Diagnosi Prenatale II
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Transcript of Diagnosi Prenatale II
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Diagnosi Prenatale II
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CROMOSOMI MARCATORI(Extra Structurally Abnormal Chromosome)
• Cromosomi di cui non è riconoscibile con le metodiche classiche la provenienza
• Frequenza alla nascita 0.14-0.72/1000• Difficile correlazione genotipo-fenotipo
in diagnosi prenatale• Importante il rilievo della
caratterizzazione molecolare
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CROMOSOMI MARCATORI(Extra Structurally Abnormal Chromosome)
In più del 50% dei casi è oggi possibile fare previsioni fenotipiche corrette:
• Invdup15 (50% ESAC)
• Cromosomi sessuali
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CROMOSOMI MARCATORI(Extra Structurally Abnormal Chromosome)
Amniocentesi paziente di 41 aa
Presenza di un ESAC in tutti i cloni
de novo piccole dimensioni
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CROMOSOMI MARCATORI(Extra Structurally Abnormal Chromosome)
CBG positivo DA/DAPI positivoFISH centromero 15 positiva
Invdup(15)
Definizione del tipo
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CROMOSOMI MARCATORI(Extra Structurally Abnormal Chromosome)
FISH sonde pericentromeriche(D15S11; GABR3) NEGATIVA
Invdup(15) tipo I
Assenza di anomalie del fenotipo
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CROMOSOMI MARCATORI(Extra Structurally Abnormal Chromosome)
Rischio di Disomia Uniparentale 15q11-q13 da origine
postzigotica del marcatoreMaterna Paterna
s. Prader/Willi s. Angelman
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D15S130 D15S165
P F M P F M
Polimorfismi Cromosoma 15 - Tecnica PAGE
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CROMOSOMI MARCATORI(Extra Structurally Abnormal Chromosome)
ESCLUSIONE DISOMIA UNIPARENTALE
CON MARCATORI POLIMORFICI DEL
CROMOSOMA 15
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CROMOSOMI MARCATORI(Extra Structurally Abnormal Chromosome)
Amniocentesi paziente di 35 aa
Presenza di un ESAC
de novo piccole dimensioni
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CROMOSOMI MARCATORI(Extra Structurally Abnormal Chromosome)
CBG positivo DA/DAPI negativoFISH 13,14,15,21,22,X,Y negativa
Rischio alterazioni fenotipiche 5%
Ecografia/Ecocardiografia
Riduzione rischio di 1/3
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CROMOSOMI MARCATORI(Extra Structurally Abnormal Chromosome)
Paziente in gravidanza di 31 aa
Riscontro ecografico NT aumentata
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Toshiba Instruments
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CROMOSOMI MARCATORI(Extra Structurally Abnormal Chromosome)
NT aumentata
rischio aneuploidie
Prelievo villi coriali a 11 settimane
Presenza di ESAC de novo piccole dimensioni, bisatellitato
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CROMOSOMI MARCATORI(Extra Structurally Abnormal Chromosome)
FISH 13,14,15,21,22
Positiva per centromero 22
invdup(22)
Cat/Eye syndrome
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Cat Eye syndrome
Malf. orecchio 86%Malf.anorettali 81%Malf. urogenitali 71%Coloboma occhio 61%
Altre Malformazioni
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Cat Eye syndrome
Malformazioni cardiache62%
di cui 1/3 Anomalie del Ritorno Venoso Polmonare
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Cat Eye syndrome
RITARDO MENTALE ??
Severo 7%Moderato/lieve 47%
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Cat Eye syndrome
Assenza di correlazioni tra estensione/regioni geniche presenti nel cromosoma invdup(22) ed anomalie del fenotipo
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Cat Eye syndrome
CES Tipo I vs CES Tipo II non ha utilità dal punto di vista clinico
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Mosaicismo
• Amniocentesi cellule dall’epiblasto della massa cellulare interna.
• Villocentesi – Coltura a breve termine cellule del trofoblasto.
• Villocentesi – Coltura a lungo termine cellule dello stroma (mesoderma extraembrionario).
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MOSAICISMO
• I Livello: singola cellula
• II Livello: due o più cellule in una flask con la stessa anomalia o singolo clone
• III Livello: due o più cellule in più flask con la stessa anomalia o almeno 2 cloni
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Liquido Amniotico Mosaicismi
• Livello I 2.5-7 %
• Livello II 0.7-1.1 %
• Livello III < 0.2 %
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MOSAICISMO
• PSEUDOMOSAICISMO
• MOSAICISMO CONFINATO ALLA PLACENTA (chorion, amnion)
• MOSAICISMO VERO
La grande maggioranza dei mosaicismi in diagnosi prenatale non si correla ad anomalie fenotipiche fetali
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Mosaicismo trisomia 11
Paziente di 29 anniIndicazione: familiarità s. Down
Cariotipo fetale
46,XX (10 cloni)/47,XX,+11 (1 clone)
Mosaicismo II livello
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Linee Guida work-upModerato: altre 10 cellule dalla flask con anomalia oppure altri 12 cloni.
Flask
• Cr. Sessuale sovra-numerario (SC,MC)
• Trisomia 1,2,3,4,5,6,7, 10,11,16,17,19 (SC, MC)
• 45,X - Monosomie (MC)
• Alt. bilanciate (MC)
• Marcatore (SC)
In situ
• Cr. Sessuale sovra-numerario (SCo,MCo)
• Trisomia 1,2,3,4,5,6,7, 10,11,16,17,19 (SCo, MCo)
• 45,X - Monosomie (SCo, MCo)
• Alt. bilanciate (MCo)
• Marcatore (SCo)
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Mosaicismo trisomia 11
Estensione analisi a 41 cloni
Cariotipo 46,XY (39 cloni)/47,XY,+11 (2 cloni)
Mosaicismo III livello
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Liquido AmnioticoMosaicismi - Livello III
• Conferma sino al 40 % alla cordocentesi ed al 50%(autosomi), 80% (ESAC) e 90% (cr. sessuali) al follow-up
• Tipo di Cromosoma (es. ESAC)
• Utilizzo e limiti della Cordocentesi
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Mosaicismo trisomia 11
• Solo 2 casi in letteratura, con bassa frequenza (2.7 e 5.5%), apparentemente non associati ad alterazioni fenotipiche
• Rischio s. Beckwith-Wiedemann da disomia uniparentale 11
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Meccanismi UDP
• Complementazione gametica
• Recupero dello zigote trisomico
• Duplicazione mitotica
• Errore post-zigotico
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DISOMIA UNIPARENTALE CROMOSOMA 11
Regione 11p15.5 eterodisomia paterna
Alterata espressione di geni da imprinting genomico
2 casi di s. Beckwith-Wiedemann
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DISOMIA UNIPARENTALE CROMOSOMA 11
Polimorfismi Cromosoma 11 - Tecnica PAGE
P F M P F M P F M
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Mosaicismo trisomia 11
• Esame citogenetico:Cariotipo 46,XY (150 metafasi)
Attesa Fenotipo nella norma(follow-up a 24 mesi)
• Screening molecolare con microsatelliti cromosoma 11:
Esclusione UDP
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Mosaicismo trisomia 4
Paziente di 40 anniIndicazione: età
Cariotipo fetale
46,XX (31 cloni)/47,XX,+4 (9 cloni)
Mosaicismo III livello
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Mosaicismo trisomia 4
Solo 3 casi in letteratura:- 2 con bassa frequenza ( 10%),
apparentemente non associati ad alterazioni fenotipiche
- 1 con an. faciali e malf. multiple: ad 1 anno buon follow-up
- Problema UPD
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Mosaicismo trisomia 4Counselling
• Ecografia/Ecocardiografia fetale• Prelievo sangue funicolare per esame
cariotipo ed esclusione UPD
In caso di interruzione:Esame citogenetico su tessuti diversi
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Mosaicismo trisomia 4
• Ipoplasia cerebellare
• Ventricolomegalia borderline
Fetal MRI
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Mosaicismo trisomia 4
CAV completo
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Mosaicismo trisomia 4
• Micrognazia• Ipotelorismo
• Deformità rachide (emivertebre)
• s. atresia esofagea
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Mosaicismo trisomia 4 DISOMIA UNIPARENTALE
Polimorfismi Cromosoma 4 - Tecnica PAGE
D4S243 D4S175
P CF M P CF M
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Diagnosi Malattie DNA
• Numero elevato malattie• Numero elevato di mutazioni (es.
Fibrosi cistica)• Coinvolgimento geni diversi (es. Retinite
pigmentosa)
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Diagnosi Malattie DNA - Prerequisiti
Conoscenza gene/i
• Identificazione della specifica mutazione
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Conoscenza geni
Mendeliane
• Talassemia• Fibrosi cistica• Chorea di Huntington• Distrofia di
Duchenne
Complesse(loci suscettibilità)
• ApoE Alzheimer• 19p13;Xq24 Cefalea• 12q;2q Diabete NID• 3q21 Psoriasi
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Conoscenza geni
8000 malattie
geni noti 30%
(60-70% pazienti)
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Diagnosi Malattie DNA - Prerequisiti
• Conoscenza gene/i implicati
Identificazione della specifica mutazione
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Distrofia Muscolare di Duchenne (DMD)
•Una delle più comuni malattie genetiche dell’infanzia
•Ubiquitariamente diffusa nel mondo
•Colpiti pressochè esclusivamente maschi
•Ereditata come malattia recessiva X-linked
Si manifesta con debolezza muscolare progressiva. I muscoli mostrano una pseudo-ipertrofia, molto evidente nel polpacci: in realtà le fibre muscolari sono rimpiazzate da tessuto grasso/adiposo.
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DIAGNOSI DMD
• Progressiva perdita muscolare e debolezza.
• Ridotta contrazione muscolare.
• Incurvamento della colonna vertebrale.
• Posizionamento doloroso delle articolazioni.
• Difficoltà nei movimenti quotidiani.
livelli CK
Biopsia muscolare
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DIAGNOSI DMD • ANALISI DI DELEZIONE (60% circa dei casi):
– PCR multipla per 26 esoni dei 79 presenti nel gene.– Evidenziazione degli amplificati su gel-elettroforesi– Si diagnostica la delezione quando un prodotto di amplificazione è assente in due separate reazioni di amplificazione.
• ANALISI COMPLETA DEL GENE:– Se non è presente una delezione ampia, allora si ricorre ad uno studio dettagliato del gene mediante tecniche analitiche, sino al sequenziamento diretto.– Una volta trovata la mutazione nel probando, è possibile testare rapidamente qualsiasi soggetto della famiglia a rischio.
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MULTIPLEX P.C.R.
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DIAGNOSI DMD
Paziente di 27 anni in gravidanzacon fratello affetto da DMD
Analisi Fratello
Delezione degli esoni 45-52
Studio familiare di linkage
(Analisi Aplotipo con marcatori intragenici)
Paziente Portatrice della Mutazione
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DIAGNOSI DMD
Paziente 27 anni portatrice in gravidanza
Prelievo dei Villi coriali a 10 settimane
90% dei villi 10% dei villiESTRAZIONE DNA (se possibile)
Analisi molecolare Analisi cariotipocon PCR multipla
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DIAGNOSI DMD
Paziente di 23 anni in gravidanza
con due nipoti deceduti per DMD
Studio familiare di linkage
(Analisi Aplotipo con marcatori intragenici)
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DIAGNOSI DMD
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DIAGNOSI DMD
Paziente non Portatrice dell’Aplotipo associato alla DMD
DIAGNOSI PRENATALE
NON NECESSARIA !!!
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DIAGNOSI DMD
Paziente di 26 anni in gravidanza (13 settimane)con due figli affetti da DMD
Analisi Figli
No Delezione degli esoni
Studio di linkage
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DIAGNOSI DMD
Aplotipo fetale ricombinante
Rischio DMD
per il feto: 14%(62/79 esoni derivano
dal materno normale)
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Fibrosi cistica
1000 variazioni di sequenza
- 83% (>800) mutazioni - 17% polimorfismi
Caucasici 70% F508
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31 Mutazioni
più frequenti
D.R. = 80%
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Caratterizzazione clinica complessa
Ragazza 17 anni
Alla età di 12 anni:
Iridi stellateRitardo mentale s. WilliamsPersonalità cocktail party
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SINDROME DI WILLIAMS
• Dismorfismo faciale (“elfin facies”)
• Ritardo di crescita pre e postnatale
• Deficit cognitivi (alt. integrazione spazio-visiva); lieve RM
• Stenosi aortica sopravalvolare, s. polmonare, difetti di setto, prolasso mitrale
• Ipercalcemia infantile
DELEZIONE 7q11.23 gene ELN