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Identification of Novel Gene Mutations in Lymphatic Malformation Patients
Mark Youngblood, BS, Brandon J. Sumpio, BA, Soonwook Hong, BS, Murat Gunel, MD, Deepak Narayan, MD.
Yale University School of Medicine, New Haven, CT, USA.

PURPOSE:
Lymphatic malformations are rare, sporadic congenital lesions found in lymphatic-rich tissues. Lymphatic channels become fluid filled and disconnect from the lymphatic system.
While 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 paper 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 was pre-processed 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 three of eight samples. PI3K is an intracellular signaling pathway important for regulating cell cycle and cell proliferation. High-coverage targeted re-sequencing confirmed the variants and identified ten additional samples with PIK3CA mutations. 23% had the amino acid mutation E542K and another 23% at E545K. The H1047R mutation occurred in the majority (54%) of patients.
CONCLUSION:
We have identified 3 novels mutations in lymphangioma patients in the PIK3CA protein.


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