Course: Interpreting Genomic Variation: Overcoming Challenges in Diverse Populations

ACMG/AMP guidelines The current guidelines for variant classification and interpretation stem from the expert opinion of the workgroup convened by the American College of Medical Genetics and Genomics (ACMG) in …

Given the number of different types of variants, researchers and clinicians must describe them in a standardised manner to avoid any confusion. The Human Genome Variation Society (HGVS) defined a …

In recent years, state-of-the-art artificial intelligence (AI) has been applied to improve the variant interpretation process. Implementing AI algorithms is especially helpful when a large amount of data needs to …

Iterative analysis refers to the practice of revisiting and reanalysing patient data (both clinical and genomic data) where a disease-causing variant could not be identified initially. This is a very …

The Human, Hereditary and Health in Africa initiative (H3Africa) aims to build capacity and resources that enable African scientists to perform globally competitive genomic research on the African continent. The …

One of the first diagnostic variants identified from the Deciphering Developmental Disorder in Africa (DDD-Africa) study was a variant linked with Takenouchi-Kosaki syndrome in this patient, which to our knowledge …

When interpreting genomic variation in diverse populations one is almost guaranteed that uncertainty will be a factor to deal with at times. The limitations to knowledge and resources representing patients …

In almost all regions in the world, there will be populations where consanguineous relationships are practised. In some regions, like the Middle East, Africa, and South Asia, consanguineous marriages are …

So far, we have focused on the classification and interpretation of pathogenic and benign variants. In the next steps, we will detail how to address variants of uncertain significance (VUS). …

In-house datasets of genomic variations comprise variants identified in individuals sequenced locally at clinical or research centres. Unlike population databases, which primarily aim to catalogue variations in unaffected individuals, in-house …

A childhood onset, highly penetrant severe disease probably offers an oversimplified setting for variant interpretation. This is particularly true if the variant effect size is large. However, we are often …

Determining a dose-sensitive gene or region The ClinGen Dosage Sensitivity working group collects evidence supporting/refuting the haploinsufficiency and triplosensitivity of genes and genomic regions, making the data publicly available and …

So far we presented and discussed single nucleotide changes in the DNA sequence. Here we will focus on the guidelines for investigating copy number variants. Copy number variant (CNV) classification …

In silico prediction tools can be used to provide evidence for a variant being pathogenic or benign, and are particularly useful for annotating missense variants. In the ACMG/AMP classification framework, …

Gene level predictive scores can be used to determine if a gene is likely to be associated with disease and identify the molecular mechanism. These scores are often calculated from …