Postpartum Presentation of a Variant of Uncertain Significance in COL3A1: A Case Report

Abstract

Objective

Vascular Ehlers–Danlos syndrome (vEDS) is a rare inherited connective tissue disorder associated with significant maternal morbidity and mortality during pregnancy. Conflicting recommendations exist for management, particularly in patients with variant of uncertain significance (VUS).

Study Design

We present a 39-year-old G2P1011 with a strong family history suggestive of vEDS who experienced an uncomplicated vaginal delivery followed by a large retroperitoneal hematoma requiring interventional radiology embolization and intensive care management for a postprocedural femoral pseudoaneurysm.

Results

Postpartum genetic testing revealed a heterozygous VUS in COL3A1 (c.1297G>A [p.Glu433Lys]).

Conclusion

This case illustrates the challenges of counseling and managing pregnancy in patients with suspected vEDS and VUS, highlighting the importance of risk mitigation strategies, multidisciplinary care, and nuanced interpretation of genetic results.

Key Points

• Risk stratification imaging: Whole-body vascular imaging beyond echocardiography may identify silent arterial lesions.

• Variant reclassification: Reporting pregnancy phenotypes linked to VUS in databases (ClinVar, LOVD) can accelerate variant reclassification and improve counseling.

• Structured counseling for uncertainty: Use a systematic approach when counseling patients with both a suspicious phenotype and a VUS, incorporating multidisciplinary perspectives and clearly communicating knowns and unknowns.

Keywords

vascular Ehlers–Danlos syndrome - COL3A1 variant - postpartum hemorrhage - retroperitoneal hematoma - case report

Publikationsverlauf

Eingereicht: 12. September 2025

Angenommen: 13. Oktober 2025

Artikel online veröffentlicht:
31. Oktober 2025

• References

• 1 Kang J, Hanif M, Mirza E, Jaleel S. Ehlers-Danlos syndrome in pregnancy: a review. Eur J Obstet Gynecol Reprod Biol 2020; 255: 118-123
• 2 Malfait F, Francomano C, Byers P. et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet 2017; 175 (01) 8-26
• 3 Spiegel E, Nicholls-Dempsey L, Czuzoj-Shulman N, Abenhaim HA. Pregnancy outcomes in women with Ehlers-Danlos syndrome. J Matern Fetal Neonatal Med 2022; 35 (09) 1683-1689
• 4 Murray ML, Pepin M, Peterson S, Byers PH. Pregnancy-related deaths and complications in women with vascular Ehlers-Danlos syndrome. Genet Med 2014; 16 (12) 874-880
• 5 Wright GL, Wen T, Engel DJ. et al. Delivery outcomes and postpartum readmissions associated with Ehlers-Danlos syndrome. Am J Perinatol 2014; 41 (S 01): e3045-e351
• 6 Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med 2000; 342 (10) 673-680
• 7 Frank M, Albuisson J, Ranque B. et al. The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome. Eur J Hum Genet 2015; 23 (12) 1657-1664
• 8 Haem T, Benson B, Dernoncourt A, Gondry J, Schmidt J, Foulon A. Vascular Ehlers-Danlos syndrome and pregnancy: a systematic review. BJOG 2024; 131 (12) 1620-1629
• 9 Pepin MG, Schwarze U, Rice KM, Liu M, Leistritz D, Byers PH. Survival is affected by mutation type and molecular mechanism in vascular Ehlers-Danlos syndrome (EDS type IV). Genet Med 2014; 16 (12) 881-888
• 10 Shalhub S, Black JH, Cecchi AC. et al. Outcomes in vascular Ehlers–Danlos syndrome are influenced by genotype: a multicenter cohort study. J Am Coll Cardiol 2025; 85 (05) 517-529
• 11 Haem T, Benson B, Dernoncourt A, Gondry J, Schmidt J, Foulon A. Vascular Ehlers-Danlos syndrome and pregnancy: a systematic review. BJOG 2024; 131 (12) 1620-1629
• 12 American College of Obstetricians and Gynecologists' Presidential Task Force on Pregnancy and Heart Disease and Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 212: pregnancy and heart disease. Obstet Gynecol 2019; 133 (05) e320-e356
• 13 Lindley KJ, Braverman AC, Warnes CA. Management of women with congenital or inherited cardiovascular diseases: a guide from pre-conception through the postpartum period. J Am Coll Cardiol 2021; 77 (06) 744-757
• 14 Virani SS, Kelly DT, Durbin EM. AHA/ACC clinical guideline methodology: guidance for authors and peer reviewers. Circulation 2023; 148 (19) e123-e130
• 15 Morales A, Hershberger RE. Variants of uncertain significance: should we revisit how they are evaluated and disclosed?. Circ Genom Precis Med 2018; 11 (06) e002169
• 16 Cheng S, Pang Y, Wu C. et al. Inconsistency of variant of uncertain significance reporting for monogenic diseases in reproductive medicine from 2019 to 2022. PLoS One 2024; 19 (07) e0308771
• 17 Fasching L, Kornblum C, Kern I. et al. Reclassification of copy number variants in a longitudinal cohort study: clinical implications and lessons learned. Genome Med 2023; 15 (01) 56
• 18 Isselbacher EM, Preventza O, Hamilton Black III J. et al; Peer Review Committee Members. 2022 ACC/AHA guideline for the diagnosis and management of aortic disease: a report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation 2022; 146 (24) e334-e482
• 19 Westphal DS, Parrott A, Leren IS. et al. Impact of genetic variant reclassification in inherited arrhythmia syndromes: implications for clinical care. Heart Rhythm 2024; 21 (01) 48-57
• 20 Richards S, Aziz N, Bale S. et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424