May 10, 2012 — A practical test of the value of exome sequencing in diagnosing children with unexplained intellectual disabilities, developmental delay, and/or congenital anomalies in a clinical setting has yielded very promising results. Of 12 children in the study, investigators found diagnostic mutations in 7. The study is scheduled for publication online May 11 in the Journal of Medical Genetics.
Exome sequencing focuses on the protein-encoding parts of the genome, which include most of the genes behind single-gene disorders. The technology, which uses next-generation sequencing, is increasingly being used to solve diagnostic challenges.
Anna Need, PhD, from the Center for Human Genome Variation, Duke University School of Medicine, Durham, North Carolina, and colleagues sequenced the exomes of 12 children with unaffected parents in whom single-gene tests or chromosomal microarray tests had not led to diagnosis. The study differed from others in that it did not compare DNA sequences among patients with the same phenotype.
Each child met at least 2 criteria: intellectual disability and/or developmental delay, 1 major congenital anomaly, 2 to 3 minor congenital anomalies, and facial dysmorphia. Teratogen exposure, asphyxia at birth, or trauma could not have caused the symptoms.
Variants of uncertain significance were not reported to the parents. The researchers confirmed potentially causal variants with a Clinical Laboratory Improvement Amendments–certified laboratory before a genetic counselor discussed the findings with the parents.
The study detected 19 de novo variants. Of the 12 probands, 6 received likely genetic diagnoses, and 4 of those had mutations in genes known to cause Mendelian disorders (TCF4, EFTUD2, SCN2A, and SMAD4). A seventh proband had a mutation in EFTUD2 that explained 1 clinical feature, macular degeneration. The detected mutations were novel and the phenotypes atypical.
The authors cite several advantages of exome sequencing. Many patients feel relief on receiving a diagnosis, even if treatment is unavailable, said coauthor Vandana Shashi, MD, in a prepared statement. The information is important in genetic counseling because if a child's mutation arose de novo, then siblings would not face elevated risk. This would not be the case if the parents have the mutation, but not the phenotype (ie, the gene is incompletely penetrant).
Identifying a mutation can also inform preventive care. For example, physicians would advise the parents of the child with the mutation in SCN2A, which encodes a sodium channel protein, to avoid certain antiseizure drugs that worsen symptoms. A final advantage is economic: Dozens of single-gene tests can easily cost more than exome sequencing.
Sequencing exomes will lead to more diagnostic tests. Coauthor David Goldstein, PhD, suggests in a prepared statement that tertiary medical centers set up large genetic databases to facilitate diagnoses and that discovery of how the functions of the identified genes cause symptoms be used to select treatments.
Finding mutations in 4 known genes in children who had not been diagnosed using conventional genetic tests suggests reassessment of some Mendelian disorders. "It may be possible to identify conditions with broader phenotypic presentations than is possible in the strictly 'phenotype first' framework," the researchers write.
Exome sequencing has limitations. It does not detect mitochondrial disorders, uniparental disomy, epigenetic changes, incomplete penetrance, copy number variants, control sequences, epistatic interactions, or all exons.
The authors have disclosed no relevant financial relationships.
J Med Genet. Published online May 11, 2012.
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Cite this: Next-Generation Exome Sequencing Works in Clinical Setting - Medscape - May 10, 2012.