The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders.
OBJECTIVE
The purpose of this study was to assess the diagnostic yield of the traditional, comprehensive clinical evaluation and targeted genetic testing, within a general genetics clinic. These data are critically needed to develop clinically and economically grounded diagnostic algorithms that consider presenting phenotype, traditional genetics testing, and the emerging role of next-generation sequencing (whole-exome/genome sequencing).


METHODS
We retrospectively analyzed a cohort of 500 unselected consecutive patients who received traditional genetic diagnostic evaluations at a tertiary medical center. We calculated the diagnosis rate, number of visits to diagnosis, genetic tests, and the cost of testing.


RESULTS
Thirty-nine patients were determined to not have a genetic disorder; 212 of the remaining 461 (46%) received a genetic diagnosis, and 72% of these were diagnosed on the first visit. The cost per subsequent successful genetic diagnosis was estimated at $25,000.


CONCLUSIONS
Almost half of the patients were diagnosed using the traditional approach, most at the initial visit. For those remaining undiagnosed, next-generation sequencing may be clinically and economically beneficial. Estimating a 50% success rate for next-generation sequencing in undiagnosed genetic disorders, its application after the first clinical visit could result in a higher rate of genetic diagnosis at a considerable cost savings per successful diagnosis.
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Vandana
V
Shashi
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Allyn
A
McConkie-Rosell
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Bruce
B
Rosell
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Kelly
K
Schoch
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Kasturi
K
Vellore
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Marie
M
McDonald
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Yong-Hui
YH
Jiang
Center for Human Genome Variation, Duke University Medical Center, Durham, North Carolina, USA.
Pingxing
P
Xie
Center for Human Genome Variation, Duke University Medical Center, Durham, North Carolina, USA.
Anna
A
Need
David B
DB
Goldstein
Center for Human Genome Variation, Duke University Medical Center, Durham, North Carolina, USA.
David G
DG
Goldstein
D000465:Algorithms; D059472:Exome; D005260:Female; D030342:Genetic Diseases, Inborn / Q000175:diagnosis* / Q000235:genetics; D005820:Genetic Testing / Q000191:economics / Q000379:methods*; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing / Q000191:economics / Q000379:methods*; D006801:Humans; D008297:Male; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA / Q000191:economics / Q000379:methods*