RESUMO
Background: Neurodevelopmental disorders are a group of conditions characterized by developmental delays leading to abnormal brain functions. The methods of diagnosis and treatment of these conditions are complicated, and their treatment involves a combination of various forms of therapy. In recent years, the development of high-resolution technologies has played an important role in revealing the microdeletions, microduplications, and single-nucleotide variants of the chromosomes and how they are linked to the development of neurodevelopmental disorders. The wide implementation and application of molecular methodologies have started to shed light on the functional importance of using the appropriate methods in detecting these genetic variations that are categorized as either pathogenic or benign. The study aimed to compare the diagnostic yield of comparative hybridization (CGH) and whole exome sequencing (WES) in neurodevelopmental disorders among children attending the King Abdullah Specialist Children Hospital, Riyadh, Saudi Arabia. Methods: A retrospective study was conducted between 2015 and 2018 on 105 patients diagnosed with neurodevelopmental disorders through array-based CGH (Array-CGH) and WES. Results: In a sample of 105 patients, 16% was the hit rate of copy number variations (CNVs). WES was requested for CNV-negative patients (n = 79), of which 30% was the hit rate of pathogenic or likely pathogenic single-nucleotide variants. There was a difference in the diagnostic yield between CGH (16%) and WES (30%). Conclusion: WES was a better approach than Array-CGH to detect various DNA mutations or variants. Our findings could guide clinicians, researchers, and testing laboratories select the most cost-effective and appropriate approach for diagnosing their patients.
RESUMO
BACKGROUND: Testing strategies is crucial for genetics clinics and testing laboratories. In this study, we tried to compare the hit rate between solo and trio and trio plus testing and between trio and sibship testing. Finally, we studied the impact of extended family analysis, mainly in complex and unsolved cases. METHODS: Three cohorts were used for this analysis: one cohort to assess the hit rate between solo, trio and trio plus testing, another cohort to examine the impact of the testing strategy of sibship genome vs trio-based analysis, and a third cohort to test the impact of an extended family analysis of up to eight family members to lower the number of candidate variants. RESULTS: The hit rates in solo, trio and trio plus testing were 39, 40, and 41%, respectively. The total number of candidate variants in the sibship testing strategy was 117 variants compared to 59 variants in the trio-based analysis. We noticed that the average number of coding candidate variants in trio-based analysis was 1192 variants and 26,454 noncoding variants, and this number was lowered by 50-75% after adding additional family members, with up to two coding and 66 noncoding homozygous variants only, in families with eight family members. CONCLUSION: There was no difference in the hit rate between solo and extended family members. Trio-based analysis was a better approach than sibship testing, even in a consanguineous population. Finally, each additional family member helped to narrow down the number of variants by 50-75%. Our findings could help clinicians, researchers and testing laboratories select the most cost-effective and appropriate sequencing approach for their patients. Furthermore, using extended family analysis is a very useful tool for complex cases with novel genes.