Clinicoradiographic and genetic features of cerebral small vessel disease indicate variability in mode of inheritance for monoallelic HTRA1 variants

Abstract Background Biallelic pathogenic variants in HTRA1 cause CARASIL. More recently, monoallelic variants have been associated with the autosomal dominant disorder CADASIL2 but not all carriers develop disease manifestations. We describe the clinicoradiologic and mutation spectrum of four new CA...

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Autores principales:	Karthik Muthusamy, Alejandro Ferrer, Eric W. Klee, Klaas J. Wierenga, Ralitza H. Gavrilova
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	CADASIL2 cerebral small vessel disease HTRA1 leukoencephalopathy stroke Genetics QH426-470
Acceso en línea:	https://doaj.org/article/2962f7d32b1f48f1a28dc54b74eb2e4e
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spelling	oai:doaj.org-article:2962f7d32b1f48f1a28dc54b74eb2e4e2021-11-10T16:39:24ZClinicoradiographic and genetic features of cerebral small vessel disease indicate variability in mode of inheritance for monoallelic HTRA1 variants2324-926910.1002/mgg3.1799https://doaj.org/article/2962f7d32b1f48f1a28dc54b74eb2e4e2021-10-01T00:00:00Zhttps://doi.org/10.1002/mgg3.1799https://doaj.org/toc/2324-9269Abstract Background Biallelic pathogenic variants in HTRA1 cause CARASIL. More recently, monoallelic variants have been associated with the autosomal dominant disorder CADASIL2 but not all carriers develop disease manifestations. We describe the clinicoradiologic and mutation spectrum of four new CADASIL2 individuals. Methods Medical records at Mayo Clinic between 2013 and 2020 were retrospectively reviewed to identify patients with cerebral small vessel disease related to monoallelic HTRA1 variants. Results Four patients met the study inclusion criteria for cerebral small vessel disease related to HTRA1 monoallelic variants. The mean age at onset of first clinical stroke was 51.25 years (range 41–64 years). The mean disease duration was 6.5 years (range 4–12). All individuals had recurrent strokes within the duration of follow‐up with a mean number of strokes per patient being 5.5 (range 2–12). Three individuals had leukoencephalopathy with brain stem involvement. Microhemorrhages were seen on brain MRI in three patients. HTRA1 monoallelic variants identified in our cohort were missense variants in three patients and a novel frameshift variation in one patient. Interestingly, two of these missense variants were previously reported in an autosomal recessive pattern of inheritance and here are associated with a dominant effect. Conclusions Clinicoradiologic characteristics of heterozygous HTRA1‐related CSVD may overlap with sporadic CSVD. Heterozygous HTRA1 variants can contribute to dominant or recessive disease mechanisms.Karthik MuthusamyAlejandro FerrerEric W. KleeKlaas J. WierengaRalitza H. GavrilovaWileyarticleCADASIL2cerebral small vessel diseaseHTRA1leukoencephalopathystrokeGeneticsQH426-470ENMolecular Genetics & Genomic Medicine, Vol 9, Iss 10, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	CADASIL2 cerebral small vessel disease HTRA1 leukoencephalopathy stroke Genetics QH426-470
spellingShingle	CADASIL2 cerebral small vessel disease HTRA1 leukoencephalopathy stroke Genetics QH426-470 Karthik Muthusamy Alejandro Ferrer Eric W. Klee Klaas J. Wierenga Ralitza H. Gavrilova Clinicoradiographic and genetic features of cerebral small vessel disease indicate variability in mode of inheritance for monoallelic HTRA1 variants
description	Abstract Background Biallelic pathogenic variants in HTRA1 cause CARASIL. More recently, monoallelic variants have been associated with the autosomal dominant disorder CADASIL2 but not all carriers develop disease manifestations. We describe the clinicoradiologic and mutation spectrum of four new CADASIL2 individuals. Methods Medical records at Mayo Clinic between 2013 and 2020 were retrospectively reviewed to identify patients with cerebral small vessel disease related to monoallelic HTRA1 variants. Results Four patients met the study inclusion criteria for cerebral small vessel disease related to HTRA1 monoallelic variants. The mean age at onset of first clinical stroke was 51.25 years (range 41–64 years). The mean disease duration was 6.5 years (range 4–12). All individuals had recurrent strokes within the duration of follow‐up with a mean number of strokes per patient being 5.5 (range 2–12). Three individuals had leukoencephalopathy with brain stem involvement. Microhemorrhages were seen on brain MRI in three patients. HTRA1 monoallelic variants identified in our cohort were missense variants in three patients and a novel frameshift variation in one patient. Interestingly, two of these missense variants were previously reported in an autosomal recessive pattern of inheritance and here are associated with a dominant effect. Conclusions Clinicoradiologic characteristics of heterozygous HTRA1‐related CSVD may overlap with sporadic CSVD. Heterozygous HTRA1 variants can contribute to dominant or recessive disease mechanisms.
format	article
author	Karthik Muthusamy Alejandro Ferrer Eric W. Klee Klaas J. Wierenga Ralitza H. Gavrilova
author_facet	Karthik Muthusamy Alejandro Ferrer Eric W. Klee Klaas J. Wierenga Ralitza H. Gavrilova
author_sort	Karthik Muthusamy
title	Clinicoradiographic and genetic features of cerebral small vessel disease indicate variability in mode of inheritance for monoallelic HTRA1 variants
title_short	Clinicoradiographic and genetic features of cerebral small vessel disease indicate variability in mode of inheritance for monoallelic HTRA1 variants
title_full	Clinicoradiographic and genetic features of cerebral small vessel disease indicate variability in mode of inheritance for monoallelic HTRA1 variants
title_fullStr	Clinicoradiographic and genetic features of cerebral small vessel disease indicate variability in mode of inheritance for monoallelic HTRA1 variants
title_full_unstemmed	Clinicoradiographic and genetic features of cerebral small vessel disease indicate variability in mode of inheritance for monoallelic HTRA1 variants
title_sort	clinicoradiographic and genetic features of cerebral small vessel disease indicate variability in mode of inheritance for monoallelic htra1 variants
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/2962f7d32b1f48f1a28dc54b74eb2e4e
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Clinicoradiographic and genetic features of cerebral small vessel disease indicate variability in mode of inheritance for monoallelic HTRA1 variants

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