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Abstract

COL4A1- and COL4A2-Related Disorders—Clinical Features, Diagnostic Guidelines, and Management †

by
Diana Tambala
1,2,‡,
Rachel Vassar
3,‡,
John Snow
1,4,
Simona Balestrini
5,6,
Anna Bersano
7,
Stéphanie Guey
8,
Eleonora Bonaventura
9,
Sabrina Signorini
10,11,
Stefano Sartori
12,
Enrico Bertini
13,
Davide Tonduti
9,14,
Cecilia Parazzini
15,
Marina Macchiaiolo
16,
Maria Federica Pelizza
12,
Anna Pichiecchio
17,18,
Laura Massella
19,
Thibault Coste
20,21,
Simona Orcesi
11,17,
Davide Politano
11,17,
Giacomo Bacci
22,
Elisa Marziali
22,
Helene Dollfus
23,
Anna Mandelli
24,
Marcello Chinali
25,
Emmanuelle Plaisier
26,
Paolo Simioni
27,
Raffaella Colombati
28,
Renzo Guerrini
5,6,
Elisabeth Tournier-Lasserve
29,30,
Douglas B. Gould
31,32,33,34 and
Patricia L. Musolino
1,2,4,*add Show full author list remove Hide full author list
1
Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
2
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
3
Department of Neurology, University of California San Francisco, San Francisco, CA 94158, USA
4
Harvard Medical School, Boston, MA 02115, USA
5
Neuroscience and Human Genetics Department, Meyer Children’s Hospital IRCSS, 50139 Florence, Italy
6
Neuroscience, Psychology, Drug Area and Child Health Department, University of Florence, 50121 Florence, Italy
7
Cerebrovascular Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
8
French Reference Center for Rare Vascular Diseases of the Brain and the Eye, Lariboisière Hospital, 75010 Paris, France
9
Unit of Pediatric Neurology, C.O.A.L.A (Center for Diagnosis and Treatment of Leukodystrophies), V. Buzzi Children’s Hospital, 20154 Milan, Italy
10
Developmental Neuro-Ophthalmology Unit, Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, 27100 Pavia, Italy
11
Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, 27100 Pavia, Italy
12
Pediatric Neurology and Neurophysiology Unit, Department of Women’s and Children’s Health, University of Padua, 35128 Padua, Italy
13
Research Unit of Neuromuscular Disease, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
14
Department of Biomedical and Clinical Sciences, University of Milan, 20157 Milan, Italy
15
Pediatric Radiology and Neuroradiology Department, Children’s Hospital V. Buzzi, 20154 Milan, Italy
16
Rare Diseases and Medical Genetics Unit, University-Hospital Pediatric Department (DPUO), Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
17
Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy
18
Neuroradiology Department, IRCCS Mondino Foundation, 27100 Pavia, Italy
19
Division of Nephrology, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
20
Department of Neurovascular Genetics, AP-HP, 75010 Paris, France
21
Inserm 1141 Neurodiderot, Université Paris Cité, 75019 Paris, France
22
Pediatric Ophthalmology Unit, Meyer Children’s Hospital IRCCS, University of Florence, 50139 Florence, Italy
23
Medical Genetics Department, Strasbourg University Hospital (HUS), 67085 Strasbourg cedex, France
24
Department of Pediatric Anesthesiology and Reanimation, “Vittore Buzzi” Children’s Hospital, 20154 Milan, Italy
25
Echocardiography Laboratory of the Department of Pediatric Cardiology and Cardiac Surgery, Pediatric Hospital Bambino Gesù, 00165 Roma, Italy
26
Department of Nephrology, Association pour l’Utilisation du Rein Artificiel Paris Plaisance, 75014 Paris, France
27
General Internal Medicine and Thrombotic and Hemorrhagic Unit, Department of Medicine, University Hospital of Padova, 35128 Padova, Italy
28
Pediatric Oncology Hematology Unit, Department of Women’s and Children’s Health, University of Padua, 35128 Padua, Italy
29
Department of Neurovascular Molecular Genetics AP-HP, Saint-Louis Hospital, 75010 Paris, France
30
Reference Center for Rare Vascular Diseases of the Central Nervous System and the Retina (CERVCO), APHP Lariboisière Hospital, 75010 Paris, France
31
Departments of Ophthalmology and Anatomy, University of California San Francisco, San Francisco, CA 94158, USA
32
Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94158, USA
33
Aging Research Institute, University of California San Francisco, San Francisco, CA 94158, USA
34
Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94158, USA
 
add Show full affiliation list
 
remove Hide full affiliation list
*
Author to whom correspondence should be addressed.
†
Presented at the 2nd COL4A1-A2 International Conference, Rome, Italy, 10 February 2025.
‡
These authors contributed equally to this work.
Proceedings 2025, 120(1), 12; https://doi.org/10.3390/proceedings2025120012
Published: 28 July 2025
Versions Notes

Background: The COL4A1 and COL4A2 genes encode the alpha-1 and alpha-2 chains of type IV collagen, which are fundamental components of the basement membrane, playing key roles in both structural support and cellular regulation [1]. Mutations in these genes result in a range of conditions collectively referred to as COL4A1/A2-related disorders. While typically inherited in an autosomal dominant pattern, autosomal recessive cases have also been reported [2,3,4,5]. These disorders can affect multiple organ systems—including the brain, eyes, kidneys, and more—with significant variability in presentation, making diagnosis and treatment particularly challenging [6,7].
Methods: An adapted eDelphi methodology was employed to reach expert consensus among specialists from various medical fields on the clinical assessment and management of COL4A1/A2-related disorders. Agreement on recommendations was defined as 70% or greater.
Results: Consensus was successfully achieved on clinical guidelines for the evaluation and management of COL4A1/A2-related conditions. These recommendations were shaped through extensive discussions at the conference, where physicians shared their expertise and experience in the medical care of affected individuals. This collaborative exchange guided and informed the consensus and laid the foundation for these guidelines. As a result, genetic counseling and testing are recommended for individuals with symptoms consistent with COL4A1/A2-related disorders, as well as for family members who may be at risk. Comprehensive evaluation—including neurological and ophthalmologic imaging, along with cardiovascular and renal monitoring—is advised to ensure appropriate diagnosis, surveillance, and management.
Conclusions: Due to the rarity and diverse manifestations of these disorders, effective care requires coordinated, multidisciplinary management guided by emerging knowledge of their molecular basis [8]. Ongoing research is crucial to improve the understanding of genotype–phenotype correlations and modifying factors, and participation in clinical studies is strongly encouraged to advance therapies.

Author Contributions

Study conception and design: D.T. (Diana Tambala), R.V., J.S., S.B., A.B., S.G., E.B. (Eleonora Bonaventura), S.S. (Sabrina Signorini), S.S. (Stefano Sartori), E.B. (Enrico Bertini), D.T. (Davide Tonduti), C.P., M.M., M.F.P., A.P., L.M., T.C., S.O., D.P., G.B., E.M., H.D., A.M., M.C., E.P., P.S., R.C., R.G., E.T.-L., D.B.G. and P.L.M.; Data collection: D.T. (Diana Tambala) and R.V.; Analysis and interpretation of results: D.T. (Diana Tambala) and R.V.; Draft manuscript preparation: D.T. (Diana Tambala), R.V., J.S., D.B.G. and P.L.M.; Approval of the final version of the manuscript: D.T. (Diana Tambala), R.V., J.S., S.B., A.B., S.G., E.B. (Eleonora Bonaventura), S.S. (Sabrina Signorini), S.S. (Stefano Sartori), E.B. (Enrico Bertini), D.T. (Davide Tonduti), C.P., M.M., M.F.P., A.P., L.M., T.C., S.O., D.P., G.B., E.M., H.D., A.M., M.C., E.P., P.S., R.C., R.G., E.T.-L., D.B.G. and P.L.M. All authors have read and agreed to the published version of the manuscript.

Funding

This manuscript received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Institutional Review Board Statement

IRB approval was not sought as the study involved expert panel discussions and surveys conducted under professional settings without patient data.

Informed Consent Statement

Participation in this study was voluntary, and informed consent was implied by completion of the anonymous online survey.

Data Availability Statement

Data from the individual responses for the modified Delphi consensus will be made available upon reasonable request. The remainder of the content of the manuscript is based on established clinical practice information, expert consensus, and a literature review of cited references.

Conflicts of Interest

No potential conflicts of interest were reported by the authors.

References

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Share and Cite

MDPI and ACS Style

Tambala, D.; Vassar, R.; Snow, J.; Balestrini, S.; Bersano, A.; Guey, S.; Bonaventura, E.; Signorini, S.; Sartori, S.; Bertini, E.; et al. COL4A1- and COL4A2-Related Disorders—Clinical Features, Diagnostic Guidelines, and Management. Proceedings 2025, 120, 12. https://doi.org/10.3390/proceedings2025120012

AMA Style

Tambala D, Vassar R, Snow J, Balestrini S, Bersano A, Guey S, Bonaventura E, Signorini S, Sartori S, Bertini E, et al. COL4A1- and COL4A2-Related Disorders—Clinical Features, Diagnostic Guidelines, and Management. Proceedings. 2025; 120(1):12. https://doi.org/10.3390/proceedings2025120012

Chicago/Turabian Style

Tambala, Diana, Rachel Vassar, John Snow, Simona Balestrini, Anna Bersano, Stéphanie Guey, Eleonora Bonaventura, Sabrina Signorini, Stefano Sartori, Enrico Bertini, and et al. 2025. "COL4A1- and COL4A2-Related Disorders—Clinical Features, Diagnostic Guidelines, and Management" Proceedings 120, no. 1: 12. https://doi.org/10.3390/proceedings2025120012

APA Style

Tambala, D., Vassar, R., Snow, J., Balestrini, S., Bersano, A., Guey, S., Bonaventura, E., Signorini, S., Sartori, S., Bertini, E., Tonduti, D., Parazzini, C., Macchiaiolo, M., Pelizza, M. F., Pichiecchio, A., Massella, L., Coste, T., Orcesi, S., Politano, D., ... Musolino, P. L. (2025). COL4A1- and COL4A2-Related Disorders—Clinical Features, Diagnostic Guidelines, and Management. Proceedings, 120(1), 12. https://doi.org/10.3390/proceedings2025120012

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