Biallelic Variants in theCOLGALT1Gene Causes Severe Congenital Porencephaly A Case Report

Objective We describe a third patient with brain small vessel disease 3 (BSVD3), being the first with a homozygous essential splice site variant in theCOLGALT1 gene, with a more severe phenotype than the 2 children reported earlier. Methods Analysis of whole exome sequencing (WES) data of the child and parents was performed. We validated the missplicing of the homozygous variant using reverse transcription PCR and Sanger sequencing of the mRNA in a lymphocyte culture. Results The patient presented antenatally with porencephaly on ultrasound and MRI. Postnatally, he showed a severe developmental delay, refractory epilepsy, spastic quadriplegia, and a progressive hydrocephalus. WES revealed a homozygous canonical splice site variant NM_ 024656.3:c.625-2A>C. PCR and Sanger sequencing of the mRNA demonstrated that 2 cryptic splice sites are activated, causing a frameshift in the major transcript and in-frame deletion in a minor transcript. Conclusions We report a third patient with biallelic pathogenic variants in COLGALT1, confirming the role of this gene in autosomal recessive BSVD3. From the Department of Neurology (M.W.A.T., R.J.V., J.N.), Maastricht University Medical Center+; Department of Human Genetics (E.-J.-K., M.P.), Radboud University Medical Center, Nijmegen; and Department of Human Genetics (S.C.E.H.S.), and University Eye Clinic Maastricht (N.J.C.B.), Maastricht University Medical Center+, the Netherlands. Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article. The Article Processing Charge was funded by the authors. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1 Brain small vessel disease 1 (BSVD1, OMIM#175780) and 2 (BSVD2, OMIM#614483) are autosomal dominant syndromes associated with, respectively, COL4A1 and COL4A2 variants. These variants can cause a broad spectrum of cerebrovascular, renal, ocular, cardiac, and muscular abnormalities. BSVD is caused by a defect in the α1α1α2 trimer made from the proteins Col4a1 and Col4a2 that forms type IV collagen. Because of inappropriate 3D-construction, there is an instability of the basal membrane in arteries, creating a high vulnerability to cerebrovascular incidents. This leads to the characterizing symptoms of BSVD: porencephalic cysts, periventricular leukoencephalopathy, lacunar infarcts, and cerebral microbleeds and calcifications. Variants in the COLGALT1 gene cause brain small vessel disease 3 (BSVD3, OMIM #618360). The COLGALT1 gene encodes the collagen beta galactosyltransferase 1 (ColGalT1) protein. ColGalT1 initiates glycosylation of CoL4a1 (and perhaps Col4a2), an important step in the formation of the triple helix of collagen IV. Miyatake et al. described 2 patients with a compound heterozygous variant in the COLGALT1 gene and showed that reduced ColGalT1 activity results in decreased CoL4a1 protein, thereby resulting in reduced secretion of type IV collagen. Here, we describe a third patient with BSVD3 and the first with a homozygous variant in the COLGALT1 gene.