Genomic medicine begins with health and disease in patients and their families. MGH CGM faculty are developing new models of participant recruitment and engagement to enable disease research.
Faculty Working in this Domain
Publications
Questions being addressed in the center
How can we leverage discoveries in neuropsychiatric genetics to improve patient outcomes in child psychiatry?
What is the role of cognition in the liability that is shared across different forms of neuropsychiatric illness? Can interventions that target cognition improve patient outcomes?
Can DNA sequence data contribute to the clinical evaluation of youth with severe neuropsychiatric illness?
Patients, families, researchers and the lay public
What genes underlie the common cardiac disorder mitral valve prolapse, and what do they tell us about valve development?
What tissues, proteins, and molecular pathways can be targets of potential novel or co-adjuvant therapeutics for children and adults with neurogenetic diseases?
Projects underway to answer these questions
We have developed a research partnership with a pediatric neuropsychiatric assessment clinic at MGH. To date, we have collected DNA and cognitive and psychiatric phenotypes on over 1400 youth referred for neuropsychiatric evaluation. We are growing this cohort in order to conduct cross-sectional clinical translational analyses of common genetic risk variants. We also aim to follow these youth over time to relate genetic risk profiles to young adult outcomes.
Cognitive impairments are found in a range of neuropsychiatric conditions that are known to share genetic underpinnings. In the LOGIC cohort, we are investigating the possibility that cognition partially mediates the genetic risk that is shared across different types of psychopathology.
We have collaborated with another CGM faculty member, Dr. Talkowski, who has developed a strategy for whole genome sequencing based on large-insert jumping libraries. We used this method to characterize a pilot sample of 30 youth with severe neuropsychiatric presentations (including early onset psychosis or mood disorders or ADHD or ASD with notable comorbidities and/or a history of psychiatric hospitalization).
Genetic analyses: unbiased search for Huntington’s disease modifiers
Systems genetics: Huntington’s disease allelic series
Genotype-phenotype: Huntington’s disease families, clinicians, researchers
We are developing new tools for visualizing risk in clinical populations, allowing clinicians to make better use of emerging clinical and genomic predictors.
Mucolipidosis Type IV is caused by mutation of the mucolipin-1 lysosomal membrane channel. This is a devastating disease that causes severe psychomotor and mental retardation in infants, and progressive retinal disease leads to blindness by the time patients are in their early teens. Our goal is to develop gene therapy for both the retinal and CNS dysfunction.
Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery. Despite a clear heritable component, the genetic etiology leading to non-syndromic MVP has remained elusive. We used a large multigenerational family segregating non-syndromic MVP to identify a novel missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds)
The New England Precision Medicine Consortium
Answers found
A specific question we are examining is whether risk for typically adult-onset mental illness relates to traits in our youth clinical cohort that could be amenable to intervention. We have found an association between polygenic risk for SCZ and working memory across diagnoses in our pilot sample.
We have shown that executive cognition associates with dimensions of autism spectrum disorder (ASD), bipolar disorder and psychosis that can be modeled as a general psychopathology factor. We are now extending this model to include common genetic variation. We are also conducting randomized, double-blind placebo-controlled trials of computerized cognitive training in youth with neuropsychiatric illness.
In youth referred for neuropsychiatric evaluation, we found evidence of complex DNA sequence rearrangements, including three of potential clinical significance, that would have been cryptic to chromosomal microarray or karyotyping. Further work is needed to determine whether balanced and cryptic structural variation may warrant evaluation in youth with severe neuropsychiatric illness.
STARBEAM (ALD-102) (NCT01896102): We completed a single-arm, open-label, phase 2/3 safety and efficacy trial of Lenti-D™, an investigational gene therapeutic approach utilizing a lentiviral vector encoding the ALD protein to transduce autologous hematopoietic stem cells that aims to restore functional protein expression in microglia and halt disease progression in childhood cerebral adrenoleukodystrophy.
In our overall effort to advance treatments for adrenoleukodystrophy, we founded the consortium ALD Connect, a research network that spans 7 academic institutions and 5 patient advocacy organizations. The consortium was awarded a contract from PCORI and received the Global Genes Award in 2014. It has brought together stakeholders from academia, patient advocacy and industry and thereby accelerated trial development in this rare condition.
Huntington’s disease motor onset modifier genes located. Top locus does not modify disease duration.
Huntington’s disease CAG repeat mutation elicits effects from conception
We contribute: education, advocacy, research, the clinic
We developed machine learning approaches that apply electronic health records to predict suicide and other causes of mortality in individuals with psychiatric illness.
The familial mutation reduced protein stability in both zebrafish and cultured cells. Adult haploinsufficient Dchs1 mice had anatomic and functional prolapse of thickened, elongated leaflets recapitulating the human MVP phenotype. Dchs1 haploinsufficiency was associated with developmental defects in valve shape and cellular patterning during fetal morphogenesis. Understanding the role of DCHS1 in mitral valve development and MVP pathogenesis holds potential for therapeutic insights for this very common disease.
Leveraging longitudinal electronic health records (EHRs) for phenotyping, genomic analysis and risk prediction. We have developed algorithms enabling high-throughput phenotyping for large-scale genomic studies using natural language processing of EHRs. We also developed and validated EHR-based models that were able to identify nearly half of all suicides and suicidal behaviors an average of 3 – 4 years in advance.