Cerebral small vessel disease due to a unique heterozygous
            <i>HTRA1</i>
            mutation in an African man

Oluwole, Olusegun John; Ibrahim, Hussein; Garozzo, Debora; Hamouda, K. Ben; Hassan, Saly Ismail Mostafa; Hegazy, Ahmed Metwaly; Msaddi, Abdul Karim

doi:10.1212/nxg.0000000000000382

Cited by 11 publications

(16 citation statements)

References 9 publications

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“…WES detected three variants in other known CSVD‐related genes; previously reported variants in HTRA1 and TREX1 and a novel variant in COLGALT1 (Table 1). A heterozygous HTRA1 variant c.847G>A, p.(Gly283Arg) detected in a female patient has previously been reported in a patient with CSVD 16 . Variants affecting function in HTRA1 cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) 17 and autosomal dominant CSVD ( HTRA1 ‐CSVD) characterized by milder clinical features of CARASIL 18‐20 .…”

Section: Resultsmentioning

confidence: 96%

“…A heterozygous HTRA1 variant c.847G>A, p.(Gly283Arg) detected in a female patient has previously been reported in a patient with CSVD. 16 Variants affecting function in HTRA1 cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) 17 and autosomal dominant CSVD (HTRA1-CSVD) characterized by milder clinical features of CARASIL. [18][19][20] The age at onset of the patient carrying the HTRA1 variant c.847G>A was 55 years, and she had no vascular risk factors (Table 2).…”

Section: Sequence Analysesmentioning

confidence: 99%

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Genetic analysis reveals novel variants for vascular cognitive impairment

Mönkäre

Kuuluvainen

Schleutker

et al. 2022

Acta Neuro Scandinavica

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Objectives The genetic background of vascular cognitive impairment (VCI) is poorly understood compared to other dementia disorders. The aim of the study was to investigate the genetic background of VCI in a well‐characterized Finnish cohort. Materials & Methods Whole‐exome sequencing (WES) was applied in 45 Finnish VCI patients. Copy‐number variant (CNV) analysis using a SNP array was performed in 80 VCI patients. This study also examined the prevalence of variants at the miR‐29 binding site of COL4A1 in 73 Finnish VCI patients. Results In 40% (18/45) of the cases, WES detected possibly causative variants in genes associated with cerebral small vessel disease (CSVD) or other neurological or stroke‐related disorders. These variants included HTRA1:c.847G>A p.(Gly283Arg), TREX1:c.1079A>G, p.(Tyr360Cys), COLGALT1:c.1411C>T, p.(Arg471Trp), PRNP: c.713C>T, p.(Pro238Leu), and MTHFR:c.1061G>C, p.(Gly354Ala). Additionally, screening of variants in the 3′UTR of COL4A1 gene in a sub‐cohort of 73 VCI patients identified a novel variant c.*36T>A. CNV analysis showed that pathogenic CNVs are uncommon in VCI. Conclusions These data support pathogenic roles of variants in HTRA1, TREX1 and in the 3′UTR of COL4A1 in CSVD and VCI, and suggest that vascular pathogenic mechanisms are linked to neurodegeneration, expanding the understanding of the genetic background of VCI.

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Section: Resultsmentioning

confidence: 96%

Section: Sequence Analysesmentioning

confidence: 99%

Genetic analysis reveals novel variants for vascular cognitive impairment

Mönkäre

Kuuluvainen

Schleutker

et al. 2022

Acta Neuro Scandinavica

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“…From a literature search performed up to March 1, 2020 in the PUBMED database, 41 probands of HTRA1 -related autosomal dominant CSVD were included from 10 case reports and four original articles (Supplementary Table 1), [ 20 – 33 ] with 22 probands of gene confirmed CARASIL included from 14 case reports and one original article (Supplementary Table 2). [ 2 , 6 – 19 ]…”

Section: Resultsmentioning

confidence: 99%

HTRA1-related autosomal dominant cerebral small vessel disease

Liu

Zhu

Zhou

et al. 2020

Chinese Medical Journal

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Background Homozygous or compound heterozygous mutations in high temperature requirement serine peptidase A1 ( HTRA1 ) gene are responsible for cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Recently, increasing evidence has shown that heterozygous HTRA1 mutations are also associated with cerebral small vessel disease (CSVD) with an autosomal dominant pattern of inheritance. This study was aimed to analyze the genetic and clinical characteristics of HTRA1 -related autosomal dominant CSVD. Methods We presented three new Chinese cases of familial CSVD with heterozygous HTRA1 mutations and reviewed all clinical case reports and articles on HTRA1 -related autosomal dominant CSVD included in PUBMED by the end of March 1, 2020. CARASIL probands with genetic diagnosis reported to date were also reviewed. The genetic and clinical characteristics of HTRA1 -related autosomal dominant CSVD were summarized and analyzed by comparing with CARASIL. Results Forty-four HTRA1 -related autosomal dominant CSVD probands and 22 CARASIL probands were included. Compared with typical CARASIL, HTRA1 -related autosomal dominant probands has a higher proportion of vascular risk factors ( P < 0.001), a later onset age ( P < 0.001), and a relatively slower clinical progression. Alopecia and spondylosis can be observed, but less than those in the typical CARASIL. Thirty-five heterozygous mutations in HTRA1 were reported, most of which were missense mutations. Amino acids located close to amino acids 250–300 were most frequently affected, followed by these located near 150∼200. While amino acids 250∼300 were also the most frequently affected region in CARASIL patients, fewer mutations precede the 200th amino acids were detected, especially in the Kazal-type serine protease domain. Conclusions HTRA1 -related autosomal dominant CSVD is present as a mild phenotype of CARASIL. The trend of regional concentration of mutation sites may be related to the concentration of key sites in these regions which are responsible for pathogenesis of HTRA1 -related autosomal dominant CSVD.

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“…Up to this study, there have been 40 single heterozygous HTRA1 mutations ( Figure 2 ) ( Verdura et al, 2015 ; Ihara, 2016 ; Nozaki et al, 2016 ; Bougea et al, 2017 ; Di Donato et al, 2017 ; Ito et al, 2018 ; Kono et al, 2018 ; Lee et al, 2018 ; Pati and Battisti, 2018 ; Thaler et al, 2018 ; Wu et al, 2018 ; Zhang et al, 2018 ; Favaretto et al, 2019 ; Liu et al, 2020 ; Ohta et al, 2020 ; Oluwole et al, 2020 ; Zhuo et al, 2020 ; Bekircan-Kurt et al, 2021 ; Grigaitė et al, 2021 ; Shang et al, 2021 ; Cao et al, 2022 ). In this study, we collected 95 Chinese CSVD patients and performed genetic analysis in the probands.…”

Section: Discussionmentioning

confidence: 96%

Identified novel heterozygous HTRA1 pathogenic variants in Chinese patients with HTRA1-associated dominant cerebral small vessel disease

et al. 2022

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Background: Homozygous and compound heterozygous mutations in HTRA1 cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Recently, heterozygous pathogenic variants in HTRA1 were described in patients with autosomal dominant cerebral small vessel disease (CSVD). Here, we investigated the genetic variants in a cohort of Chinese patients with CSVD.Methods: A total of 95 Chinese index patients with typical characteristics of CSVD were collected. Whole exome sequencing was performed in the probands, followed by Sanger sequencing. Pathogenicity prediction software was applied to evaluate the pathogenicity of the identified variants.Results: We detected five heterozygous HTRA1 pathogenic variants in five index patients. These pathogenic variants included four known variants (c.543delT, c.854C>T, c.889G>A, and c.824C>T) and one novel variant (c.472 + 1G>A). Among them, c.854C>T, c.824C>T, and c.472 + 1G>A have never been reported in China and c.889G>A was once reported in homozygous but never in heterozygous. Three of them were distributed in exon 4, one in exon 2, and another splicing variant in intron 1. Four out of five probands presented typical features of CARASIL but less severe. The common clinical features included lacunar infarction, cognitive decline, alopecia, and spondylosis. All of them showed leukoencephalopathy, and the main involved cerebral area include periventricular and frontal area, centrum semiovale, thalamus, and corpus callosum. Anterior temporal lobes and external capsule involvement were also observed. Three probands had intracranial microbleeds.Conclusion: Our study expanded the mutation spectrum of HTRA1, especially in Chinese populations, and provided further evidence for “hot regions” in exon 1–4, especially in exon 4, in heterozygous HTRA1 pathogenic variants. Our work further supported that patients with heterozygous HTRA1 pathogenic variants presented with similar but less-severe features than CARASIL but in an autosomal dominantly inherited pattern.

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Cerebral small vessel disease due to a unique heterozygous HTRA1 mutation in an African man

Cited by 11 publications

References 9 publications

Genetic analysis reveals novel variants for vascular cognitive impairment

Genetic analysis reveals novel variants for vascular cognitive impairment

HTRA1-related autosomal dominant cerebral small vessel disease

Identified novel heterozygous HTRA1 pathogenic variants in Chinese patients with HTRA1-associated dominant cerebral small vessel disease

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