Focused Exome Sequencing Gives a High Diagnostic Yield in the Indian Subcontinent.

The genetically isolated yet heterogeneous and highly consanguineous Indian population has shown a higher prevalence of rare genetic disorders. However, there is a significant socioeconomic burden for genetic testing to be accessible to the general population. In the current study, we analyzed next-generation sequencing data generated through focused exome sequencing from individuals with different phenotypic manifestations referred for genetic testing to achieve a molecular diagnosis. Pathogenic or likely pathogenic variants are reported in 280 of 833 cases with a diagnostic yield of 33.6%. Homozygous sequence and copy number variants were found as positive diagnostic findings in 131 cases (15.7%) because of the high consanguinity in the Indian population. No relevant findings related to reported phenotype were identified in 6.2% of the cases. Patients referred for testing due to metabolic disorder and neuromuscular disorder had higher diagnostic yields. Carrier testing of asymptomatic individuals with a family history of the disease, through focused exome sequencing, achieved positive diagnosis in 54 of 118 cases tested. Copy number variants were also found in trans with single-nucleotide variants and mitochondrial variants in a few of the cases. The diagnostic yield and the findings from this study signify that a focused exome test is a good lower-cost alternative for whole-exome and whole-genome sequencing and as a first-tier approach to genetic testing.

A taxonomic schema of potential pitfalls in clinical variant analysis based on real-world evidence.

The classification and interpretation of genetic variants associated with genetic diseases have been shown to vary between clinical genetic laboratories. This can lead to errors introduced in the interpretation and public presentation of genetic findings in the literature and available databases. This qualitative study utilizes real-world evidence to introduce a taxonomic schema of potential pitfalls associated with public and commercial resources commonly used for sequence variant analysis. Databases, articles and other resources continue to evolve over time. A modified and expanded version of Reason's Model of Human Error with respect to variant analysis is proposed and discussed. This study complements professional standards and published recommendations of interpretive considerations associated with variant analysis and expands the scope of professional competency.

Lost in Interpretation: Evidence of Sequence Variant Database Errors.

Variant databases serve as a resource for clinical molecular genetics laboratories. There is evidence of widespread interpretive and syntactic errors within the entries of both small and large-scale variant databases used for germline clinical molecular genetic interpretation reports. The over-dependence on variant databases for variant annotation, classification and reporting may be a potential source of error to clinical molecular genetics laboratories. Recent evidence suggests 12-50% of clinical test reports are in significant conflict with clinical reports from other laboratories. A non-systematic literature review of evidence of discrepancies within frequently used genetic variant databases used for generating clinical genetic tests is provided. The implications of and recommendations for addressing variant annotation, classification and interpretive errors are discussed.

And the helix may set you free.

The first application of DNA forensics evidence was carried out by Dr. Alec Jefferies in 1983, in a British court case that sought to identify the relationship between an emigrant and her son. Since then, genotyping technology (also known as DNA fingerprinting and genetic profiling) has been developed and applied to identifying individuals for a wide variety of purposes including exonerating convicts. Faulty forensic evidence is a common cause of wrongful convictions. And once convicted, access to the forensic evidence remains a clear barrier to possible exoneration. In fact, it is DNA exoneration that is driving state legislators to address some of the apparent legislative flaws that govern forensic evidence testing in the U.S.