Genetics of Ehlers-Danlos Syndrome

Ehlers-Danlos Syndrome (EDS) is a genetic disease that affects collagen synthesis and
structure resulting in multisystem connective tissue involvement with twelve different
subtypes. The clinical manifestations of EDS include skin hyperextensibility, skin fragility,
joint hypermobility, muscle hypotonia, easy bruising, and mast cell hypersensitivity. We
recently reported a cases series of EDS patients with different signs and symptoms. Most were
evaluated along with their parents for evidence of acquired or inherited bone diseases. What
is remarkable is that 93% of our cases at least one parent had clinically documented evidence
for EDS a genetic disorder that compromises the structural integrity of the collagen/elastin
matrix. Most of the parents were unaware they had this genetic disorder and the diagnosis was
made for the first time in our clinic. Our previous study for reviewing patient's medical
records was approved by the Boston University Medical Center's IRB. We have access to EDS
patients from referrals and from Dr Holick's clinic. We plan to collect the blood and saliva
samples from EDS patients and their relatives for this genetic study.

Genetic evaluation in limited number of our patients showed some causative variations. For
example, one of our cases the patient was evaluated at an outside hospital for a causative
variant in the COL5A1, COL5A2, FKBP14, and TNXB genes, which were negative, but she was found
later to have a causative variant in serpin peptidase inhibitor, clade F, member 1 (SERPINF1)
gene. A causative variation in SERPINF1 gene has been associated with osteogenesis imperfecta
(OI) /EDS overlap syndrome and the mutation in this gene causes type VI OI.

The highly variable clinical presentation of patients with the hypermobility and clinical
signs for EDS prompted an effort to classify patients with EDS into more homogeneous groups
that can aid in diagnosis and management. This resulted in the establishment of 14 types
(include 6 major types and 8 minor types). This classification acknowledges the presence of
"others" including "unspecified" forms making it clear that the clinical and genetic
heterogeneity of EDS could not be fully captured by that classification. Indeed, there have
been numerous reports of patients with hereditary disorders of connective tissue, which have
overlapping clinical manifestations of EDS, but do not meet the diagnostic criteria.

For decades, the genetic basis of heritable disorders of connective tissue had remained
largely unknown. The rise of molecular genetics and its advances in next-generation
sequencing has unlocked doors that continues to lead to major advances in understanding the
causative genes for many genetic disorders.

Evaluation of subjects with these conditions often includes molecular testing which has
important counseling, therapeutic and sometimes legal implications. An accurate molecular
diagnosis can provide the basis for counseling regarding prognosis and reproductive options.
Accurate genetic diagnosis has been shown to provide psychological benefits to patients and
their families. In order to facilitate sequencing of multiple genes causing some of the
common forms of these heritable conditions, we have designed this genetic study to obtain
data for the genetic variations of EDS by next generation sequencing. The next generation
sequencing panel may be of value in guiding future clinical pathways for genetic diagnosis in
EDS. We plan to recruit EDS patients and their relatives for genetic testing. We also plan to
submit a NIH grant for this purpose and provide required preliminary data through this pilot
grant about genetic variation of EDS.

The primary objective is to compare genetic variations in EDS patients with their relatives.
We expect to find some genetic variations that may explain clinical signs and symptoms in EDS
patients.

Secondary objective is to provide a novel testing panel on a single diagnostic platform for
EDS. After performing next generation sequencing, we plan to design a genetic panel for EDS.

A third objective will be to determine if saliva can be as good and reliable source of DNA
for genetic testing as DNA obtained from blood.

Inclusion Criteria:

- Children and adults of any age

- Both gender

- Positive history of hypermobility or other related signs/symptoms of EDS these
include among others a history of gastroparesis, orthostatic hypotension and easy
bruising in EDS patient group.

Exclusion Criteria:

- Diagnosed as other metabolic or genetic disorders in EDS suspected subjects.