Disease Association Studies

Disease association studies across the developmental continuum

The Talkowski lab is interesting in disease detecting across the full developmental continuum including fetal anomalies, fetal demise, structural birth defects, and autism spectrum disorder (ASD). We are actively developing molecular and computational pipelines for whole-genome sequencing in prenatal diagnostic practice. We previously performed the first clinical diagnosis of a prenatal sample by large-insert whole-genome sequencing, which identified a balanced translocation that disrupted CHD7, resulting in a predicted diagnosis of CHARGE syndrome that was confirmed by clinical features at birth. In another study, we identified chromothripsis by jumping library sequencing in a prenatal sample in collaboration with Dorothy Warburton and Michael Macera of Columbia University. Our laboratory is performing large-scale validation of whole-genome sequencing in routine prenatal genetic testing for structural variation (article found here).

Fetal Genomics Consortium

The Fetal Genomics Consortium (FGC) is a collaboration of academic and industry partners with a unifying goal to discover the genomic and phenotypic architectures of the perinatal period. Programs include genome sequencing studies of fetal anomalies, fetal demise, comprehensive non-invasive prenatal screening, and aggregation of phenotype and genotype datasets across centers in a cloud-based repository for use by the research and clinical communities. We envision these efforts in precision medicine to have a significant impact on maternal fetal medicine and neonatal health.

Balanced Chromosomal Abnormalities

We have also led genomics efforts to identify genes disrupted by genomic rearrangements, particularly balanced chromosomal abnormalities (BCAs). Our previous studies have performed structural variation to discovery genes associated with autism spectrum disorder (ASD), related neurodevelopmental disorders, and psychiatric disorders. The precise mapping of balanced chromosomal breakpoints has provided a remarkable yield of novel genes for which haploinsufficiency represents a significant causal factor for early onset neurodevelopmental abnormalities. In our latest study, we aggregated 63,237 exomes (>20,000 ASD) to explore shared and distinct genes, mutations, and cellular expression patterns across ASD, developmental delay (DD), and schizophrenia (SCZ) cohorts. We leveraged all of this information and a powerful Bayesian analytic framework (TADA) to discover 71 genes contributing risk to ASD at a statistical threshold approximately equivalent to exome-wide significance (FDR<0.001), and 183 genes at FDR < 0.05 (paper found here).