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Whole exome and targeted sequencing reveal novel mutations associated with inherited PCOS condition in an Indian cohort

Abstract

A cohort of polycystic ovary syndrome (PCOS) women presents themselves with persistent abnormal reproductive hormone levels and has a familial representation of characteristics. In our study, we have aimed to identify genetic variants which are inherited across such PCOS families and also validate them among Indian population. Independent discovery was done by whole exome sequencing in a three-generation family (Family P01). Validation was done by targeted sequencing at 30,000x using HaloPlex panel in 9 families (P01-P09). The variants were filtered and reported according to American College of Medical Genetics and Genomics (ACMG) guidelines. Mutation burden analysis and in-silico functional analyses were performed. After careful annotation analyses, we report 24 likely pathogenic variants from 21 genes, out of which 8 are novel structural variants, 14 missense variants and 2 intronic variants. Out of these, 3 variants from the genes FSHR, SCARB1, and INSR are involved in the ovarian steroidogenesis pathway and 5 variants from genes DFFB, ACTG1, GPX4, CYC1 and ALDOA directly or indirectly trigger the apoptotic pathways. Three ovarian steroidogenesis variants, FSHR, SCARB1 and INSR were screened among Indian women using a case-control approach to validate these variant’s pathogenicity in Indian PCOS women. Variants of SCARB1 and INSR were found to be pathogenic to Indian PCOS women, while FSHR variants did not show significant association to PCOS cases.

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Data availability

WES sequence data for the five samples used as the discovery sample set and used for creating panel for targeted sequencing is submitted to the SRA with accession number SUB8748632. Also, novel variants from panel SNP data listed in Table 2a & 2b have been submitted to the dbSNP and dbVar and ClinVar.

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Acknowledgements

We are very grateful to the families who participated in the study. The authors are thankful to Dr.Rajapriya Ayyappan, M.D., FRCOG (London), Om Fertility Clinic, Chennai, Tamil Nadu, India for her support in clinical confirmation of the PCOS patients. We would also like to thank Dr. Vinod Scaria, M.B.B.S, Ph.D., Senior Scientist, CSIR-IGIB, New Delhi, India for his suggestions and guidance in the methodology. The team from PCOS Foundation, India supported the authors in identifying PCOS volunteers for this study and also in database management.

Funding

The author DMJ was supported by Women Scientist Scheme – A, Department of Science and Technology, Government of India for carrying out this research work (WOS-A/LS-253/2017).

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DMJ: Conceptualization, data curation, data analysis, funding acquisition, software visualization, and manuscript writing. SR: formal analysis and methodology design. VC: formal analysis, investigation, and software support. RS: Conceptualization and formal analysis. RM: methodology and data analysis. SJ: case control study. UB: conceptualization, funding acquisition, Investigation, supervision, validation, and manuscript review.

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Correspondence to Usha Balasundaram.

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Janani, D.M., Ramasubramanyan, S., Chellappa, V. et al. Whole exome and targeted sequencing reveal novel mutations associated with inherited PCOS condition in an Indian cohort. J Hum Genet 68, 39–46 (2023). https://doi.org/10.1038/s10038-022-01093-2

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