PROJECT SUMMARY/ABSTRACT
Cerebral palsy (CP) is a major neurodevelopmental disorder affecting an estimated 1:323 individuals.
CP affects the motor stream of development, and people with CP may have difficulty walking, talking, eating, or
using their hands. Some may have involuntary muscle activation and/or movements that may be painful and/or
disruptive, affecting quality of life and inclusion. Although environmentally-mediated causes of CP such as
perinatal stroke, prematurity, prenatal infection or lack of oxygen have been known to lead to CP for some
time, recent findings from our group and others indicates that for as many as one-third of individuals with CP, a
genetic mutation may be the cause of their CP symptoms. Identifying the genetic basis of CP is important
because our data suggests that the identification of a genetic cause of a patient’s CP can lead to a change in
management > 20% of the time and this number is expected to grow steadily.
Genetic forms of CP may occur sporadically in approximately one-half of cases. However, ~1/3 of
genetic cases of CP are estimated to exhibit autosomal recessive inheritance, wherein both parents are
unaffected carriers of the condition. Most current research in CP is focused on parent-child trio-based studies.
We propose a different approach, focusing instead on families with multiple affected children with CP inter-
related by blood. We have enrolled hundreds of such families in collaborations with physician colleagues in the
Middle East, Africa and Southeast Asia. Studying highly genetically-informative families such as these is
anticipated to represent a powerful approach for cerebral palsy-associated gene discovery.
The signs and symptoms of the families we have enrolled in our studies have been diligently
catalogued, including assessments by multiple specialists, and the collection of facial photographs and patient
videos that highlight their movement disorders. These resources, as well as detailed laboratory and
radiological assessments will allow us to comprehensively catalog the symptoms of the individuals we have
partnered with for these studies. We will then perform whole exome sequencing to identify changes in the
genome found in affected members of the family but not in healthy individuals. Once a candidate gene is
identified, we will connect with colleagues worldwide to find patients with similar symptoms who harbor
variant(s) in the same gene. We will then conduct a series of laboratory analyses in order to confirm or refute a
role for the candidate gene in CP. This will include both classic and massively parallel unbiased studies of
RNA, protein, and/or metabolites, and assessment in complementation studies, cell-based assays, fly models
and human induced pluripotent stem cell-neurons/astrocytes from patient samples. Impact: We anticipate that
this approach will allow us to identify dozens of novel CP-associated genes, which in turn will facilitate clinical
advances in diagnosis and management as mechanism-based therapies continue to be developed.
