COL4A1COL4A2: Study of Pathological Conditions Involving Multiple Organs Caused by Mutations in the COL4A1 and COL4A2 Genes

Study of the Familial Phenotype Associated With Mutations in the COL4A1 and COL4A2 Genes

This observational and diagnostic study aims to better understand the clinical features and biological mechanisms associated with mutations in the COL4A1 and COL4A2 genes, which are known to cause a rare inherited small-vessel disease affecting the brain and other organs. These mutations can lead to a wide range of symptoms involving the brain, eyes, heart, blood vessels, kidneys, and muscles, and affected individuals within the same family may show very different clinical manifestations.

The study will systematically collect clinical and diagnostic information from individuals with confirmed COL4A1/COL4A2 mutations and their first-degree family members, including both affected and unaffected relatives. Family members who carry, or may carry, the mutation will be offered non-invasive eye and heart examinations to detect early or previously unrecognized organ involvement.

In addition, blood samples will be analyzed to study the activity of specific enzymes called matrix metalloproteinases (MMP2 and MMP9), which are thought to play a role in blood vessel damage in this condition. By linking genetic findings, clinical features, and laboratory data, the study seeks to clarify how these mutations cause disease and to identify early signs of organ involvement.

The overall goal of the study is to improve early diagnosis, guide the development of routine multi-organ screening strategies for affected individuals and families, and support future research toward targeted treatments.

Study Overview

• Status: Recruiting
• Conditions: COL4A1-Related Brain Small Vessel Disease With Haemorrhage; COL4A1\2
• Intervention / Treatment: Diagnostic test: Ophtalmological and cardiological screening

Detailed Description

This is an observational, prospective cohort study designed to characterize the clinical spectrum and underlying biological mechanisms associated with pathogenic or likely pathogenic variants in the COL4A1 and COL4A2 genes. These genes encode type IV collagen, a key structural component of basement membranes, and their alteration is associated with a rare autosomal dominant small-vessel disease with variable multi-organ involvement.

Individuals with a confirmed COL4A1/COL4A2 mutation identified through clinical genetic testing will be invited to participate together with their first-degree family members. Adult relatives who are confirmed carriers or are suspected carriers of the same mutation will be included in the diagnostic component of the study. Adult non-carrier relatives will serve as controls for selected laboratory analyses.

Participants will complete a structured questionnaire collecting standardized information on neurological, ophthalmological, cardiovascular, renal, muscular, and other systemic manifestations. Carrier or suspected carrier relatives will be offered non-invasive diagnostic screening, including ophthalmological assessments (anterior segment photography and optical coherence tomography) and cardiological evaluations (resting electrocardiogram, ambulatory ECG monitoring, and echocardiography), performed within routine clinical care settings.

A blood sample will be collected from affected individuals and adult non-carrier relatives. Plasma will be stored and analyzed to assess the activity of matrix metalloproteinases MMP2 and MMP9 using established laboratory techniques. These analyses aim to explore molecular pathways potentially involved in vascular and tissue damage associated with COL4A1/COL4A2 variants.

The study does not include a scheduled follow-up; data are collected at a single time point per participant. Results will be analyzed using descriptive and exploratory statistical methods to evaluate the prevalence and pattern of multi-organ involvement and to explore associations between genetic variants, clinical features, and laboratory findings.

The knowledge gained from this study is intended to support improved clinical characterization of COL4A1/COL4A2-related disease, inform the development of structured multi-organ screening strategies, and provide a foundation for future therapeutic research

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: SIMONA Balestrini, Md, PhD; Phone Number: +390555662719; Email: simona.balestrini@meyer.it

Study Locations

• Italy
  • FI
    • Florence, FI, Italy, 50139
      • Recruiting
      • Meyer Children's Hospital IRCSS
      • Contact: Simona Balestrini; Phone Number: 3713764672; Email: simona.balestrini@meyer.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Individuals (pediatric or adult) with a pathogenic or likely pathogenic mutation in the COL4A1 or COL4A2 genes and a clinical phenotype consistent with small vessel disease.
• Adult first-degree family members (parents, siblings, or children) who are confirmed carriers or suspected carriers of the same COL4A1/COL4A2 mutation.
• Adult first-degree family members who are non-carriers of the pathogenic mutation and who agree to provide a blood sample to be used as controls for laboratory analyses.
• Ability to provide written informed consent; for minors, consent provided by a parent or legal guardian.

Exclusion Criteria:

• Refusal or inability to provide informed consent.
• Individuals who do not meet the inclusion criteria above.
• Any condition that, in the opinion of the investigators, would preclude participation in study procedures or reliable data collection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: COL4A1/2 variant carriers; This is a single-arm observational study with defined participant subgroups. No experimental interventions are administered. Participants include individuals with pathogenic or likely pathogenic COL4A1 or COL4A2 variants and their first-degree family members. All participants undergo observational data collection through a structured clinical questionnaire. Adult family members who are confirmed or suspected carriers of the mutation are additionally offered non-invasive diagnostic assessments, including ophthalmological examinations (anterior segment photography and optical coherence tomography) and cardiological evaluations (resting ECG, ambulatory ECG, and echocardiography), performed as part of routine clinical care. A blood sample is collected from affected individuals and adult non-carrier relatives for exploratory laboratory analyses of matrix metalloproteinase (MMP2/MMP9) activity. Non-carrier relatives serve as a biological control group for these analyses.

Diagnostic test: Ophtalmological and cardiological screening; Participants who are confirmed or suspected carriers of a COL4A1 or COL4A2 pathogenic variant are offered non-invasive diagnostic ophthalmological and cardiological screening to assess potential organ involvement associated with the genetic condition. The ophthalmological screening includes anterior segment photography of both eyes and optical coherence tomography (OCT) to evaluate retinal structure, macular thickness, and retinal nerve fiber layer. The cardiological screening includes a resting electrocardiogram (ECG), ambulatory ECG monitoring, and transthoracic echocardiography to assess heart rhythm, conduction, and cardiac structure and function. These procedures are performed within routine clinical care settings and are used solely for observational and diagnostic purposes; no therapeutic intervention is administered as part of the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Prevalence and pattern of multi-organ involvement	Single time point at study enrollment (baseline assessment)

Collaborators and Investigators

• Sponsor: Meyer Children's Hospital IRCCS

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2021
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: January 21, 2026
• First Submitted That Met QC Criteria: January 21, 2026
• First Posted (Actual): January 29, 2026

Study Record Updates

• Last Update Posted (Actual): January 30, 2026
• Last Update Submitted That Met QC Criteria: January 28, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: COL4A1COL4A2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No