title: ArchetypalNOTCH3mutations frequent in public exome: implications for CADASIL.
abstract: To determine the frequency of distinctive EGFr cysteine alteringNOTCH3mutations in the 60,706 exomes of the exome aggregation consortium (ExAC) database.
  
  
  
  ExAC was queried for mutations distinctive for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), namely mutations leading to a cysteine amino acid change in one of the 34 EGFr domains of NOTCH3. The genotype-phenotype correlation predicted by the ExAC data was tested in an independent cohort of Dutch CADASIL patients using quantified MRI lesions. The Dutch CADASIL registry was probed for paucisymptomatic individuals older than 70 years.
  
  
  
  We identified 206 EGFr cysteine alteringNOTCH3mutations in ExAC, with a total prevalence of 3.4/1000. More than half of the distinct mutations have been previously reported in CADASIL patients. Despite the clear overlap, the mutation distribution in ExAC differs from that in reported CADASIL patients, as mutations in ExAC are predominantly located outside of EGFr domains 1-6. In an independent Dutch CADASIL cohort, we found that patients with a mutation in EGFr domains 7-34 have a significantly lower MRI lesion load than patients with a mutation in EGFr domains 1-6.
  
  
  
  The frequency of EGFr cysteine alteringNOTCH3mutations is 100-fold higher than expected based on estimates of CADASIL prevalence. This challenges the current CADASIL disease paradigm, and suggests that certain mutations may more frequently cause a much milder phenotype, which may even go clinically unrecognized. Our data suggest that individuals with a mutation located in EGFr domains 1-6 are predisposed to the more severe "classical" CADASIL phenotype, whereas individuals with a mutation outside of EGFr domains 1-6 can remain paucisymptomatic well into their eighth decade.
authors.affiliation: Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands; Department of Human Genetics Leiden University Medical Center Leiden The Netherlands.
authors.forename: Julie W
authors.initials: JW
authors.lastname: Rutten
authors.affiliation: Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands; Department of Human Genetics Leiden University Medical Center Leiden The Netherlands.
authors.forename: Hans G
authors.initials: HG
authors.lastname: Dauwerse
authors.affiliation: Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands.
authors.forename: Gido
authors.initials: G
authors.lastname: Gravesteijn
authors.affiliation: Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: van Belzen
authors.affiliation: Department of Radiology Leiden University Medical Center Leiden The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: van der Grond
authors.affiliation: Neurogenetics Unit National Hospital for Neurology and Neurosurgery London United Kingdom.
authors.forename: James M
authors.initials: JM
authors.lastname: Polke
authors.affiliation: Neurogenetics Unit National Hospital for Neurology and Neurosurgery London United Kingdom.
authors.forename: Manuel
authors.initials: M
authors.lastname: Bernal-Quiros
authors.affiliation: Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands.
authors.forename: Saskia A J
authors.initials: SA
authors.lastname: Lesnik Oberstein