sindromedi alportrtdc.it/download/presentazioni_xiii/renieri.pdf · 2015-03-19 · syndrome,...
TRANSCRIPT
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Sindrome di Alport
XIII CORSO RESIDENZIALEDALLA DIAGNOSI PRENATALE ALLA TERAPIA POSTNATALE
NEFROLOGIA, DIAGNOSI PRENATALE NON INVASIVA, GENOMICA
Carrara 23-24 ottobre 2014
Alessandra RenieriU.O. Genetica Medica, Università di Siena
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ASHGAmerican Society of Human Genetics
ASHG 1995 Oct, Minneapolis
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ASHGAmerican Society of Human Genetics
ASHG 1995 Oct, Minneapolis
Renieri A. Bruttini M, Galli L, Neri, TM …..De Marchi M. Mutation scanning of the entire COL4A5 coding sequence in Alport syndrome and genotype phenotype correlation.
Mencarelli MA., Hedet L, Storey H, van Geel M …… Renieri A. Digenic inheritance in Alport syndrome.
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24 anni di attività
oltre 1000 famiglie oltre 1000 famiglie per un totale di 3.248 individui
consulenze genetiche inconsulenze genetiche inoltre 500 oltre 500 famiglie famiglie
arrivo sangue e datiarrivo sangue e datiddi altre 500 i altre 500 famigliefamiglie
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RD-Connect:
Biobanca Genetica di Sienawww.biobank.unisi.it
Cell lines and DNA bank of Rettsyndrome, X-linked mental
retardation andother genetic diseases
Cell lines and DNA bank of
hereditary cancers
GBSGenetic Biobank
of Siena
Biobanca Alport3.248 campioni di DNA
261 campioni di sangue 213 campioni di plasma
45 linee cellulari
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Registro Italiano Sindrome di Alport
oltre 1000 famiglie oltre 1000 famiglie
Scientific board del RegistroGhiggeri Marco Nefrologia Ist Gaslini GenovaGiani Marisa Nefrologia Policlinico MilanoMassella Laura Ospedale Bambino Gesù RomaManno Carlo Nefrologia BariLa Manna Angela Pediatria Sec Univ di NapoliPecoraro Carimine Nefrologia A.O.Santobono NapoliPennesi Marco Pediatria TriestePeruzzi Licia, Nefrologia, Ospedale Inf R M Torino
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Sindrome di Alport (ATS)
Nefropatia ereditaria progressiva eterogenea dal punto vista
clinico e genetico
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Collagene alfa 3-4-5 eterotrimero
Componente essenziale della Membrana Basale Glomerulare matura Prodotto esclusivamente dai podociti
4. Network del Collagene
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Tipi di eredità monogenicanella ATS
• legata al cromosoma X - COL4A5
• autosomica recessiva - COL4A3 e COL4A4
• autosomica dominante - COL4A3 e COL4A4
Gubler MC (2008) Inherited diseases of the glomerular basement membraneNat Clin Pract Nephrol 4: 24–37, 2007
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I
II
III
64aa IRC lieve
ESRD a 33aa
ipoacusia
ESRD a 18aa
ipoacusiaESRD a
22aaipoacusia
Microematuria intermittente
Alport X-legata
COL4ACOL4A55
65%
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Alport Autosomica Recessiva
Longo I, et al. Nephrol Dial Transplant 2006;21(3):665-71.
3209insA w
3386del27 w
3209insA 3386del273209insA 3386del27ww
COL4A317 yMicrohematuriamacrohematuriaCRF (creatininemia 2 mg%)Bilateral mixed hearing lossDelayed growth
9 yMicrohematuriamacrohematuriaCreatinininemia 0,4 mg%
43 yMicrohematuriaMacrohematuriaCreatininemia 0,9 mg%
COL4ACOL4A33
4%
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Alport Autosomica Dominante
Pescucci C, et al. Kidney Int. 2004;65(5):1598-603.
54 y CRF
88 y deathDialysis since the age of 84Bilateral neurosensory hearing loss
67 yMicrohematuria - ProteinuriaCRF (creatininemia 1,4mg%)Bilateral neurosensoryhearing loss
G1045Vw
43-20 yMicrohematuria
COL4A3
G1045Vw
COL4ACOL4A33
30%
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Clinical evaluation
X-linked
COL4A5
DHPLC
Sequencing
MLPA
Autosomal
COL4A3
DHPLC
Sequencing
COL4A4
DHPLC
Sequencing
Test Genetico con Sequenziamento Tradizionale
Analizzato un gene alla volta = Tempo risposta 12 mesi
Fino a Settembre 2010
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Test Genetico con Sequenziamento massivo
paralleloda Ottobre2010
COL4A5COL4A4COL4A3
Tutti e 3 i geni analizzati insieme = Tempo risposta 15 gg !!
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Sequenziamento massivo parallelo
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Sequenziamento massivo parallelo
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COL4A3 c.2746+1G>T
COL4A4 c.1553G>A
COL4A3
COL4A4COL4A5
Sequenziamento Massivo Parallelo
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MM
7 yMicrohematuriaMacrohematuria since 4y
45 yMicrohematuria
wtwt
M wtwtwtM
wtwt
wt
p.Gly518Glu
c.2746+1G>T
forma digenica
Famiglia 1
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M1 = COL4A4 p.Gly1151Ala
M2 = COL4A3 p.Gly300Arg
Microhaematuria
M2wtwt
M1wtwt
wtwt
55 yCRFSNHL
M1M2wtwt M1
M2wt
wt
wtwt M1
wt
36 yMicrohaematuria
M1M2wt
wt
M2 = COL4A3 p.Gly520Arg
M1 = COL4A4 p.Cys1566Trpfs*37
I:2I I:1
II:2
I:2
II:1
I:1I
II
IIMicrohaematuria
M2wt wt
wt
II:3
M2wt wt
wt
II:120 yIntermittenthaematuria
60 yPreemptiverenaltransplantation
28 yHaematuria
23 yIntermittenthaematuria
wt
Famiglia 2 e 3
Famiglia 2
Famiglia 3
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Ipotesi: Ereditarietà DigenicaL’eterogeneità clinica nella ATS è dovuta
a varianti polimorfiche con effetto modificatore???
COL4A4COL4A4
12 mutations
COL4A3COL4A38 mutations+
COL4A5COL4A54 mutations
+
12 Famiglie con 12 Famiglie con Ereditarietà Ereditarietà DigenicaDigenica
EuropeanEuropean collaborative collaborative studystudy
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Eredità digenica autosomica con mutazioni concatenate in trans
COL4A3 p.Gly520Arg
60 yESRD
COL4A4 p.Cys1566Trpfs*37
28 yMicro-hematuria
55 yCRFSNHL
MMwt
wtM
Mwt
wt
Mwt wt
wt
rischio di ricorrenza come autosomica recessiva = 25%
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Eredità digenica autosomica con mutazioni concatenate in cis
40 yCRF at 20
COL4A4 p.Ser969X
COL4A3 p.Cys1665Tyr
32 yintermittenthematuria 45 y
hematuriaproteinuriaCRF, SNHL
40 y ESRD
COL4A3 del ex1
COL4A4 del ex1-4
MM
wtwt
wtwt
wtwt
MM
wtwt
wtwt
wtwt
rischio di ricorrenza come
autosomica dominante = 50%
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Eredità digenica mistaautosomica e X-legata
COL4A5 Gly644Asp
COL4A4 Gly692Val
69 yMicro-hematuria
45 yHematuriaproteinuriaSNHL
M
wt
wt
wt
M
wtM
wt
COL4A5 p.Gly953Val COL4A4 c.3817+1G>T
54 yESRD at 44
17 yHematuria
Mwt
wt
M
wt
wt
M
rischio di ricorrenza
complesso da valutare caso per
caso
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Eredità triallelica
COL4A5 p.Gly684Val
COL4A4 c.1623+5G>T
ESRD
Hematuria Hematuria HematuriaHematuria HematuriaProteinuria
HematuriaProteinuria
COL4A4 p.Pro1587Arg
wtM
M
wt
M
wtM
M wt MM
wtM
wtM M
wtM
wtM M
M
M
wtwt
wt
wt
rischio di ricorrenza
complesso da valutare caso per
caso
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M1
M2
M1
M2
M1
M1
50% delle molecole di tripla elica sono difettose
75%delle molecole
di tripla elica sono difettose
Combinazioni di tripla elica con collagene alfa mutato
Normale
Eterozigote
Omozigote
100% delle molecole di tripla elica sono difettose
Doppio Eterozigote
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La forma digenicaha gravità intermedia
tra la dominate e la recessiva
Inheritance AD DI AR
% triple helixdisrupted 50 75 100
ESRD age 56 y 40-44 y 31 y
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sommariosommario 11
ØAbbiamo dimostrato per la prima voltaEderitàEderità DigenicaDigenica
nnellaella sindromesindrome di di AlportAlport
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sommariosommario 22
ØEredità digenicaautosomica con mutazioni concatenate in cisha RR come la forma dominate ma è più grave
? 50%wtMM
wt
wtwtwt
wtwt
MM
wt
ØEredità digenicaautosomica con mutazionconcatenate in trans ha RR come la forma recessiva ma è più lieve
? 25%MMwt
wt
Mwtwt
wtwt
Mwt
wt
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sommariosommario 33
ØEredità triallelica
? 0 ---> 50%; A MX wt
M
wtM
wtwt
X MA M wt
? 0 ---> 50%A MX wt
wt
wtwtwt
wtX MA M wt
ØEreditò digenicanon concatenata mista autosomica/XL
Metà di questi fenotipo grave
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sommariosommario 44
ØAlport digenico ha gravità intermediarispetto a dominate e recessivo
ØL’analisi di tutti e 3 i geni insieme in un pannello next gen è fortemente
raccomandato per stabilire il correttorischio di ricorrrenza e la corretta prognosi
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DIAGNOSI PRENATALE1. Amniocentesi 2. Villocentesi
• presenza del cffDNA nel plasma materno;
• concentrazione progressiva: da 3,4 % al 6,2%;
• origine:1. Placentare;2. Cellule fetali;3. Diffusione passiva.
3. NIPT (Non invasive prenatal test)
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Estrazione DNA da plasma donne in gravidanza
Plasma
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Next Generation Sequencing
c.1721 C>T (p.P574L) nell’esone 25 di COL4A3
CC TT
CT
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Reference Variante EsoneVariante
dopo mappatura
Patogenicità Ref.DNA
madre (%)
DNA padre (%)
COL4A3107351
C>T25
c.1721C>T p.P574L
polimorfismo Slajpah* 100 (46) 0 (41)
Padre
Madre
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Reference Variant3 EsoneVariante
dopo mappatura
Patogenicità Ref.DNA da plasma F
(%)
DNA da plasma R
(%)
COL4A3107351
C>T25
c.1721C>T p.P574L
polimorfismo Slajpah* 95,5 (222) 91,95 (87)
cffDNA
94,5% allele T5,5 % allele C
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fetoaffetto
Impossibile v isualizzare l'immagine. La memoria del computer potrebbe essere insufficiente per aprire l'immagine oppure l'immagine potrebbe essere danneggiata. Riavviare il computer e aprire di nuovo il file. Se v iene visualizzata di nuovo la x rossa, potrebbe essere necessario eliminare l'immagine e inserirla di nuovo.
Impossibile v isualizzare l'immagine. La memoria del computer potrebbe essere insufficiente per aprire l'immagine oppure l'immagine potrebbe essere danneggiata. Riavviare il computer e aprire di nuovo il file. Se v iene visualizzata di nuovo la x rossa, potrebbe essere necessario eliminare l'immagine e inserirla di nuovo.
Cellule delliquidoamniotico
Sorting
Presursorirenali
Differenziazione in podociti
AKSCs
ATS e terapia cellulare
fetosano
Dic 2013Feto con mutazione COL4A5
Feb 2014Feto con mutazione COL4A4
AKSCs
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ATS e terapia cellulareAffected podocyte Control podocyte
RNASeq RNASeq
Comparison
Data analysis
Immunofluorescence & western analysis
Immunofluorescence & western analysis
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Cellule staminali del liquido amniotico
Exome Sequencing
ExomeSequencing II
10 controls
Cell culture
GBSGenetic Biobank of Siena
Cellule staminali dal liquido amniotico
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Ringraziamenti
“Banca di DNA e linee cellulari da pazienti con syndrome di Rett, ritardo mentale X-linked e altre malattie genetiche” nell’ambito del Telethon Network of Genetic Biobanks
Donazione in favore di “Graziano and Marco Laurini”
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Genetica Medica Siena
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COL4A4
COL4A3
COL4A3
COL4A3
COL4A3
COL4A5
NPHS2
SegregationSegregationanalisysanalisys
ClinicalClinical revaluationrevaluation
Ereditarietà DigenicaMutazioni Patogenetiche
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COL4A4
c.2996G>Ap.Gly999Glu
MAF 0.007/16
c.1634G>C p.Gly545Ala
MAF 0.0266/57
Varianti Funzionali?
COL4A41
COL4A32
COL4A51
COL4A5+
COL4A31
COL4A34
Variazioni Polimorfiche