Focus Areas in the Genomic Medicine Cycle
Major leadership positions

CGM Director

MGH Department/Division


MGH Unit(s)



We study alterations to genome structure and function and their impact on human disease.

The Talkowski lab integrates molecular and computational genomics methods to study the genetic etiology of disorders affecting prenatal, neonatal, and early childhood development, as well as neurodevelopmental and psychiatric disorders. Our lab is also interested in variant-to-function studies to understand genomic perturbations to regulatory pathways in rare diseases and the applications of emerging technologies to clinical diagnostic screening.

We are performing human genomic research in four primary domains:

    1. Delineation of genomic variation and genome biology
    2. Discovery of genes that can contribute to human disease when altered
    3. Functional characterization of genetic mutations and therapeutic targeting
    4. Translation of genomics technologies into new genetic diagnostic methods

Priority Projects

  1. An atlas of structural variation across global populations. Structural variants (SVs) are large genomic alterations (>50 nucleotides) that represent a major driver of diversity between all human genomes and are an important component of human disease etiology. Our team is developing an extensive SV atlas across global populations in the genome aggregation database (gnomAD) initiative and new metrics to define genomic regions that are intolerant to changes in gene dosage – or dosage sensitivity. The gnomAD SV resource currently consists of >130,000 whole genome and >650,000 whole exome sequenced individuals. The lab has developed and implemented new analytic pipelines to capture structural variants from whole exome (GATK-gCNV) and genome (GATK-SV) sequencing to establish highly sensitive and specific methods to capture SVs. Our methods have uncovered entirely new classes of recurrent complex rearrangements of the human genome, including examples of localized chromosome shattering that resolve to a nearly balanced state in the human germline – known as ‘chromothripsis’. These methods and the SV reference resource is publicly accessible in the gnomAD browser (Collins et al., 2020, Nature).
  2. Genomic studies of the Developmental Continuum. How genetic changes contribute to stillbirth and spontaneous pregnancy loss has not been studied at scale. We are performing genome sequencing of families who have experienced stillbirth to dissect the genetic underpinnings of pregnancy loss, elucidate genetic variation intolerant to post-natal life, and model such variations in animals. Furthermore, we are interested in dissecting the genetic contribution of structural anomalies in pregnancy and at birth to gain insight into the prenatal presentation of diseases. All the data collected will be shared in a federated database for prenatal sequencing and phenotype data in an unprecedented effort to improve clinical care and research efforts in prenatal medicine.
  3. Functional modeling of genomic variation in human disease. The Talkowski lab has a long-standing interest in the molecular basis of neuropsychiatric and neurodevelopmental disorders. We use iPSC-derived neuronal cells to measure the effects of disease-associated mutations on early neurodevelopment across different types of neural cells and developmental timepoints. We are actively studying autism, Prader-Willi syndrome (PWS), and cohesinopathies, and a rare and fully lethal Mendelian disorder indigenous to the Philippines – X-linked dystonia parkinsonism (XDP). In one exemplar that has advanced to translational implications, we have identified a potential driver locus responsible for the phenotypes observed in PWS and created a series of methods to deliver a noncoding RNA back to neuronal cells to rescue synaptic deficits observed. In another, XDP, we have identified a causal mobile element insertion (an SVA) that disrupts normal splicing of the TAF1 gene and can be ameliorated with antisense oligonucleotide (ASO) therapies. We are actively pursuing similar studies for all human reciprocal genomic disorders (RGDs) such as 16p11.2, 22q11.2, and many others, as well as a compendium of 48 genes associated with chromatin modification, transcriptional regulation, and synaptic function in autism.
  4. The All of Us Research Program (AoU). AoU is a bold NIH initiative to build a biomedical research resource with clinical, survey, and genetic data from a diverse group of participants in the United States. The Talkowski Lab is applying our GATK-SV pipeline to generate structural variant (SV) calls that will be made widely available to researchers registered with AoU. The pilot SV call set of 11,390 samples will be released in early 2023, and the program aims to scale to 1 million samples over time. Our team also co-leads the analyses of long-read genome sequencing in AoU, including the analyses of 10,000 long-read genome sequenced individuals in AoU. These data will be an invaluable resource for population genetics, disease-association studies, and diagnostic screening because of the availability of individual genotypes and matched phenotypic information.
  5. A non-invasive prenatal diagnostic test. Non-invasive prenatal screening (NIPS) offers a blood test for the detection of aneuploidies such as trisomy 21 (Down’s syndrome) early in pregnancy. Our team has developed a high-resolution NIPS (hrNIPS) method that can capture all mutations and copy number variants (CNVs) across all 18,000 genes in the fetal genome early in prenatal development. This method also offers a maternal carrier screen from the same test. Using our customized computational pipelines, we demonstrate that hrNIPS can capture all diagnostic variants detected in standard-of-care invasive fetal testing and offers the opportunity for re-interpretation of the fetal exome for disease prediction, prevention, and treatment throughout the lifespan.

Lab Members

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Lab/Contact Telephone


Primary Email

mtalkowski [@]

Lab Website