• molecular genetics
• diagnostics tests

Somatic overgrowth syndromes (SOS) comprise a group of disorders that are characterised by excessive tissue growth caused by mosaic variants in genes involved in regulating cell growth/cell cycle. For example, somatic mutations in PIK3CA/AKT1 pathway cause multiple asymmetric overgrowth disorders including CLOVES syndrome, Klippel–Trenaunay syndrome, megalencephaly capillary malformation syndrome, Proteus syndrome, megalencephaly polymicrogyria polydactyly hydrocephalus syndrome and hemihyperplasia multiple lipomatosis. These disorders are characterised by segmental overgrowth with lymphatic or vascular malformations, epidermal nevi, skeletal abnormalities, fibroadipose overgrowth, megalencephaly and increased risk for cancer. Due to the somatic nature of these disorders, detection of the underlying mutations has been challenging, as it requires genetic testing to be performed on affected tissues collected surgically. This has also contributed to underdiagnosis of these conditions.

The mutation spectrum of SOS overlaps with that in cancer. For example, besides PIK3CA and AKT1, somatic mutations in many other common oncogenes, including MTOR, GNAS, GNAQ, GNA11, NRAS, IDH1, IDH2, MAP2K1, SMO and so on, are identified in various SOS.1–9 This indicates that these disorders and cancer share the same molecular mechanisms that result in excessive cellular proliferation. Furthermore, targeted therapies are either available or under investigation in clinical trials for some of the pathways. Identification of actionable …