Abstract
Rapid advances in molecular techniques provide multiple testing options available to the clinician. Currently, with the combination of clinical expertise and state-of-the-art molecular genetic testing a specific diagnosis can be identified in approximately 50% of patients evaluated in genetics clinic. Considerations for choosing the best test in a given diagnostic situation will depend on the availability of the testing platform, whether parental samples are required as part of the evaluation, cost effectiveness and the greatest diagnostic yield. In particular, traditional G-banded chromosome studies have a diagnostic yield of 3-5%; they are still the test of choice for a suspected chromosomal disorder such as Trisomy 21, but have the disadvantage of requiring tissue culture facilities. In contrast, DNA microarrays and next generation sequencing platforms do not require tissue culture and have an increased diagnostic yield of 12-15% and 25-30%, respectively. However, the identification of variants of unknown significance (VUS) is common to both DNA microarrays and next generation sequencing. Using these genetic testing platforms may require extensive interrogation of databases and analysis of parental samples to determine the significance of a specific finding. DNA microarrays are the current recommended first-line test for individuals with multiple anomalies, developmental and intellectual disabilities, and autism by the American College of Medical Genetics. The results of 10 years of experience using BAC and oligo DNA microarray panels at Group Health Cooperative (GHC) conservatively identified a genomic imbalance in 16.2% (36/222) of the patients tested, with a similar number of patients (14.9%) with an identified VUS. During a limited clinical study of 20 patients in Viet Nam with congenital anomalies and developmental and intellectual disabilities, 22% were found to have an identified pathogenic genomic abnormality and 22% had a VUS. While the sensitivity associated with new molecular techniques has resulted in an increased diagnostic yield and an expanded spectrum of clinical phenotypes, it has been complicated by the high rate of VUS identification. These issues will be addressed as more patients of varied ethnic backgrounds are studied and international collaborations integrate clinical findings and molecular results across global populations. Medical genetics services are essential to ensure that patients receive the most appropriate genetic testing, result interpretation, and follow-up testing for VUSs, as indicated, to allow appropriate medical care, surveillance and recurrence risk counseling for both the patient and extended family.