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Whole exome sequencing identify hemizygous deletions in ugt2b28 and usp17l2 in a three-generation family with endometriosis

2018; Elsevier BV; Volume: 110; Issue: 4 Linguagem: Inglês

10.1016/j.fertnstert.2018.07.1085

1556-5653

Hans Albertsen, George N. Goulielmos, Rakesh Chettier, Charoula Matalliotaki, Maria I. Zervou, Michail Matalliotakis, Kristel L. Ward,

Endometriosis Research and Treatment

Endometriosis is a highly heritable disorder; yet common genetic variations identified by genome-wide association studies explain less than 5% of the heritability suggesting that recent familial mutations might be responsible for part of the missing heritability. Next generation sequencing gives the opportunity to look for less-common variants with large effects. In this study, we looked for deleterious exonic variants in a three-generation family with seven affected women with surgically confirmed endometriosis. Whole exome sequencing was performed on seven related women with surgically confirmed endometriosis (grandmother, 3 daughters, 3 granddaughters). Exome sequencing was performed using the AmpliSeq technology on Ion Proton platform (Thermo Fisher, Inc). Variants were determined using Ion Proton protocol and confirmed using the GATK (Genome Analysis Toolkit) pipeline. Deletions were identified by observing three-or-more homozygous neighboring variants in the matriarch that failed to segregate in a Mendelian manner in her daughters/grand-daughters. We identified two hemizygous deletions segregating in this three-generation family. A deletion was found in UGT2B28, spanning seven informative sequence variants across at least 14kb, a deletion in USP17L2 spans three informative variants across at least 2kb. Both deletions are present in the affected grand-mother and segregate in as many as four and five of her descendants respectively. These results implicate two additional genes in the pathogenesis of endometriosis. UGT2B28 is phase II detoxification gene involved in glucuronidation of many substrates including steroid hormones and lipid-soluble drugs. Copy number variation of UGT2B28 affects steroid hormone abundance and has been implicated in cancer risk and progression. USP17L2 is a deubiquitinase that regulates key cellular processes like proliferation, migration and apoptosis through the activation of small GTPases like RAC1A, CDC42 and RHOA. USP17L2 plays a central role in the regulation of the transcription factors SNAIL, SLUG and TWIST which are key gate-keepers of epithelial-to-mesenchymal transition (EMT). We have previously proposed that the pathogenesis of endometriosis involves loss of mesothelial barrier integrity and we speculate that dosage dependent loss of USP17L2 increases the risk for developing endometriosis.