Pregnancy following preimplantation genetic diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
OBJECTIVE
Presentation of a novel case, involving the design and implementation of preimplantation genetic diagnosis (PGD) for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).


METHODS
The disease-causing mutation, c.459C>T (R153C) in exon 4 of the Notch3 gene, was previously identified in the affected father. The family already had a pregnancy termination following prenatal diagnosis and chose to undergo PGD. A PGD protocol was designed to include informative, linked short tandem repeat (STR) markers and an intragenic single nucleotide polymorphism (SNP), coupled to mutation identification. Biopsy was performed at day 3 and blastocysts were transferred on day 5 after fertilization. Standard prenatal diagnosis procedures were employed to confirm the PGD results.


RESULTS
One blastomere was removed at day 3 from each of eight embryos. Detection of the c.459C>TNotch3 mutation, coupled to informative polymorphic markers, unambiguously identified three unaffected embryos. Blastocyst transfer resulted in a singleton pregnancy and subsequent prenatal diagnosis confirmed that the fetus was disease-free.


CONCLUSIONS
Given the dominant, highly penetrant and potentially serious effects of Notch3 mutations, PGD for CADASIL may be considered and implemented as a reproductive option, following proper genetic counseling.
Konialis
C
C
Diagnostic Genetic Center, Athens, Greece. genetic@ath.forthnet.gr
Hagnefelt
B
B
Kokkali
G
G
Pantos
C
C
Pangalos
C
C
D046589:CADASIL / Q000175:diagnosis*; D004252:DNA Mutational Analysis; D019924:Embryo Disposition; D005260:Female; D005307:Fertilization in Vitro; D006580:Genetic Carrier Screening; D006801:Humans; D008297:Male; D011247:Pregnancy; D019836:Preimplantation Diagnosis; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics
C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch