P-301 Exome sequencing reveals novel candidate variants for endometriosis and endometrial serous adenocarcinoma in a single family having multiple affected members
Authors: Kina B.G , Topbas Selcuki N.F , Yalcin Bahat P , Usta T , Tuncer F.N , Oral E 
Published: June 2022

Abstract

Study question
Could genetic evaluation of a family, having multiple affected members with endometriosis, contribute to identifying novel rare variants for the missing heritability of the disease?

Summary answer
Two novel genetic variants one in each of TNFRSF1B and GEN1 genes detected only in all affected family members, suggesting potential new biomarkers forendometriosis.

What is known already
Endometriosis is an estrogen-dependent, chronic inflammatory disease that affects 10% of women during the reproductive ages. Despite the estimated 50% heritability for the condition, only 26% was associated with common genetic variants through GWAS studies. The necessity of identifying rare variants for the missing heritability is implicated in the literature. In this respect, only one familial study has suggested novel candidate variants utilizing whole exome sequencing (WES).

Study design, size, duration
A single family having 4 women diagnosed with endometriosis out of 6 were recruited for genetic delineation utilizing whole exome sequencing (WES). The average follow-up period of the patients were five years.

Participants/materials, setting, methods
Total of 6 women from the same family. Four women with endometriosis were diagnosed. WES was performed on these 3 women with endometriosis utilizing the Twist Core Exome Target Capture and Enrichment Kit on the Illumina Nextseq 550 platform with 50X coverage. Bioinformatics analyses along with variant prioritization at MAF &lt;1% for all normal populations were performed on Genomize SEQ platform. Candidate genes were subjected to confirmation by Sanger sequencing followed by familial segregation.

Main results and the role of chance
All endometriosis patients presented with dysmenorrhea. Additionally, one of them reported having dyschezia, one had chronic pelvic pain and the other patient complained having dyspareunia. The 3 patients who underwent WES analysis were also under treatment for endometriosis related infertility. 2 out of these 3 patients had a positive history for endometriosis surgery and presented with recurrent endometriomas. Novel heterozygous missense variants one in each of TNFRSF1B and GEN1 genes were determined in all affected members, while a novel heterozygous missense variant in CRABP1 was detected only in daughters descending from the mother with cancer history. All variants were predicted to be deleterious by in silico tools

Limitations, reasons for caution
Our findings are limited to the family of interest and needs to be replicated in larger cohorts. Designation of the novel findings as causative mutations, functional validations need to be performed.

Wider implications of the findings
The novel genetic variants detected will help in providing genetic counseling to the family. Our findings, when replicated in larger cohorts and validated functionally, will provide significant contribution to the elucidation of the molecular mechanisms of the pertinent conditions.

Trial registration number
not applicable