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. 2024 Jan;12(1):e2312.
doi: 10.1002/mgg3.2312. Epub 2023 Nov 27.

Whole exome sequencing reveals novel candidate variants for endometriosis utilizing multiple affected members in a single family

Busra Gizem Kina  1   2 , Nura Fitnat Topbas Selcuki  3 , Pinar Yalcin Bahat  4 , Taner Usta  5 , Sevcan Aydin  1   2 , Nilufer Rahmioglu  6   7 , Feyza Nur Tuncer  1 , Engin Oral  8
Affiliations

Whole exome sequencing reveals novel candidate variants for endometriosis utilizing multiple affected members in a single family

Busra Gizem Kina et al. Mol Genet Genomic Med. 2024 Jan.

Abstract

Background: 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. Thus, necessity of identifying rare variants for the missing heritability is implicated in the literature. Therefore, our study aimed to identify novel rare genetic variants involved in the pathogenesis of endometriosis utilizing a family of multiple affected members.

Methods: A family composed of four affected women along with their two unaffected mothers were recruited at a single gynecology and infertility clinic specialized in endometriosis. All patients presented with endometriomas, which was visualized by transvaginal ultrasonography. Two affected individuals had received laparoscopic endometrioma excision and therefore were diagnosed with recurrent disease. One mother had a history of endometrial serous adenocarcinoma (ESC) for which she underwent hysterectomy with bilateral oophorectomy. Three endometriosis cases were whole exome sequenced on Illumina NextSeq 550 platform with an average of 90% coverage. Candidate genes were confirmed by Sanger sequencing and followed-up with family segregation.

Results: Novel rare variants were identified in TNFRSF1B (NM_001066.3: c.1072G>A, p.(Ala358Thr)) and GEN1 (NM_001130009.3: c.1574C>T, p.(Ser525Leu)) as possible genetic causes of endometriosis. A third novel rare variant was identified in CRABP1 (NM_004378.3:c.54G>C, p.(Glu18Asp)) only on the mother with ESC history and her daughters.

Conclusion: Novel candidate genetic variants that might contribute to endometriosis were suggested that need replication through independent cohorts or validation by functional studies. The family has also received genetic counseling and that the affected daughters are on clinical follow-up, accordingly.

Keywords: endometrial serous adenocarcinoma; endometriosis; family; novel genetic variants; whole exome sequencing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Results on whole exome sequencing and segregation analysis of the family. (a) Pedigree of the family is depicted. Star sign indicates members with available genetic material; plus sign marks members subjected to whole exome sequencing (WES). (b) Integrative Genomics Viewer (IGV) images of variants detected by WES are shown. (c) Allele frequencies of pertinent variants are summarized. (d) Chromatograms of the variants in familial segregation analysis are depicted.
See this image and copyright information in PMC

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