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Background The genetic features and management of lateralized overgrowth have been elusive. This study was performed to investigate the causative genes and outcomes of alpelisib-treated patients with lateralized overgrowth. Methods Fourteen patients with lateralized overgrowth were enrolled. Clinical features and whole-body magnetic resonance imaging (WB-MRI) findings were evaluated. Deep sequencing with a customized 143 gene panel of affected tissue and peripheral white blood cells was performed. Propranolol was administered and clinical outcomes were examined. The PIK3CA inhibitor alpelisib was administered via a managed access program. Results Genetic testing identified PIK3CA (n = 7, 50%), KRAS (n = 2, 14.3%), PTEN (n = 1, 7.1%), MAP2K3 (n = 1, 7.1%), GNAQ (n = 1, 7.1%), TBC1D4 (n = 1, 7.1%), and TEK (n = 1, 7.1%) mutations. Propranolol was administered in 12 patients, and 7 experienced relief of symptoms. Alpelisib was administered in two volunteers with a PIK3CA mutation, and the WB-MRI after 1 year of treatment showed a reduction in proliferated masses. Conclusions Deep sequencing identified diverse genetic features of lateralized overgrowth. Targeted therapy with a PIK3CA inhibitor would be the primary therapeutic strategy for PIK3CA-related overgrowth syndrome.