Abstract
Our purpose was to develop a next-generation sequencing procedure to search for NOTCH3 and HTRA1 mutations in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) features. A total of 70 patients were sequenced with semiconductor chips in an Ion Torrent Personal Genome Machine. The putative mutations were confirmed through Sanger sequencing of the corresponding patient. Six patients had a typical cysteine-involving NOTCH3 mutation. A new non-reported NOTCH3 variant (p.Pro2178Ser) was found in two patients. One patient was heterozygous for a non-reported HTRA1 variant, likely non-pathogenic (p.Ser139Ala). We found a typical NOTCH3 mutation in 9 % of the patients. None of the patients had HTRA1 variants with likely pathogenic effect. The next-generation sequencing (NGS) procedure here described would facilitate the rapid and cost-effective screening of large cohorts of CADASIL patients.
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References
Bianchi S, Zicari E, Carluccio A et al (2015) CADASIL in central Italy: a retrospective clinical and genetic study in 229 patients. J Neurol 62:134–141
Chabriat H, Vahedi K, Iba-Zizen MT et al (1995) Clinical spectrum of CADASIL: a study of 7 families. Lancet 346:934–939
Choi JC, Lee KH, Song SK, Lee JS, Kang SY, Kang JH (2013) Screening for NOTCH3 gene mutations among 151 consecutive Korean patients with acute ischemic stroke. J Stroke Cerebrovasc Dis 22:608–614
Coto E, Menéndez M, Navarro R et al (2006) A new de novo Notch3 mutation causing CADASIL. Eur J Neurol 2006(13):628–631
Dong Y, Hassan A, Zhang Z et al (2003) Yield of screening for CADASIL mutations in lacunar stroke and leukoaraiosis. Stroke 34:203–206
Dubroca C, Lacombe P, Domenga V et al (2005) Impaired vascular mechanotransduction in a transgenic mouse model of CADASIL. Stroke 36:113–117
Gómez J, Reguero JR, Morís C et al (2014) Mutation analysis of the main hypertrophic cardiomyopathy genes using multiplex amplification and semiconductor next-generation sequencing. Circ J 78:2963–71
Hara K, Shiga A, Fukutake T et al (2009) Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease. N Engl J Med 360:1729–1739
Haritunians T, Chow T, De Lange RP et al (2005) Functional analysis of a recurrent missense mutation in Notch3 in CADASIL. J Neurol Neurosurg Psychiatry 76:1242–1248
Joutel A, Corpechot C, Ducros A et al (1996) Notch3 mutations in CADASIL, an hereditary adult-onset condition causing stroke and dementia. Nature 383:707–710
Joutel A, Vahedi K, Corpechot C et al (1997) Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 350:1511–1515
Kalaria RN, Viitanen M, Kalimo H et al (2004) The pathogenesis of CADASIL: an update. J Neurol Sci 226:35–39
Kalimo H, Ruchoux MM, Viitanen M, Kalaria RN (2002) CADASIL: a common form of hereditary arteriopathy causing brain infarcts and dementia. Brain Pathol 12:371–384
Miao Q, Paloneva T, Tuominen S et al (2004) Fibrosis and stenosis of the long penetrating cerebral arteries: the cause of the white mater pathology in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Brain Pathol 14:358–364
Tavira B, Gómez J, Santos F, Gil H, Alvarez V, Coto E (2014) A labor- and cost-effective non-optical semiconductor (Ion Torrent) next-generation sequencing of the SLC12A3 and CLCNKA/B genes in Gitelman’s syndrome patients. J Hum Genet 59:376–380
Tikka S, Baumann M, Siitonen M et al (2014) CADASIL and CARASIL. Brain Pathol 2014(24):525–244
Acknowledgments
This work was supported by a Grant FIS-Instituto Salud Carlos III-European FEDER funds. J.G. was the recipient of an educational grant from Asociación Parkinson Asturias.
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The authors declare no conflict of interest.
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Angela Fernández and Juan Gómez contributed equally to this work.
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Fernández, A., Gómez, J., Alonso, B. et al. A Next-Generation Sequencing of the NOTCH3 and HTRA1 Genes in CADASIL Patients. J Mol Neurosci 56, 613–616 (2015). https://doi.org/10.1007/s12031-015-0560-3
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DOI: https://doi.org/10.1007/s12031-015-0560-3