrive;  Ra idw ig g in b tw e 1-6ye rs p e ht a e e n a ;  C ra te ticfa ia fe ture (na w o b nta d m te a o s p ha c ris c l a s rro ing f ifro l ia e r; lm nd ha e e s ye );  Hyp g na is (g nita hyp p s ; p e l d fic nc oo d m e l o la ia ub rta e ie y);  De lo m nta d la m nta re rd tio ve p e l e y/ e l ta a n;  Mino c ria r rite :  Typ a b ha r p b m ; ic l e vio ro le s  Sle pd turb nc s e is a e ;  Sho s ture rt ta ;  Hyp p m nta n; o ig e tio  Ac m ria ro ic .
  23. 23. PRADER-WILLI SYNDROME Crs 15
  24. 24. Prader-Willi syndrome GENETICS  La k o e re s n o no a c f xp s io f rm lly a tive c paternally inhe d g ne a c m s m rite e s t hro o o e 15 11-q q 13 - a im rinte re io o n p d g n n c m s m 15 hro o o e ;  75 o p tie % f a nts ha a p te lly s a ve a rna m ll d le n; e tio  2 % o p tie 4 f a nts ha ve a m te lly a rna unip re l d o y o c m s m 15 a nta is m f hro o o e  1% o p tie ha a d fe t o im rinting f a nts ve e c f p c nte o c m s m 15 e r f hro o o e
  25. 25. Prader-Willi syndrome PATHOGENESIS  In 15 11-q c m s m l c a re io q 13 hro o o a ritic l g n (P d r-W ra e illi/Ang lm n c a re io e a ritic l g n) w re id ntifie m re g ne (SNRP e e d o e s N, GABRB3 GABRA5 GABRG3 ZNF12 , , , 7, IP , P W AR1, P AR5 s m o the e b ing ) o e f s e im rinte (m te l o p te l); p d a rna r a rna  The m jo c a r linic l a p c in P d r-W a s e ts ra e illi s ro e a d to a a no a func n ynd m re ue n b rm l tio o hyp tha m in a s nc o s tura f o la us b e e f truc l a m lie o thiso a no a s f rg n
  26. 26. Prader-Willi syndrome GENETICS IC SPW SA mat N IC SPW SA pat ICIC SPW SA Prader-Willi Syndrome mat Deletion pat IC SPW SA mat DUP 15 IC SPW SA mat IC SPW SA mat IC mutation IC SPW SA patm ACTIVE INACTIVE
  27. 27. Prader-Willi syndrome DIAGNOSIS HIGH RESOLUTION KARYOTYPE ABNORMAL De novo 15q11-13 NORMAL deletion Unbalanced translocation FISH Karyotype in both parents Microdeletion NORMAL Maternal 15 UPD Methylation test, gene mutation analysis Defect in imprinting center
  28. 28. PRADER-WILLI SYNDROME
  29. 29. PRADER-WILLI SYNDROME Abnormal chromosome 15 Normal chromosome 15
  30. 30. PRADER WILLI SYNDROME GENETIC COUNSELING  The ris o p re tha ha a c k f a nts t ve hild w P s ro e ith W ynd m toha a the a c dc ve no r ffe te hildis:  In thec s o ade novo c m s m l d le n < 1%; ae f hro o o a e tio  In thec s o ade novo c m s m l m ro e tio < 1%; ae f hro o o a ic d le n  In thec s o ade novo unb la e tra lo a n < 1%; ae f a nc d ns c tio  In the c s o a inhe d unb la e tra lo a n – 5 0 ae f n rite a nc d ns c tio -2 % d p nd o c m s m sa p re l o in; e e ing f hro o o e nd a nta rig  In the c s o a m tio in im rinting c nte o 15 p te lly ae f uta n p e r n a rna inhe d c m s m (m tio p vid rite hro o o e uta n ro ing fro p te l m a rna g nd o r) – 5 % - the m tio is tra m d in a ra m the 0 uta n ns itte n a s m l d m nt p tte uto o a o ina a rn
  31. 31. PRADER WILLI SYNDROME GENETIC COUNSELING  The ris o a a c d ind ua to ha a a no a k f n ffe te ivid ls ve n b rm l childis:  Us lly isve lo b c us o hyp g na is ; ua ry w e a e f oo d m  In c s sw d le n/m ro e tio - 5 %: a e ith e tio ic d le n 0  Theb ysw o ith P s ro eha c re w P s ro e W ynd m ve hild n ith W ynd m ;  The g irlsw P s ro eha c re w Ang lm n s ro e ith W ynd m ve hild n ith e a ynd m  In c s sw UP theris is< 1%; a e ith D k  In c s s w m tio in im rinting c nte the ris is 5 % the a e ith uta n p e r k 0 c re ha hild n ving P o Ang lm n s ro e d p nd W r e a ynd m e e ing o f m tio styp ; uta n’ e
  32. 32. ANGELMAN SYNDROME  Ang lm n s ro e (AS) is a d tinc ne g ne e a ynd m is t uro e tic s ro e firs d s rib d in 19 5 ynd m , t e c e 6.  Ang lm n s ro e(AS) is c ra te e b s ve e a ynd m ha c ris d y e re m nta re rd tio a s nt s e c d m rp fa ia e l ta a n, b e p e h, ys o hic c l fe ture , m ro e ha a s ic c p ly, e ile tic s izure , EEG p p e s a no a s ne lo ic l p b m a s m tim b rm litie , uro g a ro le s nd o e e hyp p m nta n. o ig e tio  The b ha ura p no e inc e hyp ra tivity, e vio l he typ lud s e c s e ing p b m , ha p p rs na a p rio s o le p ro le s p y e o lity nd e d f ina p p tela hte p ro ria ug r.
  33. 33. ANGELMAN SYNDROME Crs 15
  34. 34. ANGELMAN SYNDROME GENETICS  La k c o e re s n o no a f xp s io f rm lly a tive c maternally inhe d g ne a c m s m rite e s t hro o o e 15 11-q q 13 - a n im rinte p d re io g n o n c m s m 15 hro o o e ;  6 -75 o p tie 0 % f a nts ha a m te lly s a ve a rna m ll d le n; e tio  2 % o p tie ha a p te lly unip re l -5 f a nts ve a rna a nta d o y o c m s m 15 is m f hro o o e  2 % o p tie ha a d fe t o im rinting -5 f a nts ve e c f p c nte o c m s m 15 e r f hro o o e  10 o p tie ha a m tio in the UBE3 % f a nts ve uta n A g ne e
  35. 35. ANGELMAN SYNDROME GENETICS IC SPW SA mat N IC SPW SA pat ICIC SPW SA pat Angelman Syndrome Deletion mat IC SPW SA pat DUP 15 IC SPW SA pat IC SPW SA pat IC mutation IC SPW SA matp ACTIVE INACTIVE
  36. 36. Prader-Willi syndrome DIAGNOSIS HIGH RESOLUTION KARYOTYPE ABNORMAL De novo 15q11-13 NORMAL deletion Unbalanced translocation FISH Karyotype in both parents Microdeletion NORMAL Paternal 15 UPD Methylation test, gene mutation analysis Defect in imprinting center Mutation in UBE3A gene
  37. 37. ANGELMAN SYNDROME Abnormal chromosome 15 Normal chromosome 15
  38. 38. ANGELMAN SYNDROME GENETIC COUNSELING  The ris o p re tha ha a c k f a nts t ve hild w Ang lm n ith e a s ro etoha a the a c dc ynd m ve no r ffe te hildis:  In thec s o ade novo c m s m l d le n < 1%; ae f hro o o a e tio  In thec s o ade novo c m s m l m ro e tio < 1%; ae f hro o o a ic d le n  In thec s o ade novo unb la e tra lo a n < 1%; ae f a nc d ns c tio  In the c s o a inhe d unb la e tra lo a n – 5 0 ae f n rite a nc d ns c tio -2 % d p nd o c m s m sa p re l o in; e e ing f hro o o e nd a nta rig  In thec s o a m tio in im rinting c nte o 15 m te lly ae f uta n p e r n a rna inhe d c m s m (m tio p vid rite hro o o e uta n ro ing fro m te l m a rna g nd the – 5 % - the m tio is tra m d in a ra fa r) 0 uta n ns itte n a s m l d m nt p tte uto o a o ina a rn  In the c s o a m tio in UBE3 g ne – up to 5 % if is ae f uta n A e 0 p s nt ag na a m s ic m re e o d l o a is .
  39. 39. CONCLUSIONS  The m ro e tio s ro e m d d the m d a ic d le n ynd m s o ifie e ic l thinkingin m d rn g ne s o e e tic ;  The ec ng sim ly m rec m o nts s ha e p o o p ne :  Thep tho e m c nis s a g nic e ha m ;  Them tho sus din d g s ; e d e ia no is  Thep s ib o s ilitie o p p xis s f ro hyla ;  Thew ystoc lc tetheg ne ris . a a ula e tic ks  Thefuturec rta e inly w fill theg p b tw e c g ne a ill a e e n yto e tic nd m le ula g ne a this s a eis re e d to m ro e tio o c r e tic nd pc s rve ic d le n s ro e . ynd m s
  40. 40. Aknowledgments to Genetic team of Iasi and Oradea that examined the patients presented in this work The professors and techniciens teams from Dresden University (Germany) and Neijmegen (Netherland)
  41. 41. Thank you for atention I will wait you in the capital of Moldavia region

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