PRS AAPS Oral Proofs 2016
Mark Youngblood, BS, Brandon J. Sumpio, BA, Soonwook Hong, BS, Murat Gunel, MD, Deepak Narayan, MD
From the Yale University School of Medicine, New Haven, Conn.
PURPOSE: Lymphatic malformations are rare, sporadic congenital lesions found in lymphatic-rich tissues. Lymphatic channels become fluid filled and disconnect from the lymphatic system. Although lymphatic remodeling is done constantly in utero, 1 in 250 infants show nuchal translucency, an indicator of aberrant lymphatic development; however, 1 in 5000 newborns have lymphatic malformations. Thus remodeling must occur in utero. This article examines the genes associated with the lymphangiomas and classifies subsets of genes that may be important in downstream regulation.
METHODS: Eight lymphangioma samples with matching blood underwent whole-exome sequencing (WES) to identify somatic driver mutations. Data were preprocessed with MarkDuplicates (Picard) and BaseQualityScoreRecalibration (GATK). Variant calling was performed with HaplotypeCaller (GATK) and annotated using Annovar. The results of this discovery cohort were validated in an independent group of 30 samples using molecular inversion probe sequencing. This provided high-coverage targeted reads of genomic areas of interest identified in WES.
RESULTS: WES identified recurrent alterations to the PIK3CA gene in 3 of 8 samples. PI3K is an intracellular signaling pathway important for regulating cell cycle and cell proliferation. High-coverage targeted resequencing confirmed the variants and identified 10 additional samples with PIK3CA mutations. Twenty-three percent had the amino acid mutation at E542K and another 23% at E545K. The H1047R mutation occurred in the majority (54%) of patients.
CONCLUSIONS: We have identified 3 novels mutations in lymphangioma patients in the PIK3CA protein.