Disease Association Studies

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).

The Talkowski lab is also a major contributor to the organization, sequencing, analysis, and interpretation efforts of the Fetal Genomics Consortium (FGC) consortium. The Fetal Genomics Consortium is a collaboration of academic and industry partners with a unifying goal to discover the genomic and phenotypic architectures of fetal anomalies that occur during pregnancy. Our programs include genome sequencing and deep phenotyping of fetal samples ranging from those harboring structural anomalies detected on ultrasound to fetal demise. Our collective goal is to sequence, analyze, and interpret genomic variation underlying fetal anomalies, and to aggregate all fetal genomics datasets under a cloud-based data resource with associated phenotype codes for the research community. We envision these efforts in precision medicine to have a significant impact on maternal fetal medicine and neonatal health.

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).