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Next Generation DNA Sequencing in Patients With Idiopathic Male Infertility

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02021721
Recruitment Status : Terminated (Lack of funding)
First Posted : December 27, 2013
Last Update Posted : July 31, 2020
Hamad Medical Corporation
Weill Cornell Medical College in Qatar
Information provided by (Responsible Party):
Weill Medical College of Cornell University

Brief Summary:

Hypothesis: To identify new gene mutations that can be related to patients with idiopathic male factor infertility.

Primary Objective: To detect possible genetic abnormalities in families with more than one sibling with male infertility.

Secondary Objective: To evaluate using next generation DNA sequencing in cases of infertility

Condition or disease

Detailed Description:
Infertility involves about 15% of couples who attempt to conceive and the male factor accounts for about half of the cases. Idiopathic, azoospermia, or oligozoospermia, which may be genetically based, constitute a significant number of male infertility cases.In the recent years, there is increasing recognition of the genetic abnormalities as a cause of male infertility. Genetic factors contribute up to 15 - 30% of male infertility cases. These abnormalities may be numerical chromosomal abnormality; the most common is Klinefelter syndrome, or structural e.g. Y-chomosome microdeletion, DNA mutations or mitochondrial DNA mutations. They account for 5%-10% cases of oligozoospermia, to 15%-25% cases with non-obstructive azoospermia. In azoospermia, sex chromosome abnormalities are predominant. However, autosomal structural chromosomal abnormalities are the chief genetic cause of oligozoospermia and may be balanced or unbalanced. In a substantial proportion of cases (32% of infertile men, or 1.5% of the male population), the underlying causes are unknown (idiopathic infertility). While cytogenetic studies have been successful in revealing some causes most non-obstructive azoospermic men are still idiopathic. They are believed to carry unknown autosomal mutations based on studies of familial male infertility that often involves two or more siblings.Regulation of the complex process of spermatogenesis depends on the cooperation of many genes which are expressed at various stages of differentiation, where mitotic, meiotic cell divisions, and postmeiotic development finally lead to the spermatozoa. Identification of genes playing a crucial role in spermatogenesis is mainly based on the observations of rodents, particularly the mouse model. In humans, such identification remains largely unavailable because of the difficulty in gaining access to tissue samples from a male gonad and the limited possibilities of functional verification in humans. Hence the genetic causes of male infertility have not yet been well recognized. Next-generation sequencing (NGS) is an effective tool for Mendelian gene identification. So far, more than 30 Mendelian disease genes have been identified using NGS, including recessive and dominant diseases. NGS data can also be used to discover linkage and homozygosity intervals, as well as determine copy number number of specific intervals (Becker et al. 2011, Krawitz et al. 2010). 15, 16 The two major branches of next-generation DNA sequencing are whole-exome (WE) and whole genome (WG) sequencing. While WGS is more comprehensive and useful for population genetics or for diseases in which complex non-exonic inheritance is suspected, WES remains a more powerful, cost-effective tool for detecting rare mutations within a patient population. Our use of WGS or WES will depend on the nature of the patients recruited for the study. In cases where depth of coverage requirements are high, WES would be better-suited as it allows for 4-6 exomes to be covered at such depth for the same cost of 1 genome at 30X. This would aid in sampling rarer alleles within the population and discovering novel mutations in patients that are not present in their unaffected family members. This is especially useful in cases of diseases where wide allelic heterogeneity may exist, as patients who test negative for the most common mutations may have a novel mutation that would otherwise have been undetectable by traditional methods. Multiple members of the same family may be affected by infertility with similar or different presentations of testicular failure with different histopathologies. In the presence of normal karyotyping and Y-chromosome microdeletion, we are usually left with unknown genetic abnormality. Genetic causes of male factor infertility can be broadly assumed to be a result of either de novo mutations inherited by the patient from one of his parents or from polymorphisms circulating in the population. In both cases, a search for potential genetic causes for infertility must rely on comparison of the DNA sequence of the patient with a controlled fertile member of his family.

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Study Type : Observational
Actual Enrollment : 5 participants
Observational Model: Family-Based
Time Perspective: Prospective
Official Title: Next Generation DNA Sequencing in Patients With Idiopathic Male Infertility
Study Start Date : November 2012
Actual Primary Completion Date : July 2020
Actual Study Completion Date : July 2020

Subjects who fulfill the inclusion criteria will be pre-identified by consultation with their attending physicians and by thorough review of the literature to establish that the disease is indeed genetic and unsolved.

Primary Outcome Measures :
  1. Next generation sequencing [ Time Frame: 1 hour ]
    Use next generation sequencing to discover novel genes

Biospecimen Retention:   Samples With DNA

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Patients with be recruited from HMC infertility clinic.

Inclusion Criteria:

  • The study will include male patients diagnosed with infertility, fitting one of the following categories:
  • More than one family member complaining of male infertility
  • All ethnicities will be included in this study
  • Family members will be invited to join the study

Exclusion Criteria:

  • Patients in whim infertility is suspected to be caused by environmental factors more than genetic factors
  • Patients whose cause of infertility has already been determined by other clinical testing
  • Patients fulfilling the inclusion criteria but the other affected family member could not be recruited or did not approve of being included in the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02021721

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Hamad Medical Corporation
Doha, Qatar
Sponsors and Collaborators
Weill Medical College of Cornell University
Hamad Medical Corporation
Weill Cornell Medical College in Qatar
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Principal Investigator: Ronald Crystal, MD Weill Medical College of Cornell University
Principal Investigator: Haitham El Bardisi, MD Hamad Medical Corporation
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Responsible Party: Weill Medical College of Cornell University Identifier: NCT02021721    
Other Study ID Numbers: 13-00058 [JIRB]
12195/12 ( Other Identifier: HMC IRB )
First Posted: December 27, 2013    Key Record Dates
Last Update Posted: July 31, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Additional relevant MeSH terms:
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Infertility, Male