Genetic Disorders

Genes are packages of DNA that compose the blueprint for the human body, from its one-cell stage through the lifespan. A child inherits a set of genes from both parents, which combine at conception to form a whole genome. Occasionally, a mutation in the DNA sequence results in a defective gene.

The mutation may either pass down from a parent with the mutated gene, or take a novel form, such as from a mistake in the process of copying the DNA. Some mutations cause the gene to not work properly, which occasionally leads to a lifelong disability, such as in mobility or learning. Genetic disorders commonly appear during infancy and childhood, when the development of the human body is rapidly laying the foundation for the rest of a lifetime.

Extreme cases of genetic pediatric disorders (referred to as "extreme phenotypes" in scientific literature) are the subject of this study. The medical resources required to diagnose a child with a rare or extreme disorder are usually extensive and do not always lead to a resolution. While some cases fall into recognizable syndromes with known genetic bases, many do not.

Full Genome Analysis

Most current clinical methods of genetic testing only detect common mutations already the subject of extensive study. Access to an individual's complete genome would enable scanning for mutations across all genes simultaneously, for any disorder or condition with a known genetic link. In a high proportion of cases, it has proven beneficial to sequence the full genome of infants with extreme symptoms for whom other diagnostic methods have failed.

A real-life example of this scenario involved a child born with small and immature muscles and other conditions that did not produce a diagnosis for any specific disorder – even after several years and many failed tests, including focused gene sequencing. The research team ultimately sequenced the child's full genome, which successfully identified a genetic basis for the condition.

Full Genome Analysis (FGA) is a method of genome sequencing developed by a member of the research team to serve extreme cases like the one described above. Whereas other methods only sequence minor, well-understood sections of the genome, FGA takes stock of all genetic material without skipping any sections. Adopting this method into routine clinical practice would require developing standards and a more complete catalog linking genetic variations with clinical outcomes.


Reading the human genome to identify genetic causes of disorders only very recently became possible. While several methods can sequence and analyze a persons genetic background, most do not provide a complete view of the genome, which is necessary for understanding rare disorders or those without a known cause. To address this gap, the research team developed a method called Full Genome Analysis (FGA) that reads the genome in a more complete manner than all other available techniques. The method serves two main purposes: 1) diagnosing clinical cases in which underlying mechanisms remain unidentified using other methods and 2) providing a tool to systematically discover genetic mutations previously unknown to cause disease.

This project brought together doctors and scientists to study the utility of FGA in clinics. The multidisciplinary and multi-institute research team applied FGA to 45 pediatric cases of extreme undiagnosed disorders with suspected genetic causes. Most the children were from traditionally under-served backgrounds, including communities of color–important because current genetic references do not reflect California's true demographic spread.

After sequencing the genomes of the affected children, their parents, and in some cases, their siblings, the new method identified the likely cause of disorder in 40% of cases (18 total). In response to this success, the research team developed a standardized pipeline for the acquisition and delivery of FGA data for clinical decision-making.

The long-term goal of this work is to contribute genomic data to a catalog of all genetic mutations and variations that can cause human disease. Doing so would allow any clinician in the world the opportunity to diagnose even the rarest genetic disorders. Conducted with prevention in mind, FGA would enable clinicians to assess disease risk and potentially take therapeutic action before symptoms become extreme and biological damage has occurred.

Research Team and Collaborators

Research Team

  • Children’s Hospital Oakland Research Institute
    • David Martin, MD
    • Dario Boffelli, PhD
  • University of California, San Francisco
    • Puy-Yan Kwok, MD, PhD
    • Ophir Klein, MD, PhD
    • Anne Slavotinek, MD, PhD
    • Joseph Shieh, MD, PhD
    • Bryce Mendelsohn, MD, PhD
    • Renata Gallagher, MD
    • Jessica Tenney, MD
    • Daniah Beleford, MD
    • Hazel Perry, MD


  • UCSF Benioff Children’s Hospital Oakland
    • Art D'Harlinque, MD
  • University of California, Berkeley
    • Steven Brenner, PhD
    • Andrew Sharo
    • Jingqi Chen, PhD
  • Human Longevity
    • Brandon Hunter, MS, MBA
  • GenomeOne
  • Illumina