CLINICAL RESEARCH STUDIES

ONGOING STUDIES: PRESENTLY ENROLLING SUBJECTS

Pregnancy in EDS type IV - A realistic management plan for delivery and postpartum care 

Published reports of peripartum arterial aneurysm/rupture or uterine rupture have alerted affected individuals and physicians to an increased risk of a life-threatening event without recommending strategy or a plan for care.  We are uncertain if delivery by cesarean section improves outcome, if there is a change in risk in subsequent pregnancy following a C-section, if the presence of known arterial aneurysms increases the risk of pregnancy complications, and if any drug intervention can make a difference in outcome.  Women with EDS type IV who have undertaken pregnancies are recruited and interviewed (or records reviewed) to detail successes and problems in their pregnancies.  The research genetic counselors are working in collaboration with Suzanne Peterson, MD, an obstetrician and Maternal Fetal Medicine specialist, and with Mitzi L. Murray, MD, Clinical Geneticist to collect and analyze data on more than 100 pregnancies. 

EDS type IV Pregnancy Study Consent Forms:
ADULT consent: Patient is 18 years of age or older
PROXY consent: Patient/Relative is deceased (next of kin)
HIPAA authorization form

Contact: 
Mitzi Murray, MD (mlmurray@uw.edu
Melanie Pepin, MS, CGC (mpepin@uw.edu)
Dru Leistritz, MS, CGC (dru2@uw.edu)
(206)543-5464 
 

Whole exome sequencing as a means of understanding genetic disorders.

Whole exome sequencing allows us to learn the complete sequence of all 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 UW Little-Go Project lead by Dr. Debbie Nickerson working to 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, Nager syndrome, a disorder that includes limb and craniofacial developmental defects, and recessive forms of OI. For inquiries on the Nager Syndrome study, please contact Maggie McMillan in the Bamshad Laboratory by email at margaret.mcmillin@seattlechildrens.org.

Whole Exome Sequencing:  use Research Repository Study Consent Forms

 

Exomic Sequencing Project contact information:
Contact: Melanie Pepin, MS, CGC (mpepin@uw.edu)

 

 

RECENTLY PUBLISHED CLINICAL RESEARCH STUDIES

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