{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T22:10:42Z","timestamp":1757542242443,"version":"3.41.2"},"reference-count":64,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T00:00:00Z","timestamp":1660089600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81671075","81501110","81901171","81971029","82071216"],"award-info":[{"award-number":["81671075","81501110","81901171","81971029","82071216"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp; Gen Med"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Biallelic <jats:italic>HTRA1<\/jats:italic> pathogenic variants are associated with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Recent studies have indicated that heterozygous <jats:italic>HTRA1<\/jats:italic> variants are related to autosomal dominant hereditary cerebral small vessel disease (CSVD). However, few studies have assessed heterozygous <jats:italic>HTRA1<\/jats:italic> carriers or the genotype\u2013phenotype correlation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The clinical data of two unrelated Chinese Han families with CSVD were collected. Panel sequencing was used to search for pathogenic genes, Sanger sequencing was used for verification, three\u2010dimensional protein models were constructed, and pathogenicity was analyzed. Published <jats:italic>HTRA1<\/jats:italic>\u2010related phenotypes included in PubMed up to September 2021 were extensively reviewed, and the patients' genetic and clinical characteristics were summarized.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We report a novel heterozygous variant c.920T&gt;C p.L307P in the <jats:italic>HTRA1<\/jats:italic>, whose main clinical and neuroimaging phenotypes are stroke and gait disturbance. We report another patient with the previously reported pathogenic variant <jats:italic>HTRA1<\/jats:italic> c.589C&gt;T p.R197X characterized by early cognitive decline. A literature review indicated that compared with CARASIL, <jats:italic>HTRA1<\/jats:italic>\u2010related autosomal dominant hereditary CSVD has a later onset age, milder clinical symptoms, fewer extraneurological symptoms, and slower progression, indicating a milder CARASIL phenotype. In addition, <jats:italic>HTRA1<\/jats:italic> heterozygous variants were related to a higher proportion of vascular risk factors (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.001) and male sex (<jats:italic>p<\/jats:italic>\u00a0=\u00a0.022).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings broaden the known mutational spectrum and possible clinical phenotype of <jats:italic>HTRA1<\/jats:italic>. Considering the semidominant characteristics of <jats:italic>HTRA1<\/jats:italic>\u2010related phenotypes, we recommend that all members of <jats:italic>HTRA1<\/jats:italic> variant families undergo genetic screening and clinical follow\u2010up if carrying pathogenic variants.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.2032","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T08:11:35Z","timestamp":1660119095000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Report of two pedigrees with heterozygous\u00a0<i>HTRA1<\/i> variants\u2010related cerebral small vessel disease and literature review"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9551-8141","authenticated-orcid":false,"given":"Hui","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Neurology Xiangya Hospital, Central South University  Changsha 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