Dataset Information

DLG2 variants in patients with pubertal disorders.

ABSTRACT: PURPOSE:Impaired function of gonadotropin-releasing hormone (GnRH) neurons can cause a phenotypic spectrum ranging from delayed puberty to isolated hypogonadotropic hypogonadism (IHH). We sought to identify a new genetic etiology for these conditions. METHODS:Exome sequencing was performed in an extended family with autosomal dominant, markedly delayed puberty. The effects of the variant were studied in a GnRH neuronal cell line. Variants in the same gene were sought in a large cohort of individuals with IHH. RESULTS:We identified a rare missense variant (F900V) in DLG2 (which encodes PSD-93) that cosegregated with the delayed puberty. The variant decreased GnRH expression in vitro. PSD-93 is an anchoring protein of NMDA receptors, a type of glutamate receptor that has been implicated in the control of puberty in laboratory animals. The F900V variant impaired the interaction between PSD-93 and a known binding partner, Fyn, which phosphorylates NMDA receptors. Variants in DLG2 that also decreased GnRH expression were identified in three unrelated families with IHH. CONCLUSION:The findings indicate that variants in DLG2/PSD-93 cause autosomal dominant delayed puberty and may also contribute to IHH. The findings also suggest that the pathogenesis involves impaired NMDA receptor signaling and consequently decreased GnRH secretion.

SUBMITTER: Jee YH

PROVIDER: S-EPMC7510947 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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DLG2 variants in patients with pubertal disorders.

Jee Youn Hee YH Won Sehoon S Lui Julian C JC Jennings Melissa M Whalen Philip P Yue Shanna S Temnycky Adrian G AG Barnes Kevin M KM Cheetham Tim T Boden Matthew G MG Radovick Sally S Quinton Richard R Leschek Ellen W EW Aguilera Greti G Yanovski Jack A JA Seminara Stephanie B SB Crowley William F WF Delaney Angela A Roche Katherine W KW Baron Jeffrey J

Genetics in medicine : official journal of the American College of Medical Genetics 20200428 8

<h4>Purpose</h4>Impaired function of gonadotropin-releasing hormone (GnRH) neurons can cause a phenotypic spectrum ranging from delayed puberty to isolated hypogonadotropic hypogonadism (IHH). We sought to identify a new genetic etiology for these conditions.<h4>Methods</h4>Exome sequencing was performed in an extended family with autosomal dominant, markedly delayed puberty. The effects of the variant were studied in a GnRH neuronal cell line. Variants in the same gene were sought in a large co ...[more]

PMID: 32341572

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Project description:Study questionIs pubertal timing associated with risk of premenstrual disorders (PMDs) in young adulthood?Summary answerLate pubertal development is associated with decreased premenstrual symptom burden and risk of PMDs in young adulthood.What is known alreadyPMDs, including premenstrual syndrome and premenstrual dysphoric disorder, may begin during the teenage years. Few risk factors in early life have been identified for PMD development.Study design, size, durationA prospective cohort study of 6495 female participants during 1996-2013.Participants/materials, setting, methodsWe included participants from the Growing Up Today Study (GUTS). Pubertal development was indicated by the timing of menarche, breast and pubic hair growth. Self-reported age at menarche was longitudinally assessed at enrollment (in 1996/2004 for GUTS I/II) and onwards, and classified as early (age ≤ mean - SD, 11.64 years), normative and late menarche (age ≥ mean + SD, 13.95 years). Timing of pubic hair and breast growth were assessed multiple times during follow-up via Tanner scales, and classified into early, normative and late development according to mean ± SD. Using a validated questionnaire based on the Calendar of Premenstrual Experiences, we assessed premenstrual symptoms and identified probable cases of PMDs in 2013. We examined the associations of timing of pubertal development with premenstrual symptom score and disorders using multivariable linear and logistic regressions, respectively.Main results and the role of chanceIn 2013 (mean age = 26), 1001 (15.4%) individuals met criteria for a PMD. An inverse association was found between age at menarche and premenstrual symptom z-score (β -0.05 per year, 95% CI -0.07 to -0.03) and risk of PMDs (odds ratio (OR) 0.93 per year, 95% CI 0.88 to 0.99). Compared to individuals with normative menarche, individuals with late menarche had a lower risk of PMDs (OR 0.73, 95% CI 0.59 to 0.91), while individuals with early menarche had comparable odds (OR 0.98, 95% CI 0.81 to 1.18). Moreover, early growth of pubic hair was associated with increased premenstrual symptoms (z-score β 0.09 per year, 95% CI 0.02 to 0.17) and PMD risk (OR 1.28, 95% CI 1.04 to 1.56), independent of age at menarche. No associations were noted for breast development.Limitations, reasons for cautionOne major limitation is some misclassification of menarche due to recall. We, however, showed robust association among participants who were premenarcheal at baseline.Wider implications of the findingsOur findings suggest that pubertal timing, particularly timing of menarche, is inversely associated with the risk of developing premenstrual symptoms in young adulthood, and that women with later menarche have significantly lower risk of PMDs. Information on PMDs should be provided to teenage girls and their parents. If these findings are confirmed in independent populations, prevention strategies and early detection programs may be considered for women with early pubertal development.Study funding/competing interest(s)The work is supported by the National Institutes of Health and Swedish Research Council.Trial registration numberN/A.

Project description:Importance:Mutations in the titin gene (TTN) cause a wide spectrum of genetic diseases. The interpretation of the numerous rare variants identified in TTN is a difficult challenge given its large size. Objective:To identify genetic variants in titin in a cohort of patients with muscle disorders. Design, Setting, and Participants:In this case series, 9 patients with titinopathy and 4 other patients with possibly disease-causing variants in TTN were identified. Titin mutations were detected through targeted resequencing performed on DNA from 504 patients with muscular dystrophy, congenital myopathy, or other skeletal muscle disorders. Patients were enrolled from 10 clinical centers in April 2012 to December 2013. All of them had not received a diagnosis after undergoing an extensive investigation, including Sanger sequencing of candidate genes. The data analysis was performed between September 2013 and January 2017. Sequencing data were analyzed using an internal custom bioinformatics pipeline. Main Outcomes and Measures:The identification of novel mutations in the TTN gene and novel patients with titinopathy. We performed an evaluation of putative causative variants in the TTN gene, combining genetic, clinical, and imaging data with messenger RNA and/or protein studies. Results:Of the 9 novel patients with titinopathy, 5 (55.5%) were men and the mean (SD) age at onset was 25 (15.8) years (range, 0-46 years). Of the 4 other patients (3 men and 1 woman) with possibly disease-causing TTN variants, 2 (50%) had a congenital myopathy and 2 (50%) had a slowly progressive distal myopathy with onset in the second decade. Most of the identified mutations were previously unreported. However, all the variants, even the already described mutations, require careful clinical and molecular evaluation of probands and relatives. Heterozygous truncating variants or unique missense changes are not sufficient to make a diagnosis of titinopathy. Conclusions and Relevance:The interpretation of TTN variants often requires further analyses, including a comprehensive evaluation of the clinical phenotype (deep phenotyping) as well as messenger RNA and protein studies. We propose a specific workflow for the clinical interpretation of genetic findings in titin.

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DLG2 variants in patients with pubertal disorders.

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DLG2 variants in patients with pubertal disorders.

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