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Review
. 2011 Nov;11(8):855-68.
doi: 10.1586/erm.11.70.

Adopting orphans: comprehensive genetic testing of Mendelian diseases of childhood by next-generation sequencing

Stephen F Kingsmore  1 , Darrell L Dinwiddie, Neil A Miller, Sarah E Soden, Carol J Saunders
Affiliations
Review

Adopting orphans: comprehensive genetic testing of Mendelian diseases of childhood by next-generation sequencing

Stephen F Kingsmore et al. Expert Rev Mol Diagn. 2011 Nov.

Abstract

Orphan diseases are individually uncommon but collectively contribute significantly to pediatric morbidity, mortality and healthcare costs. Current molecular testing for rare genetic disorders is often a lengthy and costly endeavor, and in many cases a molecular diagnosis is never achieved despite extensive testing. Diseases with locus heterogeneity or overlapping signs and symptoms are especially challenging owing to the number of potential targets. Consequently, there is immense need for scalable, economical, rapid, multiplexed diagnostic testing for rare Mendelian diseases. Recent advances in next-generation sequencing and bioinformatic technologies have the potential to change the standard of care for the diagnosis of rare genetic disorders. These advances will be reviewed in the setting of a recently developed test for 592 autosomal recessive and X-linked diseases.

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Figures

Figure 1
Figure 1. Current circle of hopelessness of orphan diseases
R&D: Research and development.
Figure 2
Figure 2. Cost per gigabase of DNA sequence
Courtesy of the National Human Genome Research Institute.
Figure 3
Figure 3. 592-disease test workflow
LIMS: Laboratory information management system; QC: Quality control; qPCR: Quantitative PCR; UDT: Universal diagnostic test; UV: Ultraviolet.
Figure 4
Figure 4. Analytic metrics of the 592-disease test
GB: Gigabase. Modified with permission from [23].
Figure 5
Figure 5. Decision tree to classify sequence variation and evaluate genotype
(A) Variant detection and genotyping, (B) variant categorization and (C) variant interpretation for recessive disorders. BLOSUM: Blocks of Amino Acid Substitution Matrix; bp: Base pair; Dx: Diagnosis; GSNAP: Genomic Short-read Nucleotide Alignment Program; Indel: Insertion-deletion; NCBI: National Center for Biotechnology Information; SD: Standard deviation.
Figure 6
Figure 6. Diagnostic metrics of the 592-disease test
GB: Gigabase; Het: Heterozygotes; Hom: Homozygotes; NPV: Negative-predictive value; PPV: Positive-predictive value; Ref: Homozygous reference alleles. Modified with permission from [23].
See this image and copyright information in PMC

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References

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    2. •• Provides a good overview of the current status of next-generation sequencing (NGS) for clinical use, including barriers to routine adoption.

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