Biallelic COL4A2 Variants Associated With Brain Small Vessel Disease and Brain Malformations - Open Access Short Report

Sep 30, 2026

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Deleterious COL4A2 variants encoding type IV collagen alpha-2 chain drive heterogeneous cerebrovascular and developmental brain malformations. Although dominant variants are well documented, biallelic changes remain rarely reported. Two severe cases were described: case 1, an aborted fetus with cerebral calcifications, hemorrhages, periventricular leukomalacia, and cerebellar disruption; case 2, a 2-year-old girl with neurodevelopmental impairment, cortical malformations, and reduced white matter volume.

LanguageEnglish

CategoryHealthcare

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Pages7

Reading Time18 min

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Abstract

Introduction

COL4A2 and brain small vessel disease

Phenotypic spectrum and recessive model

Methods and variant identification

Case summaries

Case 1

Patient 2

Table 1: Genetic and clinical features

Clinical Genetics SHORT REPORT OPEN ACCESS Biallelic COL4A2 Variants Associated With Brain Small Vessel Disease and Brain Malformations Anees Muhammad1 | Mohammad Sadegh Shams Nosrati2,3 | Alireza Dostmohammadi4 | Reihaneh Khorasanian5 | Mariasavina Severino6 | Morteza Doustmohammadi7 | Francesca Madia3 | Siddharth Srivastava8 | Aisling Quinlan8 | Dario Paladini9 | Federico Zara2,3 | Marcello Scala2,3 1Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan | 2Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy | 3Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy | 4Department of Bioinformatics and Computational Biophysics, Faculty of Biology and Centre for Medical Biotechnology (ZMB), University of Duisburg-Essen, Essen, Germany | 5Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran | 6Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy | 7School of Medicine, Alborz University of Medical Sciences, Karaj, Iran | 8Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA | 9Fetal Medicine and Surgery Unit, Department Mother and Child, IRCCS Istituto Giannina Gaslini, Genova, Italy Correspondence: Marcello Scala ([mscala.md@gmail.com](mscala.md@gmail.com)) Received: 16 April 2025 | Revised: 10 July 2025 | Accepted: 4 August 2025 Funding: The authors received no specific funding for this work. Keywords: brain hemorrhage | brain small vessel disease | COL4A2 | collagen type IV | cortical malformations | recessive variants ABSTRACT Deleterious variants in COL4A2, encoding type IV collagen's alpha-2 chain, cause heterogeneous cerebrovascular and developmental brain malformations. While many dominant variants are known, biallelic changes are rarely reported. We reported two severe cases: Case \#1, an aborted fetus with cerebral calcifications, hemorrhages, periventricular leukomalacia, and cerebellar disruption; and Patient \#2, a 2-year-old girl with neurodevelopmental impairment, cortical malformations (frontal schizencephaly, polymicrogyria), and reduced white matter volume. Exome sequencing identified a homozygous missense COL4A2 variant in case \#1 and compound heterozygous loss-of-function variants (splicing and truncating) in case \#2. All variants were rare and predicted to affect protein stability and function in silico. Our cases reinforce the association between biallelic COL4A2 variants and brain small vessel disease, expanding the recessive COL4A2-related phenotype to include cortical malformations. 1 | Introduction Biallelic variants in COL4A2 (MIM *120090), encoding the alpha-2 chain of type IV collagen, are a major determinant of brain small vessel disease (BSVD) and various brain malformations. COL4A2 is a key basement membrane component maintaining structural integrity across tissues, including the CNS [1–3] . Deleterious COL4A2 variants are associated with diverse brain anomalies, including cerebrovascular abnormalities and cortical development malformations [2, 4] (Table 1) . Recent studies link biallelic COL4A2 variants to severe neurological disorders (e.g., encephalomalacia, cortical atrophy), suggesting a recessive form and enhancing BSVD knowledge [1–3] . This complex condition can cause severe manifestations, including recurrent ischemic and hemorrhagic strokes from fetal development into adulthood [1–3, 5] . Of note, the identification of specific diseasecausing COL4A2 variants impacting glycine residues shows tissue-specific gain/loss-of-function effects. Glycine is crucial for collagen triple helix formation within the Gly-X-Y motif; its substitution by larger amino acids typically disrupts this | Anees Muhammad and Mohammad Sadegh Shams Nosrati equally contributed to this article. | | --- | | This is an open access article under the terms of the Cre

FAQs

What role does COL4A2 play in brain small vessel disease and malformations?

COL4A2 encodes the alpha-2 chain of type IV collagen, a basement-membrane component supporting structural integrity across tissues including the CNS. Deleterious COL4A2 variants are linked to cerebrovascular abnormalities and cortical development malformations.

What genetic findings were reported in the two cases?

Exome sequencing identified a homozygous missense COL4A2 variant in case 1. Patient 2 carried compound heterozygous loss-of-function COL4A2 variants involving splicing and truncating changes.

How did the phenotypes differ between the two reported cases?

Case 1 involved severe fetal findings including cerebral calcifications, hemorrhages, periventricular leukomalacia, and cerebellar disruption. Patient 2 presented after birth with neurodevelopmental impairment, cortical malformations such as frontal schizencephaly and polymicrogyria, and reduced white matter volume.

Sep 30, 2026

Uploaded by dawugda