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The diagnostic yield for <jats:italic>COL4A1\/COL4A2<\/jats:italic> variants is around 20 to 30%, suggesting other mutated genes might be associated with this disease. This study aimed to identify novel genes that cause <jats:italic>COL4A1\/COL4A2<\/jats:italic>\u2010related disorders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole exome sequencing was performed in 2 families with suspected <jats:italic>COL4A1\/COL4A2<\/jats:italic>\u2010related disorders. We validated the role of <jats:italic>COLGALT1<\/jats:italic> variants by constructing a 3\u2010dimensional structural model, evaluating collagen \u03b2 (1\u2010O) galactosyltransferase 1 (ColGalT1) protein expression and ColGalT activity by Western blotting and collagen galactosyltransferase assays, and performing in vitro RNA interference and rescue experiments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Exome sequencing demonstrated biallelic variants in <jats:italic>COLGALT1<\/jats:italic> encoding ColGalT1, which was involved in the post\u2010translational modification of type IV collagen in 2 unrelated patients: c.452 T &gt; G (p.Leu151Arg) and c.1096delG (p.Glu366Argfs*15) in Patient 1, and c.460G &gt; C (p.Ala154Pro) and c.1129G &gt; C (p.Gly377Arg) in Patient 2. Three\u2010dimensional model analysis suggested that p.Leu151Arg and p.Ala154Pro destabilized protein folding, which impaired enzymatic activity. ColGalT1 protein expression and ColGalT activity in Patient 1 were undetectable. RNA interference studies demonstrated that reduced ColGalT1 altered COL4A1 secretion, and rescue experiments showed that mutant <jats:italic>COLGALT1<\/jats:italic> insufficiently restored COL4A1 production in cells compared with wild type.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Biallelic <jats:italic>COLGALT1<\/jats:italic> variants cause cerebral small vessel abnormalities through a common molecular pathogenesis with <jats:italic>COL4A1\/COL4A2<\/jats:italic>\u2010related disorders. Ann Neurol 2018;84:843\u2013853<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.25367","type":"journal-article","created":{"date-parts":[[2018,11,9]],"date-time":"2018-11-09T15:00:50Z","timestamp":1541775650000},"page":"843-853","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Biallelic <i>COLGALT1<\/i> variants are associated with cerebral small vessel disease"],"prefix":"10.1002","volume":"84","author":[{"given":"Satoko","family":"Miyatake","sequence":"first","affiliation":[{"name":"Department of Human Genetics Yokohama City University Graduate School of Medicine  Yokohama Japan"},{"name":"Clinical Genetics Department Yokohama City University Hospital  Yokohama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sacha","family":"Schneeberger","sequence":"additional","affiliation":[{"name":"Institute of Physiology University of Zurich  Zurich 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