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Published on: July 3, 2020
Phenotype of COL3A1/COL5A2 deletion patients
Marlies Je Kempers1, Marja Wessels2, An Van Berendoncks3
1Department of Clinical Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
Insights
Three patients with mild Ehlers-Danlos syndrome (EDS) were identified with contiguous gene deletions affecting COL3A1 and COL5A2. These genetic findings, often discovered incidentally, suggest a less aggressive approach to pregnancy for affected individuals.
Area of Science:
- Genetics
- Medical Genetics
- Rare Diseases
Background:
- Ehlers-Danlos syndrome (EDS) diagnosis relies on clinical criteria and genetic testing.
- Classical EDS (cEDS) and vascular EDS (vEDS) are common subtypes linked to COL5A1/COL5A2 and COL3A1 gene variants, respectively.
- This study investigates three cases of contiguous gene deletions impacting both COL3A1 and COL5A2, leading to haploinsufficiency and mild connective tissue disease features.
Purpose of the Study:
- To describe three patients with contiguous deletions of COL3A1 and COL5A2.
- To highlight the mild clinical presentation of these genetic alterations.
- To inform management strategies, particularly regarding pregnancy in affected individuals.
Main Methods:
- Case study approach utilizing medical history, physical examination findings, chromosomal microarray analysis (CNV-analysis), and imaging data.
- Review of genetic results, including NIPT and array comparative genomic hybridization (aCGH).
- Clinical correlation of genetic findings with patient phenotypes.
Main Results:
- Three patients presented with contiguous deletions encompassing COL3A1 and COL5A2, resulting in haploinsufficiency.
- Clinical features were mild, including thin skin and scoliosis, with no overt signs of cEDS or vEDS.
- Two patients had successful pregnancies with no major complications, suggesting a potentially less interventionist obstetric approach.
- One patient's father experienced sudden death due to aortic dissection, indicating potential familial risk.
Conclusions:
- Contiguous deletions affecting COL3A1 and COL5A2 can lead to a mild phenotype of Ehlers-Danlos syndrome.
- Diagnosis may be incidental due to the subtle clinical presentation.
- Pregnancy management for individuals with these deletions may be less conservative than previously assumed.
Introduction:
The diagnosis of Ehlers-Danlos syndrome is usually based on well-defined diagnostic criteria and the result of DNA investigation. Classical (cEDS) and vascular type (vEDS) are the most prevalent subtypes and are caused by heterozygous pathogenic variants in COL5A1, COL5A2, COL1A1 or, respectively, in COL3A1. We describe 3 cases with contiguous deletions resulting in haploinsufficiency of both genes with relative mild features of connective tissue disease.
Patients And Methods:
Information on medical history, physical information, genetic results (CNV-analysis) and imaging were obtained from the medical file.
Results:
The first patient was a 31 yr old female, diagnosed during pregnancy after the NIPT result showed an interstitial deletion of 2.3 Mb on chromosome 2q32.2, confirmed by XON array. She had normal aortic diameters. She had no signs of cEDS or vEDS except for a relatively thin skin with increased visibility of the veins. Her father died suddenly of a type A/B dissection at the age of 62 years. The second patient was diagnosed at the age of 10 years after she was referred because of her intellectual disability, autism and constipation. She was known with a thin and vulnerable skin and had a bleeding after tooth extraction. Array showed a 14,5 Mb deletion of 2q31.3q32.3 (de novo). Imaging (latest age 17 years) did not show any abnormalities. The third patient, aged 28 years, was diagnosed during pregnancy with an interstitial deletion of circa 6 Mb on chromosome 2q31.1q32.2 3, previously shown in the fetus with bilateral club feet and hydronephrosis. She had no vEDS facial features and the skin was relatively thin. She has thoracolumbar scoliosis and dural ectasia. Imaging did not reveal any vascular abnormalities. Her son, born at 37 weeks 3 days. had club feet but not other clinical signs suggestive of classical or vascular EDS.
Discussion:
Three patients are described with a contiguous deletion of varying size encompassing the COL3A1 and COL5A2 gene. Due to the mild phenotype a diagnosis of EDS was not suspected and was found coincidental. Since two of the patients were pregnant without major complications these patients may require a less defensive, approach to pregnancy/delivery.
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