Genome-wide diagnostic testing, including whole exome sequencing and microarray analysis, has become widely used as a first-line test for patients with a variety of clinical presentations. While these broad tests can provide a good diagnostic yield, they also have technical limitations and are unable to reliably diagnose some specific genetic conditions, including spinal muscular atrophy (SMA), congenital adrenal hyperplasia (CAH), Facioscapulohumeral Muscular Dystrophy (FSHD), imprinting disorders (Beckwith-Wiedemann syndrome, Prader-Willi syndrome, Angelman syndrome, Russel-Silver syndrome, etc.), and repeat expansion disorders (Fragile X syndrome and related disorders, Huntington disease, Myotonic Dystrophy, Friedreich’s ataxia, Spinocerebellar ataxia, etc.), among others. The mechanism underlying the condition must be considered to determine whether a test can rule out or rule in a diagnosis; if a disorder is being considered as part of the differential diagnosis and cannot reliably be detected by genome-based testing, then a disease- or gene-specific molecular diagnostic test is required. When an incorrect test is ordered, it may give a false sense of reassurance if a negative result is returned, and it could delay diagnosis for the patient. In addition, this is potentially a poor use of resources.
Sources:
Nimkarn S, et al. 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia. GeneReviews® [Internet]. 2002 Feb 26. PMID: 20301350.
Preston MK, et al. Facioscapulohumeral Muscular Dystrophy. GeneReviews®. 1999 Mar 8.
Prior TW, et al. Spinal Muscular Atrophy. GeneReviews®. 2000 Feb 24.
Wallace SE, et al. Resources for Genetics Professionals — Genetic Disorders Caused by Imprinting Errors and Uniparental Disomy Not Detectable by Sequence Analysis. GeneReviews®. 2017 Mar 14.
Wallace SE, et al. Resources for Genetics Professionals — Genetic Disorders Caused by Nucleotide Repeat Expansions and Contractions. 2017 Mar 14 GeneReviews®