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

Janani, Dakshina Moorthy; Ramasubramanyan, Sharada; Chellappa, Venkatesh; Rekha, Santhanam; Manickam, Ranjani; Shameli, Jeevamani; Balasundaram, Usha

doi:10.1038/s10038-022-01093-2

Cited by 5 publications

(4 citation statements)

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“…Understanding the aetiology and pathophysiology of PCOS has been a difficult task because of its plentiful causes, including environmental variables, genetic predisposition, and epigenetic changes [2,3]. On the other hand, despite having sufficient evidence to confirm the importance of familial aggregations in PCOS outcomes [7][8][9][10][11], the inheritance pattern remains unclear. PCOS affects multiple signal transduction pathways, including steroidogenesis, steroid hormone activity, gonadotrophin control, insulin secretion, energy balance, and chronic inflammation [2,4,3].…”

Section: P a G E |mentioning

confidence: 99%

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Clinical-Exome Sequencing Unveils the Genetic Landscape of Polycystic Ovarian Syndrome (PCOS) Focusing on Lean and Obese Phenotypes: Implications for Cost-Effective Diagnosis and Personalized Treatment

Dhar,

Bhattacharjee

2024

Preprint

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Background: Polycystic ovarian syndrome (PCOS) is a serious endocrine disorder that affects 15-20% of fertile women globally. It is classed as a syndrome rather than a disease because to its wide range of symptoms, which include hyperandrogenism, acne, obesity, infertility, and hair loss. Understanding the aetiology and pathophysiology of PCOS is difficult due to its multiple causes, which include environmental factors, genetic predisposition, and epigenetic modifications. Despite research supporting the role of familial aggregations in PCOS outcomes, the inheritance pattern remains unknown. The disorder has an impact on several signal transduction pathways, including steroidogenesis, steroid hormone activity, gonadotrophin regulation, insulin secretion, energy balance, and chronic inflammation. Over the last two decades, the global burden of PCOS-related infertility has risen significantly. Detecting PCOS early in youth or before puberty is critical for quick diagnosis. Objective(s): This study investigates the genetic basis behind obesity-mediated PCOS, focusing on both obese and lean individuals. It uses a comprehensive bioinformatics methodology to depict pathways and functionality enrichment, allowing for cost-effective risk prediction and management. Study design: In the present research, the study participants were chosen from a cross-sectional epidemiological survey, based on their anthropometric parameters and confirmation of PCOS. Upon voluntary participation and written consent, biological fluids (whole-blood and buccal swab) were taken from where DNA was extracted. The Clinical-exome sequencing was performed by Next-generation Illumina platform using the Twist Human Comprehensive Exome Kit. A comprehensive bioinformatics methodology was employed to identify most important unique and common genes. Results: A total of 26,550 variants were identified in clinically important exomes from two samples, with 5170 common and 2232 and 2322 unique among PCOS lean and obese phenotypes, respectively. Only 262 and 94 variants were PCOS-specific in lean and obese PCOS. Three filters were applied to shortlist the most potent variants, with 4 unique variants in lean PCOS, 2 unique variants in obese PCOS, and 5 common variants in both. The study found that leptin signalling impairment and insulin resistance, as well as mutations in CYP1A1, CYP19A1, ESR1, AR, AMH, AdipoR1, NAMPT, NPY, PTEN, EGFR, and Akt, all play significant roles in PCOS in the studied group. Conclusions: Young women in West Bengal, India, are more likely to have co-occurring PCOS, which includes estrogen resistance, leptin receptor insufficiency, folate deficiency, T2DM, and acanthosis, with obesity being a common phenotypic expression.

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Section: P a G E |mentioning

confidence: 99%

“…Its high diagnostic yield makes it costeffective and suitable for routine diagnosis in patients with a variety of phenotypes [23]. Since the last few years, a plethora of studies have been conducted to elucidate the genetic architecture of PCOS, with the majority of the studies using whole-exome sequencing methodology [9,10,[24][25][26][27].…”

Section: P a G E |mentioning

confidence: 99%

Clinical-Exome Sequencing Unveils the Genetic Landscape of Polycystic Ovarian Syndrome (PCOS) Focusing on Lean and Obese Phenotypes: Implications for Cost-Effective Diagnosis and Personalized Treatment

Dhar,

Bhattacharjee

2024

Preprint

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“…In a meta-analysis, however, the Asn680Ser was strongly associated with PCOS, whereas Thr307Ala failed to show any association 70 . A pathogenic intronic variant was recently identified in a whole-exome sequencing study conducted in an Indian cohort 71 . Similarly, a heterozygous variant in FSHR (p.Arg283Trp) was observed in a recent study on South American PCOS women 72 (Table 1).…”

Section: Gonadotropic Derangementsmentioning

confidence: 99%

“…These studies point to the INSR gene being a potential candidate for the pathogenesis of PCOS. Recently, a pathogenic intronic variant in the INSR gene was reported in a study from India employed wholeexome sequencing 71,72 . Additionally, a heterozygous likely pathogenic variant (Tyr1190His) was reported by Crespo et al in a PCOS patient with severe insulin resistance 72 .…”

Section: Insulin Resistance and Hyperinsulinemiamentioning

confidence: 99%

An Update on the Genetics of Polycystic Ovary Syndrome

Sharma,

Jain,

Tripathi

et al. 2024

JER

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PCOS is a common endocrinopathy among women of reproductive age, with a worldwide prevalence of 8 to 13%, depending on the criteria used for diagnosis. It is characterized by a constellation of features, including oligo/anovulation, clinical and/or biochemical hyperandrogenism, and polycystic ovarian morphology. PCOS is one of the common causes of female infertility. It is also associated with metabolic derangements, including obesity, insulin resistance, and compensatory hyperinsulinemia, which increase the likelihood of developing type 2 diabetes mellitus. Despite extensive research, the etiology of PCOS remains largely unknown. It seems likely that the hypothalamic-pituitary-ovarian axis dysfunction, partial folliculogenesis arrest, insulin resistance, and ovarian and adrenal androgen secretion may play a role in the pathogenesis of PCOS. Familial clustering of the cases of PCOS points to a genetic component linked with it. The initial genetic studies suggest an autosomal dominant pattern of inheritance of the disorder in some families; however, most studies support multifactorial origin. Since PCOS is a complex trait, the typical form of inheritance of PCOS follows a non-Mendelian pattern and involves complex genetic mechanisms. Studies involving linkage and association have suggested a connection between genetic variations and the risk of developing PCOS in certain families or populations. Through genome-wide association studies and next-generation sequencing techniques, several candidate genes have been identified that play a role in the etiopathogenesis of the disorder. Pathogenic variants of various genes such as INSR, IRS1, GHRL, LDLR, MC4R, ADIPOQ, UCP1, UCP2, UCP3, FTO, PCSK9, FBN3, NEIL2, FDFT1, PCSK9, CYP11, CYP17, CYP21, HSD17, STAR, POR, AKR1C3, AMH, AMHR2, INHBA, AR, SHBG, LHR, FSHR, FSH β, SRD5A, GATA4, THADA, YAP1, ERBB2, DENND1A, FEM1B, FDFT1, NEIL2, TCF7L2, etc. in some PCOS cases are linked as underlying etiologic associations. This review aims to provide insight into the current genetic knowledge about PCOS. Discovering the genetic factors and pathways involved in the disorder will help us better comprehend the underlying mechanisms of the disorder.

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Tandem mass tag-based proteomic analysis of granulosa and theca interna cells of the porcine ovarian follicle following in vitro treatment with vitamin D3 and insulin alone or in combination

Kamińska,

Świderska,

Malinowska

et al. 2025

Journal of Proteomics

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

Cited by 5 publications

References 46 publications

Clinical-Exome Sequencing Unveils the Genetic Landscape of Polycystic Ovarian Syndrome (PCOS) Focusing on Lean and Obese Phenotypes: Implications for Cost-Effective Diagnosis and Personalized Treatment

Clinical-Exome Sequencing Unveils the Genetic Landscape of Polycystic Ovarian Syndrome (PCOS) Focusing on Lean and Obese Phenotypes: Implications for Cost-Effective Diagnosis and Personalized Treatment

An Update on the Genetics of Polycystic Ovary Syndrome

Tandem mass tag-based proteomic analysis of granulosa and theca interna cells of the porcine ovarian follicle following in vitro treatment with vitamin D3 and insulin alone or in combination

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