The Biomedical Interpretation & Training Team
Next-generation sequencing technologies have fundamentally changed the study of human genetics. Thousands of disease genes have been catalogued since the completion of the draft human genome sequencing in 2001. Genetic testing has been widely adopted as a key diagnostic tool, particularly for developmental disorders and rare genetic diseases. Despite these critical advances, our knowledge of the relationship between genotype and phenotype remains incomplete. This is evident from the fact that clinical genetic testing provides a molecular diagnosis for just 25-30% of patients referred for it.
The incredible throughput and numerous applications of high-throughput sequencing instruments holds enormous potential but also brings considerable challenges. The sheer volume of data calls for a new class of bioinformatics tools to process genomic data, as well as to identify and assess the millions of genetic variants present in all individuals to identify which ones may contribute to disease.
Our Role At IGM
The Biomedical Interpretation & Training (BIT) Team of the Steve and Cindy Rasmussen Institute for Genomic Medicine at Nationwide Children’s Hospital has three key responsibilities:
- Analysis & interpretation for translational research studies. These studies are applying multiple ‘omics technologies to uncover the genetic basis of conditions that affect children, particularly rare diseases, epilepsy and pediatric cancers. Using modern techniques for genomic interrogation and analysis, the lab team searches for likely-causal genetic variants patients affected by these diseases, with an emphasis on the discovery and characterization of new disease genes.
- Development of genome analysis tools. The BIT team also develops bioinformatics tools and approaches to facilitate genomic analysis and variant interpretation. These include:
- VarScan, a variant caller for next-generation sequencing data
- VaNex, a sophisticated team-based interface for variant analysis.
- Firefly, a dynamic tool for visualizing pathogenic and benign variants from ClinVar.
- Genome analysis training. The BIT team offers an embedded training program in which postdoctorial trainees, clinical fellows, and other young scientists learn to do genome analysis. They also develop presentations, documents, and other training materials.
Areas of Research
Despite the considerable advances in gene discovery and genetic testing, most patients who undergo comprehensive genetic testing (e.g. clinical exome sequencing) fail to obtain a molecular diagnosis. Such patients often continue on a diagnostic odyssey of medical testing that can last months or years without finding an answer.
Using state-of-the-art genomic approaches — whole-genome sequencing, transcriptome analysis and long-read sequencing — and innovative bioinformatics approaches, the Biomedical Interpretation & Training Team identifies novel candidate genes and gene-phenotype associations in hopes of assisting patients and families in search of a diagnosis.
Congenital heart disease (CHD) is the most common birth defect and a leading cause of death in children. Understanding the genomic architecture of this condition is a clinical imperative but faces significant challenges. Genetic causes of CHD are extremely heterogeneous, comprising chromosomal anomalies (13% of cases), copy number variants (10-15%), and single-gene disorders (12%). At best, modern genetic testing provides diagnoses for 40% of patients, suggesting that many genes underlying CHD have yet to be discovered.
The COURAGE for Kids study is applying cutting-edge genomics to elucidate genetic factors that contribute to congenital heart defects and unexpected cardiac arrest in children. It will enroll hundreds of patients and their families to uncover CHD-relevant genes and their influence in long-term cardiac outcomes.
Neuromuscular disorders are a major cause of muscle weakness and motor difficulties in children. These conditions all affect the “motor unit” – the lower motor neuron, peripheral nerve, neuromuscular junction and muscle. The most common neuromuscular disorders in children are muscular dystrophies (e.g. Duchenne), congenital myopathies (e.g. nemaline myopathy), hereditary neuropathies (e.g. Charcot-Marie-Tooth disease) and spinal muscular atrophy (SMA). The variable clinical presentation, overlapping features and genetic heterogeneity of these conditions make them hard to diagnose. However, an accurate diagnosis is critical to providing optimal care and may also qualify patients for an increasing number of FDA-approved therapeutic options and gene therapy trials for pediatric neuromuscular disorders.
In collaboration with the Center for Gene Therapy at Nationwide Children’s Hospital, we apply RNAseq, long-read sequencing, optical genome mapping and other cutting-edge genomics tools to patients with undiagnosed or unresolved neuromuscular diseases. Our goal is to obtain a precise genetic diagnosis that might help patients qualify for gene therapy or other individualized treatment strategies.
Epilepsy is one of the most common conditions associated with neurological disorders, affecting as many as 1 in 26 individuals in the United States alone. While 20-30% of cases are caused by acquired conditions (e.g. stroke, head injury or tumor), the majority are believed to have an underlying genetic etiology.
Nationwide Children’s Hospital’s Level 4 Epilepsy Center offers advanced epilepsy surgery services, including evaluation using intracranial electrodes to identify epileptogenic zones and surgical excision of affected tissue. IGM obtains excised tissue and matched normal (blood) samples from epilepsy patients for genomic study, which usually involves exome sequencing (tissue and normal samples) and RNA-seq (tissue samples). The BIT Team works closely with the Bedrosian Lab to identify and study somatic variants in brain tissue that underlie disease etiology.
While the factors predisposing children to mood disorders such as depression and bipolar disorders and developmental behavior disorders like autism spectrum disorder are undoubtedly complex and varied, state-of-the-art genome sequencing of affected families may help elucidate genetic predisposition factors.
In partnership with Behavioral Health researchers at Nationwide Children’s, the Koboldt Lab is examining genomic factors influencing behavioral health with a particular focus on mood disorders in multiplex families.