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The goal of molecular diagnostic testing is to provide definitive diagnoses for suspected or unknown genetic conditions. A precise diagnosis is important for determining what caused a particular birth defect, for making an accurate cancer diagnosis, for assessing predisposition to adult disorders, or for providing potential therapeutic targets for present and future treatments. There are dozens of molecular-genetic techniques that are currently utilized, all with the common purpose of determining pathologic variations in the primary nucleotide sequence in the affected subject. Clinical molecular testing can be divided into those tests that look at the sequence of a specific single gene, or a more shotgun approach where panels of genes or whole exomes/genomes are sequenced in order to identify the cause of the presenting condition. However, whole exome/genome sequencing provides the individual not only with a diagnosis that explains current symptoms, but also incidental medically actionable health information that may have significant implications for the patient and his/her family. Incidental actionable medical information includes detecting carrier status for a known mendelian disorder, finding susceptibility genes for various cancers, such as BRCA1/BRCA2, or discovering genetic changes that affect response to certain drugs.


Most of the testing in molecular genetics has focused on region(s) of DNA that encode proteins (see Chapter 1, Figure 1-1).1 These coding regions are called exons. The terms “mutation” and “variant” are used here interchangeably and may be pathogenic, benign or of unknown significance. We can interpret nucleotide variations easier if we find pathogenic mutations (pathogenic variants) that alter protein structure. On the other hand, many mutations can also occur outside of the coding regions of the gene, and these may involve regulatory components of the genome, such as promoters and enhancers, that regulate gene expression, or affect messenger RNA stability (mutations in the 5′ or 3′ untranslated gene regions, known as UTRs). Mutations can partially affect gene function by rendering a protein less efficient to perform its functions (androgen receptor mutations that cause incomplete androgen insensitivity syndrome), by completely abolishing the function of the protein (CYP21A2 mutations that cause the classic form of congenital adrenal hyperplasia), by interfering with the function of the native protein (dominant negative mutations of fibrillin that cause Marfan syndrome), or by making the protein more active (fibroblast growth factor receptor 3 gene gain of function mutations that cause achondroplasia). Mutations can result from changes in a single nucleotide (point mutation) or multiple nucleotides (deletions, duplications, insertions). Point mutations within the coding region of the gene (exons) may have multiple consequences. It may cause no change in the amino acid (neutral or synonymous mutation and likely benign), may change amino acid (missense or nonsynonymous mutation which may or may not be pathogenic), or may introduce a stop codon (nonsense mutation which usually tend to be pathogenic). Point mutations outside of the exonic regions can affect splicing of ...

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