Molecular Diagnosis of Mosaic Overgrowth Syndromes Using a Custom-Designed Next-Generation Sequencing Panel

The Journal of Molecular Diagnostics : JMD
Fengqi ChangMarilyn M Li

Abstract

Recent studies have discovered a group of overgrowth syndromes, such as congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies (CLOVES) syndrome, Proteus syndrome, and megalencephaly-capillary malformation-polymicrogyria (MCAP) syndrome, are caused by somatic activating variants in genes involved in the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway. Because of the low-abundance nature of these variants, Sanger sequencing often yields negative results. We have developed and validated a next-generation sequencing (NGS) panel that targets all known variants associated with these syndromes. Fifty cases, including two prenatal cases, were tested using the panel. A pathogenic variant in the PIK3CA, PIK3R2, or AKT1 gene was identified in 28 of the 50 cases with the variant allele frequencies ranging from 1.0% to 49.2%. These variants were only present in the affected tissues in most of the cases, demonstrating a causal role in the development of these diseases. In vitro cell culture showed significant enrichment of the cells harboring variant alleles, suggesting that these variants render growth advantages to mutant cells. Phenotype-genotype correlation analysis showed PIK3CA muta...Continue Reading

Citations

Feb 16, 2018·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Lara Rodriguez-LagunaVictor Martinez-Glez
Feb 15, 2019·Molecular Genetics & Genomic Medicine·Emilie LalondeArupa Ganguly
Jul 31, 2019·Current Opinion in Pediatrics·Antonio Martinez-LopezSalvador Arias-Santiago
Sep 17, 2020·Birth Defects Research·Katherine AbellHoward M Saal
Nov 7, 2019·Current Opinion in Pediatrics·Antonio Martinez-LopezSalvador Arias-Santiago
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Jul 11, 2018·Clinical Case Reports·Virginia ValentiniLaura Ottini
Mar 8, 2019·Nature Reviews. Endocrinology·Frédéric BrioudeIrene Netchine
Mar 9, 2021·American Journal of Medical Genetics. Part a·Jirat ChenbhanichJoseph T Shieh
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Jul 21, 2021·Medicina clínica·Adriana Iriarte FusterAntoni Riera-Mestre

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AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.

CLOVES Syndrome

Congenital, Lipomatous, Overgrowth, Vascular Malformations, Epidermal Nevi and Spinal/Skeletal Anomalies and/or Scoliosis (CLOVES) syndrome is a rare genetic disorder caused by mutations in the PIK3CA gene. Symptoms include blood vessel abnormalities, small tissue tumors, skin legions and spinal abnormalities. Here is the latest research on CLOVES syndrome.

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