Detection of large deletions/duplications in NOTCH3 in CADASIL patients using MLPA. E. M. J. Boon1, M. J. Pont1, D. van Heusden1, M. J. Vollebregt1, P. Lakeman2, M. Elting2, S. A. M. J. Lesnik Oberstein1, H. B. Ginjaar1 1) Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands; 2) Clinical Genetics, VU University Medical Center, Amsterdam, Netherlands.

   Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is an adult-onset cerebrovascular disorder caused by mutations in the extracellular EGF-like domains of the NOTCH3 gene. To date only pathogenic missense mutations and small deletions in NOTCH3 have been described. To investigate whether large deletions or duplications play a role in CADASIL, we designed a multiplex ligation dependent probe amplification (MLPA) kit for all coding exons of NOTCH3. Sixty-one patients with a clinical suspicion of CADASIL were screened using direct sequencing and MLPA. In one patient a compound heterozygous mutation was detected consisting of a missense mutation in exon 13 and a deletion of exon 3-16 of the NOTCH3 gene. These results show that deletions and/ or duplications are probably rare in CADASIL, but can now be detected using our home made MLPA kit and might play a role in the pathogenesis of CADASIL.