TY - JOUR
T1 - Familial Ehlers-Danlos syndrome with lethal arterial events caused by a mutation in COL5A1
AU - Monroe, Glen R
AU - Harakalova, Magdalena
AU - van der Crabben, Saskia N
AU - Majoor-Krakauer, Danielle
AU - Bertoli-Avella, Aida M
AU - Moll, Frans L
AU - Oranen, Björn I
AU - Dooijes, Dennis
AU - Vink, Aryan
AU - Knoers, Nine V
AU - Maugeri, Alessandra
AU - Pals, Gerard
AU - Nijman, Isaac J
AU - van Haaften, Gijs
AU - Baas, Annette F
N1 - © 2015 Wiley Periodicals, Inc.
PY - 2015/6
Y1 - 2015/6
N2 - Different forms of Ehlers-Danlos syndrome (EDS) exist, with specific phenotypes and associated genes. Vascular EDS, caused by heterozygous mutations in the COL3A1 gene, is characterized by fragile vasculature with a high risk of catastrophic vascular events at a young age. Classic EDS, caused by heterozygous mutations in the COL5A1 or COL5A2 genes, is characterized by fragile, hyperextensible skin and joint laxity. To date, vessel rupture in four unrelated classic EDS patients with a confirmed COL5A1 mutation has been reported. We describe familial occurrence of a phenotype resembling vascular EDS in a mother and her two sons, who all died at an early age from arterial ruptures. Diagnostic Sanger sequencing in the proband failed to detect aberrations in COL3A1, COL1A1, COL1A2, TGFBR1, TGFBR2, SMAD3, and ACTA2. Next, the proband's DNA was analyzed using a next-generation sequencing approach targeting 554 genes linked to vascular disease (VASCULOME project). A novel heterozygous mutation in COL5A1 was detected, resulting in an essential glycine substitution at the C-terminal end of the triple helix domain (NM_000093.4:c.4610G>T; p.Gly1537Val). This mutation was also present in DNA isolated from autopsy material of the index's brother. No material was available from the mother, but the mutation was excluded in her parents, siblings and in the father of her sons, suggesting that the COL5A1 mutation occurred in the mother's genome de novo. In conclusion, we report familial occurrence of lethal arterial events caused by a COL5A1 mutation.
AB - Different forms of Ehlers-Danlos syndrome (EDS) exist, with specific phenotypes and associated genes. Vascular EDS, caused by heterozygous mutations in the COL3A1 gene, is characterized by fragile vasculature with a high risk of catastrophic vascular events at a young age. Classic EDS, caused by heterozygous mutations in the COL5A1 or COL5A2 genes, is characterized by fragile, hyperextensible skin and joint laxity. To date, vessel rupture in four unrelated classic EDS patients with a confirmed COL5A1 mutation has been reported. We describe familial occurrence of a phenotype resembling vascular EDS in a mother and her two sons, who all died at an early age from arterial ruptures. Diagnostic Sanger sequencing in the proband failed to detect aberrations in COL3A1, COL1A1, COL1A2, TGFBR1, TGFBR2, SMAD3, and ACTA2. Next, the proband's DNA was analyzed using a next-generation sequencing approach targeting 554 genes linked to vascular disease (VASCULOME project). A novel heterozygous mutation in COL5A1 was detected, resulting in an essential glycine substitution at the C-terminal end of the triple helix domain (NM_000093.4:c.4610G>T; p.Gly1537Val). This mutation was also present in DNA isolated from autopsy material of the index's brother. No material was available from the mother, but the mutation was excluded in her parents, siblings and in the father of her sons, suggesting that the COL5A1 mutation occurred in the mother's genome de novo. In conclusion, we report familial occurrence of lethal arterial events caused by a COL5A1 mutation.
KW - Adult
KW - Amino Acid Substitution
KW - Aortic Rupture/blood
KW - Arteries/metabolism
KW - Collagen Type III/genetics
KW - Collagen Type V/genetics
KW - Ehlers-Danlos Syndrome/blood
KW - Fatal Outcome
KW - Female
KW - Gene Expression
KW - Hemorrhage/blood
KW - Heterozygote
KW - High-Throughput Nucleotide Sequencing
KW - Humans
KW - Male
KW - Mutation
KW - Pedigree
KW - Phenotype
KW - Protein Structure, Secondary
KW - Protein Structure, Tertiary
U2 - https://doi.org/10.1002/ajmg.a.36997
DO - https://doi.org/10.1002/ajmg.a.36997
M3 - Article
C2 - 25845371
SN - 1552-4825
VL - 167
SP - 1196
EP - 1203
JO - American journal of medical genetics. Part A
JF - American journal of medical genetics. Part A
IS - 6
ER -