Genetic analysis of failed male puberty using whole exome sequencing
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Maleeha Akram
,
David J. Handelsman
Abstract
Objectives
Although at least 598 genes are involved in the development of the hypothalamo–pituitary–testicular (HPT) axis, mutations in only 75 genes have so far been shown to cause delayed puberty.
Methods
Six male patients with failed puberty, manifested as absence of pubertal changes by 18 years of age, underwent whole exome sequencing of genomic DNA with subsequent bioinformatics analysis and confirmation of selected variants by Sanger sequencing. Genes having plausibly pathogenic non-synonymous variants were characterized as group A (previously reported to cause delayed puberty), group B (expressed in the HPT-axis but no mutations therein were reported to cause delayed puberty) or group C (not reported previously to be connected with HPT-axis).
Results
We identified variants in genes involved in GnRH neuron differentiation (2 in group A, 1 in group C), GnRH neuron migration (2 each in groups A and C), development of GnRH neural connections with supra-hypothalamic and hypothalamic neurons (2 each in groups A and C), neuron homeostasis (1 in group C), molecules regulating GnRH neuron activity (2 each in groups B and C), receptors/proteins expressed on GnRH neurons (1 in group B), signaling molecules (3 in group C), GnRH synthesis (1 in group B), gonadotropins production and release (1 each in groups A, B, and C) and action of the steroid hormone (1 in group A).
Conclusions
Non-synonymous variants were identified in 16 genes of the HPT-axis, which comprised 4 in group A that contains genes previously reported to cause delayed puberty, 4 in group B that are expressed along HPT-axis but no mutations therein were reported previously to cause delayed puberty and 8 in group C that contains novel candidate genes, suggesting wider genetic causes of failed male puberty.
Funding source: Higher Education Commission, Pakistan https://www.hec.gov.pk/english/scholarshipsgrants/IRSIP/Pages/default.aspx
Award Identifier / Grant number: I-8/HEC/HRD/2017/7920
Acknowledgments
The authors acknowledge the Higher Education Commission (HEC), Islamabad, Pakistan for providing funds for this work. The authors also acknowledge the Shifa International Hospitals Ltd., Islamabad, Pakistan, Military Hospital, Rawalpindi, Pakistan, and Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan, for allowing the researcher to collect blood samples and other relevant information from the patients. The authors are grateful to the Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan, for giving the researcher access to their Lab for DNA extraction. The authors are grateful to The ANZAC Research Institute, NSW, Australia, for accommodating and helping the researcher during her stay in Australia.
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Research funding: The research work was funded by the Higher Education Commission, Islamabad, Pakistan with the award I.D. I-8/HEC/HRD/2017/7920. The funding organization played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission. Ms. Maleeha Akram and Prof. Dr. Syed Shakeel Raza Rizvi conceived and Ms. Maleeha Akram conducted the experiments as part of her Ph.D. research work. Prof. Dr. David J. Handelsman and Dr. Marina Kennerson helped in bioinformatics analysis of whole exome sequencing results, Sanger sequencing and the work performed at The ANZAC Research Institute, NSW, Australia. Dr. Shahid Ahmed and Dr. Osama Ishtiaq gave access to their patients and helped in samples and data collection. Dr. Muhammad Ismail and Mr. Qaisar Mansoor gave access to their Laboratory and helped in extraction of DNA from blood samples. Ms. Sania Rauf and Dr. Afzaal Ahmed Naseem helped in samples collection, undertaking the research and analysis of data. Prof. Dr. Syed Shakeel Raza Rizvi, Prof. Dr. Mazhar Qayyum and Prof. Dr. David J. Handelsman designed the experiment, supervised the research work during its execution and helped Ms. Maleeha Akram in the write up of this manuscript. Prof. Dr. Syed Shakeel Raza Rizvi and Prof. Dr. David J. Handelsman reviewed the manuscript. All authors read and approved the manuscript.
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Competing interests: Authors state no conflict of interest.
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Informed consent: Informed consent was obtained from all individuals included in this study.
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Ethical approval: The research related to human use has complied with all the relevant national regulations, institutional policies, and in accordance with the tenets of the Helsinki Declaration. The study was approved by the Ethics Committee for use of Human Subjects, Pir Mehr Ali Shah Arid Agriculture University Rawalpindi, Pakistan, and the Institutional Review Board and Ethics Committee, Shifa International Hospitals Ltd., Islamabad, Pakistan. The reference number for the Institutional Review Board and Ethics Committee, Shifa International Hospitals Ltd., Islamabad, Pakistan, was “IRB# 620-068-2016.” The research work was performed in accordance with the Declaration of Helsinki. An informed written consent was obtained from patients and/or their guardians.
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© 2022 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Review Article
- Effects of exercise combined with diet intervention on body composition and serum biochemical markers in adolescents with obesity: a systematic review and meta-analysis
- Mini Review
- Effect of stimulants on final adult height
- Original Articles
- Organic acidemias in the neonatal period: 30 years of experience in a referral center for inborn errors of metabolism
- The long-term growth, cost-effectiveness, and glycemic effects of growth hormone therapy on children born small for gestational age over 10 years: a retrospective cohort study
- Standard and high dose ergocalciferol regimens for treatment of hypovitaminosis D in epileptic children and adolescents
- Children and adolescents with type 1 diabetes mellitus in Nigeria: clinical characteristics and compliance with care
- Disordered eating and behaviors among young Egyptians with type 1 diabetes: risk factors and comorbidities
- Normal or elevated prolactin is a good indicator to show pituitary stalk interruption syndrome in patients with multiple pituitary hormone deficiency
- No pubertal growth spurt, rapid bone maturation, and menarche post GnRHa treatment in girls with precocious puberty
- Genetic analysis of failed male puberty using whole exome sequencing
- Gender diversity in adolescents with polycystic ovary syndrome
- Case Reports
- Management challenges of Rabson Mendenhall syndrome in a resource limited country: a case report
- Thyroid function tests of iodine deficiency goiter can mimic thyroid hormone resistance alpha
- Pseudohypoaldosteronism associated with hypertrophic cardiomyopathy, hypertension and thrombocytosis due to mutation in the ELAC2 gene: a case report
- Acromicric dysplasia due to a novel missense mutation in the fibrillin 1 gene in a three-generation family
- A case of severe systemic type 1 pseudohypoaldosteronism with 10 years of evolution
- Advantages of monitoring rT3 and dividing LT3 dose in the treatment of consumptive hypothyroidism associated with infantile hepatic hemangioma
Articles in the same Issue
- Frontmatter
- Review Article
- Effects of exercise combined with diet intervention on body composition and serum biochemical markers in adolescents with obesity: a systematic review and meta-analysis
- Mini Review
- Effect of stimulants on final adult height
- Original Articles
- Organic acidemias in the neonatal period: 30 years of experience in a referral center for inborn errors of metabolism
- The long-term growth, cost-effectiveness, and glycemic effects of growth hormone therapy on children born small for gestational age over 10 years: a retrospective cohort study
- Standard and high dose ergocalciferol regimens for treatment of hypovitaminosis D in epileptic children and adolescents
- Children and adolescents with type 1 diabetes mellitus in Nigeria: clinical characteristics and compliance with care
- Disordered eating and behaviors among young Egyptians with type 1 diabetes: risk factors and comorbidities
- Normal or elevated prolactin is a good indicator to show pituitary stalk interruption syndrome in patients with multiple pituitary hormone deficiency
- No pubertal growth spurt, rapid bone maturation, and menarche post GnRHa treatment in girls with precocious puberty
- Genetic analysis of failed male puberty using whole exome sequencing
- Gender diversity in adolescents with polycystic ovary syndrome
- Case Reports
- Management challenges of Rabson Mendenhall syndrome in a resource limited country: a case report
- Thyroid function tests of iodine deficiency goiter can mimic thyroid hormone resistance alpha
- Pseudohypoaldosteronism associated with hypertrophic cardiomyopathy, hypertension and thrombocytosis due to mutation in the ELAC2 gene: a case report
- Acromicric dysplasia due to a novel missense mutation in the fibrillin 1 gene in a three-generation family
- A case of severe systemic type 1 pseudohypoaldosteronism with 10 years of evolution
- Advantages of monitoring rT3 and dividing LT3 dose in the treatment of consumptive hypothyroidism associated with infantile hepatic hemangioma
