Genetic analysis of failed male puberty using whole exome sequencing
Author:
Akram Maleeha1, Handelsman David J.2, Qayyum Mazhar1, Kennerson Marina2, Rauf Sania13, Ahmed Shahid4, Ishtiaq Osama5, Ismail Muhammad6, Mansoor Qaisar6, Naseem Afzaal Ahmed1, Rizvi Syed Shakeel Raza1
Affiliation:
1. Department of Zoology, Wildlife and Fisheries , Pir Mehr Ali Shah Arid Agriculture University Rawalpindi , Rawalpindi , Pakistan 2. The ANZAC Research Institute (ARI), University of Sydney , Concord , NSW , Australia 3. Department of Biosciences , University of Wah , Quaid Avenue , Wah Cantt , Pakistan 4. Department of Endocrinology , Military Hospital , Rawalpindi , Pakistan 5. The Endocrinology and Diabetes Department , Shifa International Hospitals Ltd , Islamabad , Pakistan 6. Institute of Biomedical and Genetic Engineering (IBGE) , Islamabad , Pakistan
Abstract
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.
Funder
Higher Education Commission, Pakistanhttps://www.hec.gov.pk/english/scholarshipsgrants/IRSIP/Pages/default.aspx
Publisher
Walter de Gruyter GmbH
Subject
Endocrinology,Endocrinology, Diabetes and Metabolism,Pediatrics, Perinatology and Child Health
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