Overview…. ADPKD Autosomal Dominant Polycystic Kidney Disease

AS Alport Syndrome

ARPKD Autosomal Recessive Polycystic Kidney Disease

1 caso di consulenza genetica prenatale (se rimane tempo….)

ADPKD End Stage Polycystic Kidneys

ADPKD - Incidence 1/400-1/1000 live births. More common than HD, SCD, CF, DMD, Emophilia combined…

ADPKD

1985 – PKD1 mapped to 16p – 3’HVR/z=25.85

PKD1 gene - chr. 16p (mapped in 1985)

NB Fam.4001!

NB: Pre- and post-test counseling…….

Primogeniti non affetti……………….

Diagnosi prenatale

invasiva

per doppio rischio

mendeliano (amniocentesi,

fetoscopia)

Linkage analysis

Biopsia cutanea - fetoscopia

ADPKD…. Not so simple!

PKD1 linkage-based Prenatal Diagnosis (1994)

….Altre analisi di linkage per tipizzare potenziali donatori di rene……

1994 – PKD1 «framed»! (dopo 9 anni……)

PKD1 mutation detection in ADPKD

Genetic heterogeneity in ADPKD PKD1 (chr 16) PKD2 (chr 4) PKD3 ?

ADPKD studies……

«Ciliopatie»

….Two hits? LOH? (<1% nefroni colpiti) …..Eredità digenica (PKD1+PKD2)? ….Posizione della mutazione (solo x PKD1 – 5’ fenotipo + grave: aneurisma cerebrale) Cilio primario (immobile): sensore stimoli chimici tubulari? Pc1+Pc2 = canale del calcio…..

ADPKD ARPKD

OLIGOHYDRAMNIOS SEQUENCE

Sequenza di Potter (morte per ipoplasia polmonare)

ARPKD Autosomal Recessive PKD

(Human Genome Meeting)

Alport Syndrome – renal GBM disarrangement

Alport syndrome: Ematuria (micro/macro) Proteinuria Sordità n.s Lenticono Uremia terminale (nei M…) ma…….

Forma classica: M>F! Forme AR (AD?): M=F

1987/1989 Salt Lake City, USA Univ.of Utah Dpt. of Genetic Epidemiology & Medical Informatics (Mark Skolnick – David Barker)

Ricerca e caratterizzazione di nuovi polimorfismi (RFLP) da usare come marcatori nella diagnostica della S.Alport

Linkage studies in Alport Syndrome

- 27-29.01.1995 Nicosia (Cipro), Seminar on Inherited Kidney Diseases, Institute of Neurology and Genetics, Limassol e Nicosia, Cipro. 27.1.95, Workshop, "Mutation detection in Alport/part 2".

Jan. 1995 Seminar on Inherited Kidney Diseases

Institute of Neurology and Genetics

Limassol e Nicosia - Cipro

C.Deltas M.Weber

Can’t remember

M.De Marchi

G.Rizzoni (+)

…..Alport Syndrome

K.Tryggvasson

COL4A5 mutation detection in Italian AS families

AS G/P correlations?

Prenatal (fetal) sexing

Sindrome di Alport

- Consanguinity……

- ESRD in females…..

- Different Xs in sisters…..

AS

AS – Diagnostica molecolare 2013

PGD (Preimplantation

Genetic Diagnosis)

1. Biopsia blastomerica (morula) (1-2 cellule, 6-8cc, D3)

2. Biopsia blastocisti (trofoectoderma, 100cc, D5)

3. Analisi del globulo polare

FISH – Based Single-Cell

Preimplantation Sexing (Severe X-linked Conditions, eg Alport S)

AS Consulenze Genetiche

CG prenatale…..

CVS Chorionic Villus Sampling - Villocentesi

Cariotipo fetale su amniociti

….and so what?

Gardner RJM, Sutherland, Chromosome abnormality and genetic counseling OUP, 3° Ed, 2004

TRIPLOIDIA

Legge 194/78

Emofilia A – Inversione IVS 22

Case report

CLINICA

Circolazione fetale

Biopsia blastomerica

Analisi GP2

GP = Globulo polare

PGD