Natural history of SMAD3-related Familial Aortopathy Study

Individuals in whom a SMAD3 gene mutation has been identified by the Collagen Diagnostic Laboratory testing are invited to enroll in the CDL Research Repository.  Once enrolled, clinical data and medical history are reviewed and compared between mutation types to determine the extent of disease, age of onset, variability within family and extent and surgical approach of vascular complications. 

Consent Forms:
use Research Repository Study Consent Forms

Sam Bailey, MS, CGC ph: 206-543-5464 (


TGFBR-related Pregnancy Study

Reports of arterial (aortic) aneurysm or rupture in the perinatal period of pregnancy in women with TGFBR1, TGFBR2 or TGFB2 mutations raise concerns for an increased risk of vascular complications in pregnancy and at delivery.  Individuals in whom a TGFBR1/2 or TGFB2 mutation has been identified by Collagen Diagnostic Laboratory testing (or elsewhere) are invited to enroll in the TGFBR-related Pregnancy Study.  Once enrolled, clinical data collected by interview and medical records including vascular imaging are reviewed by the study cardiologist, Dr. Andrew Cheng.  A profile of the presentation of vascular complications before and during pregnancy is recorded for each subject.  Comparison of the profiles will be used to recommend a pre-pregnancy vascular screening plan and pregnancy management.

Consent Forms:
Adult Consent
Legally Authorized Relative Consent

Project contact information:
Dru Leistritz, MS,CGC ph: 206-543-5464 (
Melanie Pepin, MS,CGC ph: 206-221-9364 (


Whole Exome Sequencing Study as a means of understanding genetic disorders

Whole exome sequencing allows us to learn the complete sequence of all of the parts of a person's genetic material that direct the production of proteins.  Most genetic disorders result from mutations or changes in genes in the regions included in the sequencing studies.  The advent of whole exome sequencing brings an opportunity to focus the search for rare causative genes in inherited disorders.  We are members of the working group in the University of Washington Little-Go Project lead by Dr. Debbie Nickerson in a search for possible disease gene candidates.  At present, exomic sequencing research is underway looking for genes responsible for EDS type VIII, the periodontal form of EDS, Caffey disease, and recessive forms of OI.

Consent Form:
use Research Repository Study Consent Forms

Project contact information:
Melanie Pepin, MS, CGC ph: 206-221-9364 (




Recurrence risk in lethal OI - parsing the contribution of recessive genes

When David Sillence proposed a new classification of OI in the 1970s (Sillence et al 1979), he suggested that the perinatal lethal form was a recessively inherited disorder.  Work in the ensuing decade provided convincing evidence that the perinatal lethal form of OI, OI type II, resulted from new dominant mutations in the type I collagen genes, COL1A1 and COL1A2, and the recurrence was the consequence of parental mosaicism for these dominant mutations (Byers et al 1988 ;Cohn et al 1990).  Nonetheless, in some families in which consanguinity was consistent with recessive inheritance of lethal OI and in some of these families mutations could not be found in the type I collagen genes.  In the last 6 years three genes have been identified in which homozygous or compound heterozygous mutations lead to recessively inherited forms of OI than can be difficult to distinguish from the usual dominant forms.  We used data from the Research Repository to show, first, that more than 90% of infants with the lethal form of OI have mutations in type I collagen genes (Bodian et al 2008).   We then examined the risk of recurrence for those with dominant mutations and those with recessive mutations.  Even with the increasing number of families with recessively inherited forms of lethal OI, mosaicism for dominant mutations in type I collagen genes still accounts for the majority of families in which unaffected families have two or more affected children.  (Pyott SM et al 2011)


EDS type IV "null" nonsense mutations and  missense mutations - comparison of survival and complications

Ehlers-Danlos syndrome (EDS) type IV, the vascular type, results from mutations in COL3A1, the gene that encodes the proα1(III) chain of type III procollagen. We have identified heterozygous COL3A1 mutations in 508 families, about 95% of which lead to the synthesis of an abnormal type III procollagen. Mutations that result in substitutions for glycine residues in the triple helical domain of the proα1(III) chain account for two-thirds of identified mutations in COL3A1, and splicing mutations comprise most of the remainder. We identified frameshift or premature termination codons that result in nonsense mediated mRNA decay of the COL3A1 mRNA encoded by that allele ("null mutations") in 19 families (about 4% of the total); cultured cells from these individuals produced about half the normal amount of type III procollagen and no abnormal molecules, as expected. We reviewed the clinical and family histories and medical complications in 53 individuals with COL3A1 null mutations. Compared to individuals with missense or exon-skipping mutations, we found that in the cohort with COL3A1 null mutations mean life span was extended by close to 20 years, the age of first complication was delayed by almost 15 years, and major complications were limited to vascular events. The families were ascertained following a complication in a single individual but only 25% of relatives, some of whom had reached their 70s or 80s without incidents, had a complication and only 30% had any minor clinical features of EDS type IV. In families with osteogenesis imperfecta that results from mutations in the COL1A1 gene, more than 50% of affected individuals have haploinsufficiency mutations and have OI type I, the mildest OI phenotype. Because null mutations in COL3A1 are expected to be as common as those in COL1A1, our data suggest that they are far less penetrant than missense and splicing mutations yet may be causes of late onset arterial aneurysms. Since ascertainment on the basis of clinical findings alone has a low yield, genetic testing for COL3A1 mutations should be offered to all first degree relatives of an individual identified with a COL3A1 null mutation, and should be considered in those with compatible vascular complications at a young age and, potentially, in individuals with late onset arterial events. Leistritz DF et al 2011


Survival is affected by mutation type and molecular mechanism in vascular Ehlers-Danlos syndrome (EDS type IV)
Purpose: We sought to characterize the natural history of vascular Ehlers-Danlos syndrome in individuals with heterozygous COL3A1 mutations. Methods: We reviewed clinical records for details of vascular, bowel, and organ complications in 1,231 individuals (630 index cases and 601 relatives). Results: Missense and splice-site mutations accounted for more than 90% of the 572 alterations that we had identified in COL3A1. Median survival was 51 years but was influenced by gender (lower in men) and by the type of mutation. Conclusion: Although vascular Ehlers-Danlos syndrome appears to be genetically homogeneous, allelic heterogeneity is marked, and the natural history varies with gender and type of mutation in COL3A1. These findings indicate that when counseling families, confirmation of the presence of a COL3A1 mutation and its nature can help evaluate the risks of complications. These data are also important ingredients in both the selection and allocation of individuals to appropriate arms in clinical trials to assess the effects of interventions.  Pepin MG et al Genet Med 2014 June 12
Pregnancy-related deaths and complications in women with vascular Ehlers-Danlos syndrome. 
Purpose: The purpose of this study was to characterize the nature and magnitude of pregnancy risks in women with vascular Ehlers-Danlos syndrome. Methods: Pregnancy-related death rate was determined by a review of pedigrees of families with vascular Ehlers-Danlos syndrome. Maternal morbidity was characterized through semi structured interviews with women with vascular Ehlers-Danlos syndrome or their next of kin. Results: Pregnancy-related deaths occurred in 30 of 565 deliveries (5.3%). There was no difference in Kaplan-Meier survival curves between parous versus nulliparous women with vascular Ehlers-Danlos syndrome. Interviews with 39 women indicated that 46% of deliveries were uncomplicated. The most common pregnancy-related complications were third-/fourth-degree lacerations (20%) and preterm delivery (19%). Life-threatening complications occurred in 14.5% of deliveries and included arterial dissection/rupture (9.2%), uterine rupture (2.6%), and surgical complications (2.6%). There were 5 maternal deaths in 76 deliveries (6.5%). Conclusion: The risk of pregnancy-related complications is increased in women with vascular Ehlers-Danlos syndrome compared with the general population; however, survival data indicate that pregnancy does not appear to affect overall mortality compared with nulliparous women with vascular Ehlers-Danlos syndrome. The data were insufficient to determine whether mode or timing of delivery influenced risk of complications. Women with vascular Ehlers-Danlos syndrome should be engaged in a shared decision-making process when contemplating pregnancy and pregnancy management.  Murray ML et al Genet Med 2014 June 12