Abstract
Mosaicism is increasingly recognized as a cause of developmental disorders with the advent of next-generation sequencing (NGS). Mosaic mutations of PIK3CA have been associated with the widest spectrum of phenotypes associated with overgrowth and vascular malformations. We performed targeted NGS using 2 independent deep-coverage methods that utilize molecular inversion probes and amplicon sequencing in a cohort of 241 samples from 181 individuals with brain and/or body overgrowth. We identified PIK3CA mutations in 60 individuals. Several other individuals (n = 12) were identified separately to have mutations in PIK3CA by clinical targeted-panel testing (n = 6), whole-exome sequencing (n = 5), or Sanger sequencing (n = 1). Based on the clinical and molecular features, this cohort segregated into three distinct groups: (a) severe focal overgrowth due to low-level but highly activating (hotspot) mutations, (b) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, and (c) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Sixteen of 29 PIK3CA mutations were novel. We also identified constitutional PIK3CA mutations in 10 patients. Our molecular data, combined with review of the literature, show that PIK3CA-related overgrowth disorders comprise a discontinuous spectrum of disorders that correlate with the severity and distribution of mutations.
Highlights
Mosaicism refers to a biological phenomenon in which an individual derived from a single fertilized egg has two or more populations of cells with different genotypes
We show that the mutational spectrum in children with megalencephaly-capillary malformation syndrome (MCAP) is broader than other PIK3CA-related overgrowth disorders
We report on constitutional mutations of PIK3CA in a subset of children, some of whom have milder features such as diffuse megalencephaly with intellectual disability, similar to the PTEN-related disorders [52]
Summary
Mosaicism refers to a biological phenomenon in which an individual derived from a single fertilized egg has two or more populations of cells with different genotypes. Examples include Proteus syndrome (AKT1), Sturge-Weber syndrome (GNAQ), neurocutaneous melanosis (NRAS), epidermal nevi and linear nevus sebaceous syndrome (HRAS, KRAS, PIK3CA), Maffuci and Ollier syndromes (IDH1, IDH2), and encephalocraniocutaneous lipomatosis (FGFR1); disorders first proposed to be mosaic based on their asymmetric, patchy presentation, and lack of familial recurrence [7, 8]. Mosaic mutations of these genes were primarily identified with the advent of massively parallel or next-generation sequencing (NGS) methods that facilitate detection of low-frequency variation, especially in affected tissues
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