Neil Osterweil

October 29, 2013

BOSTON, Massachusetts — When all else fails, whole-exome sequencing (WES) may succeed at nailing down a tough diagnosis, say investigators.

A new review of 1200 clinical cases in which patients presented with nonspecific or unusual symptoms suggestive of a genetic disorder showed that WES was positive for a specific condition in 26% of unselected clinical samples.

"The patient with a suspected [genetic] disorder is a challenge to diagnose for many reasons. There are thousands of genetic disorders, and some of them are quite rare," said Christine M. Eng, MD, professor of molecular and human genetics and medical director of the DNA Diagnostic Laboratory at Baylor College of Medicine in Houston, Texas, who presented the results of the first 1200 completed clinical cases involving WES at her center.

Although specialized testing is needed to confirm a diagnosis of a rare disorder such as Hunter's syndrome, which occurs in only about 1 in 150,000 people, medical geneticists themselves are even rarer, with an estimated 3.5 per million population. As a result, many patients go without a diagnosis, Dr. Eng said at the American Society of Human Genetics (ASHG) 63rd Annual Meeting here.

WES is an efficient and comparatively inexpensive alternative to whole genome sequencing that looks at exons, the protein-coding regions of genes, and at adjoining sequences to aid in the diagnosis of Mendelian disorders, pharmacogenetic traits, and potentially complex traits. WES currently costs around $1000 vs about $5000 for whole genome sequencing, although the price of the latter continues to fall.

Majority of Cases Were Pediatric with Neurologic Phenotypes

Dr. Eng and colleagues reported the results of their first 250 cases in a study published last week (N Engl J Med 2013; 369: 1502-1511).

Here, she fleshed out the details with a review of an additional 950 cases. Of the 1200 unrelated patients whose tissues have undergone WES at Baylor, 1066 (89%) are children under 18 years of age and 867 (72%) have intellectual disabilities, seizure disorders, developmental delays, or autism.

The majority of ordering physicians were medical geneticists and neurologists evaluating pediatric-aged patients with neurologic phenotypes who previously had a variety of genetic and other (eg, imaging) tests without an etiologic diagnosis. Other conditions seen include skeletal disorders and pulmonary arterial hypertension.

The 309 cases (26%) considered to have been solved at the molecular level since June 2012 include 320 total diseases diagnosed (some patients had 2 molecular disorders).

Cases Solved at the Molecular Level by WES

Type of disorder Number (%)
Autosomal dominant 151 (49)
Autosomal recessive 110 (36)
X-linked 36 (12)
Mitochondrial genome 1 (0.3)
Two molecular disorders 11 (4)
Total 309


In several cases, WES provided strong evidence for pathogenicity and pointed clinicians toward a different management strategy than before the diagnosis.

WES revealed "medically actionable" mutations associated with Marfan syndrome, Fabry's disease, hereditary cancer syndromes, cardiomyopathies, and arrhythmias, among others.

And an example of a situation in which the WES led to changes in treatment included 3 patients diagnosed with congenital myasthenia.

The sequencing also revealed new diagnoses, including a Prader-Willi-like syndrome with intellectual disability and autistic symptoms linked to mutations in MAGEL2, mitochondrial encephalopathy linked to FBXL4, and 2 unrelated cases of neurodegeneration with brain iron accumulation, traced to WDR45.

Of the diagnoses, 20% have been made in genes identified and reported in the literature during the past 3 years, the researchers note.

And although the primary use of WES has been in the pediatric setting, it has also been used successfully in adults, in preconception screening and in prenatal identification of mutations resulting in fetal akinesia and multiple congenital abnormalities.

In an interview with Medscape Medical News, ASHG President Jeffrey Murray, MD, from the University of Iowa, Iowa City, who was not involved in the study, said that the bulk of mutations that cause single-gene disorders, recessives and dominants, "are found in coding sequences" — hence the rationale behind whole-exome sequencing.

In addition, "the informatics behind whole-exome sequencing is much more amenable to interpretation. If you do the whole genome, there is tons of noise out there that is hard to wade through and know what to make of, so [WES] limits the amount of noise," he noted.

The study is supported in part by grants from the National Human Genome Research Institute. Dr. Eng and Dr. Murray report no relevant financial relationships.

American Society of Human Genetics 63rd Annual Meeting. Abstract 19, presented October 23, 2013.


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