DNA sequencing can provide unequivocal diagnosis when a known pathogenic mutation is identified, as illustrated in the case of Sotos syndrome (Figure 21-6), in which the child is found to have a missense mutation. The mutation is determined to be pathogenic because this sequence variant has also been identified in other cases of Sotos syndrome. However, some missense mutations can be normal variants, so extra care is needed in interpreting this type of mutation change. This caveat becomes especially important when multiple genes are sequenced as part of a test panel. For example, the Charcot-Marie-Tooth group of disorders (ie, the hereditary sensory neuropathies) is caused by mutations in many different genes.12 Genetic screening for these genes can detect several missense mutations of unknown significance, and unless the missense mutation has previously been shown to be pathogenic, the significance of these mutations may be difficult to determine. Furthermore, it should be stressed that gene sequencing may not be able to detect a complete gene deletion, as only the normal allele present would be amplified and sequenced. Accordingly, in certain disorders, studies to detect gene deletions should also be pursued when the sequence testing does not identify a mutation (Table 21-4). For example, in the Sotos syndrome, 10% of individuals can have a complete gene deletion but this can be diagnosed using a FISH probe for the NSD1 gene region.13,14