Genetics in Medicine | Original Research Article
The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders
- Vandana Shashi MD,
- Allyn McConkie-Rosell PhD,
- Bruce Rosell BS,
- Kelly Schoch MS,
- Kasturi Vellore MD,
- Marie McDonald MD,
- Yong-Hui Jiang MD, PhD,
- Pingxing Xie PhD,
- Anna Need PhD
- & David G Goldstein PhD
- Genetics in Medicine
- (2013)
- doi:10.1038/gim.2013.99
- Accepted
- Published online
Abstract
Purpose:
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.
Conclusion:
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.
Genet Med advance online publication 8 August 2013
Keywords:
genetic diagnosis; genetic testing; medical genetics evaluation; next-generation sequencing; undiagnosed genetic disorder
References
- Costa T, Scriver CR, Childs B. The effect of Mendelian disease on human health: a measurement. Am J Med Genet 1985;21:231–242.
- Rimoin DL, Connor JM, Pyeritz RE. Nature and frequency of genetic disease, Chapter 2. In: Emery AE, Rimoin DL (eds). The Principles and Practice of Medical Genetics, 3rd edn. Churchill Livingstone: Edinburgh, NY,1997:31–34.
- Kumar P, Radhakrishnan J, Chowdhary MA, Giampietro PF. Prevalence and patterns of presentation of genetic disorders in a pediatric emergency department. Mayo Clin Proc 2001;76:777–783.
- Sagoo GS, Butterworth AS, Sanderson S, Shaw-Smith C, Higgins JP, Burton H. Array CGH in patients with learning disability (mental retardation) and congenital anomalies: updated systematic review and meta-analysis of 19 studies and 13,926 subjects. Genet Med 2009;11:139–146.
- Stevenson RE, Hall JG. Human malformations and related anomalies. In: Oxford Monographs on Medical Genetics, 2nd edn. Oxford University Press, 2006;3–75.
- van Karnebeek CD, Scheper FY, Abeling NG, et al. Etiology of mental retardation in children referred to a tertiary care center: a prospective study. Am J Ment Retard 2005;110:253–267.
- Majnemer A, Shevell MI. Diagnostic yield of the neurologic assessment of the developmentally delayed child. J Pediatr 1995;127:193–199.
- Hunter AG. Outcome of the routine assessment of patients with mental retardation in a genetics clinic. Am J Med Genet 2000;90:60–68.
- Challman TD, Barbaresi WJ, Katusic SK, Weaver A. The yield of the medical evaluation of children with pervasive developmental disorders. J Autism Dev Disord 2003;33:187–192.
- Shahdadpuri R, Lambert D, Lynch SA. Diagnostic outcome following routine genetics clinic referral for the assessment of global developmental delay. Ir Med J 2009;102:146–148.
- Schaefer GB, Lutz RE. Diagnostic yield in the clinical genetic evaluation of autism spectrum disorders. Genet Med 2006;8:549–556.
- Battaglia A, Bianchini E, Carey JC. Diagnostic yield of the comprehensive assessment of developmental delay/mental retardation in an institute of child neuropsychiatry. Am J Med Genet 1999;82:60–66.
- van Karnebeek CD, Jansweijer MC, Leenders AG, Offringa M, Hennekam RC. Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness. Eur J Hum Genet 2005;13:6–25.
- Moog U. The outcome of diagnostic studies on the etiology of mental retardation: considerations on the classification of the causes. Am J Med Genet A 2005;137:228–231.
- Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010;86:749–764.
- Shen Y, Dies KA, Holm IA, et al.; Autism Consortium Clinical Genetics/DNA Diagnostics Collaboration. Clinical genetic testing for patients with autism spectrum disorders. Pediatrics 2010;125:e727–e735.
- Moeschler JB, Amato RS, Brewster T, et al. Improving genetic health care: a Northern New England pilot project addressing the genetic evaluation of the child with developmental delays or intellectual disability. Am J Med Genet C Semin Med Genet 2009;151C:241–254.
- Engbers HM, Berger R, van Hasselt P, et al. Yield of additional metabolic studies in neurodevelopmental disorders. Ann Neurol 2008;64:212–217.
- Need AC, Shashi V, Hitomi Y, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet 2012;49:353–361.
- Rainger J, Bengani H, Campbell L, et al. Miller (Genee-Wiedemann) syndrome represents a clinically and biochemically distinct subgroup of postaxial acrofacial dysostosis associated with partial deficiency of DHODH. Hum Mol Genet 2012;21:3969–3983.
- Worthey EA, Mayer AN, Syverson GD, et al. Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med 2011;13:255–262.
- Gahl WA, Markello TC, Toro C, et al. The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases. Genet Med 2012;14:51–59.
- de Ligt J, Willemsen MH, van Bon BW, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 2012;367:1921–1929.
- Biesecker LG. Opportunities and challenges for the integration of massively parallel genomic sequencing into clinical practice: lessons from the ClinSeq project. Genet Med 2012;14:393–398.
- Biesecker LG, Burke W, Kohane I, Plon SE, Zimmern R. Next-generation sequencing in the clinic: are we ready? Nat Rev Genet 2012;13:818–824.
- Hennekam RC, Biesecker LG. Next-generation sequencing demands next-generation phenotyping. Hum Mutat 2012;33:884–886.
- Johnston JJ, Rubinstein WS, Facio FM, et al. Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. Am J Hum Genet 2012;91:97–108.
Author information
Affiliations
-
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA- Vandana Shashi,
- Allyn McConkie-Rosell,
- Bruce Rosell,
- Kelly Schoch,
- Kasturi Vellore,
- Marie McDonald &
- Yong-Hui Jiang
-
Center for Human Genome Variation, Duke University Medical Center, Durham, North Carolina, USA- Pingxing Xie,
- Anna Need &
- David G Goldstein
No hay comentarios:
Publicar un comentario