Genome Sequencing: Exploring the Diagnostic Promise

Hanners Family

Caption: Whole genome sequencing revealed that sisters Addison and Trinity Hanners, ages 7 and 10, shown here with their mother Hanna, have a rare syndrome caused by a mutation in the MAGEL2 gene.
Credit: Courtesy of the Hanners family

At the time that we completed a draft of the 3 billion letters of the human genome about a decade ago, it would have cost about $100 million to sequence a second human genome. Today, thanks to advances in DNA sequencing technology, it will soon be possible to sequence your genome or mine for  $1,000 or less. All of this progress has made genome sequencing a far more realistic clinical option to consider for people, especially children, who suffer from baffling disorders that can’t be precisely diagnosed by other medical tests.

While researchers are still in the process of evaluating genome sequencing for routine clinical use, and data analysis continues to be a major challenge, one area of considerable promise centers on neurodevelopmental disorders. Such disorders—which affect about 3 percent of children—range from relatively common conditions like autism spectrum disorder to very rare conditions that impair the development of the brain or central nervous system. In the latest study, an NIH-funded research team reports that sequencing either a patient’s whole genome or whole exome (the 1.5 percent of the genome that encodes proteins) appears to be an effective—as well as a cost-effective—strategy for diagnosing neurodevelopmental disorders that have eluded diagnosis through standard means.

Led by Sarah Soden of Children’s Mercy Hospitals and Clinics, Kansas City, MO, the team focused on 119 children, whose average age was 7, with a variety of undiagnosed neurodevelopmental disorders. Most of the children’s families had endured what Soden called a “diagnostic odyssey,” during which the affected child met dozens of times with various specialists and received a costly battery of biochemical, genetic, and neuroimaging procedures, none of which pinpointed the molecular cause of the disease. Obtaining a molecular diagnosis can be very important: it can end the long odyssey by identifying a definitive cause of the problem, suggest insights on how to treat and manage the child’s condition, and provide information to parents on their risks of having another child affected by the disorder.

In their study in Science Translational Medicine [1], Soden’s team sequenced the genome or exome of the affected child and both parents. They identified a disease-causing change in the genome and provided a molecular diagnosis for 45 percent of these children (53 of 119).  The researchers speculated that if such sequencing had been available and used at the time of symptom onset, the families would have received a diagnosis on the average more than six years earlier. What’s more, with sequencing costs rapidly declining, families would likely save money through the new approaches. Depending on how sick they were, the children had undergone an average of about $9,500 to $19,000 in unrevealing diagnostic tests over the course of their lifetimes, the researchers said.

Receiving a molecular diagnosis led to almost immediate changes in the medical care of about half of the children. Some started receiving medications known to help people with that specific diagnosis, while others discontinued unnecessary treatments. One child diagnosed with early infantile epileptic encephalopathy type 11, a severe, genetic form of epilepsy, was switched to a high-fat “ketogenic” diet, which reduced seizures, though it was not a cure. Finally, some children underwent further evaluation for possible physical complications associated with the newly diagnosed conditions.

In the case of the Hanners family from Coffee County, Kansas, genome sequencing revealed that two children—7-year-old Addison and 10-year-old Trinity—shared the same genetic mutation. The finding ended the family’s decade-long search to explain the developmental delays, autistic behaviors, poor muscle tone, and other symptoms that affected the sisters from birth.

This report comes on the heels of two other similar studies in the journal JAMA about the promise of whole exome sequencing for diagnosing a wide range of rare diseases, including neurodevelopmental disorders. In the first study, Yaping Yang and colleagues at the Baylor College of Medicine, Houston, sequenced the exomes of more than 2,000 patients, mostly children. They uncovered the molecular basis for the disease in about 25 percent of patients [2]. The results mirror those of a team led by Hane Lee at the University of California, Los Angeles, which sequenced the exomes of 814 patients, most younger than 18. When researchers sequenced the patient’s exome, they detected the molecular cause in 26% of cases. But when they sequenced the exomes of both the patients and their parents, the success rate rose to 31%. The reason for the improved success is that it is easier to identify disease-relevant mutations when one compares the child’s genetic sequence to that of their parents; finding a mutation that appears for the first time in the child greatly increases the likelihood that it is causative of the disorder, rather than just a rare variant of no significance [3].


[1] Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Soden SE, Sci Transl Med. 2014 Dec 3;6(265).

[2] Molecular findings among patients referred for clinical whole-exome sequencing. Yang Y, et al. JAMA. 2014 Nov 12;312(18):1870-9.

[3] Clinical exome sequencing for genetic identification of rare Mendelian disorders. Lee H, et al. JAMA. 2014 Nov 12;312(18):1880-7.


Autism Spectrum Disorder, Medline Plus

Early Infantile Epileptic Encephalopathy 11, Online Mendelian Inheritance in Man® Catalog of Human Genes and Genetic Disorders

Pediatric Genomic Medicine, Children’s Mercy Hospitals and Clinics, Kansas City, MO

Genetics Clinics, Baylor College of Medicine, Houston

UCLA Clinical Genomics Center, Los Angeles

NIH Undiagnosed Diseases Network, NIH Common Fund

NIH support: National Institute of Child Health and Human Development, National Human Genome Research Institute, National Center for Advancing Translational Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Neurological Disorders and Stroke

3 thoughts on “Genome Sequencing: Exploring the Diagnostic Promise

  1. Nice result. However, there are several good results derived from techniques of molecular biology used to find out molecular details of genetic diseases. However, these results do not correct wrong reasoning as for instance: “In biology all information goes from DNA through RNA to proteins”. The correct form could be In biology, all genetic information goes from DNA…This apparent small detail has led, among other errors, for example to medical Schools considering that the learning molecular details of normal regulation were no longer needed. The knowledge of the entire genome could allow for MD knowledge to be obtained from the genetic defects.

  2. Although we may be able to find a molecular disorder in our genome, we still fall short of treatment…this leads to the quandary of if we should know what is wrong with our personal genome and what benefits we are entitled to after knowing its sequence.


  3. Important point raised by Evans. However, even before the genome project, Human genetics have an expertise in genetic counseling that may deal with this question in a good manner.

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