Genetics of Reproductive Disorders (Including Kallmann Syndrome) and Cleft Lip and/or Palate

Sponsor

Centre Hospitalier Universitaire Vaudois (Other)

Overall Status

Recruiting

CT.gov ID

NCT01601171

Collaborator

Swiss National Science Foundation (Other)

2,000

Enrollment

Location

216

Duration (Months)

9.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to explore the genetic basis of reproductive disorders and cleft lip and/or palate.

Condition or Disease	Intervention/Treatment	Phase
Kallmann Syndrome Hypogonadotropic Hypogonadism Hypothalamic Amenorrhea Polycystic Ovarian Syndrome Precocious Puberty Cleft Lip and Palate Cleft Palate Cleft Lip

Detailed Description

The World Health Organization estimates approximately 10% of couples experience some sort of infertility problem.

In humans, puberty is the process through which we develop reproductive capacity.

The timing of puberty varies greatly in the general population and is influenced by both genetic and environmental factors. In extreme cases of pubertal delay, puberty progresses only partially or not at all and results in the clinical picture of congenital hypogonadotropic hypogonadism (CHH), either accompanied by anosmia in 50% of cases (Kallmann syndrome [KS]) or by normal sense of smell (nCHH), with a male: female ratio of 4:1.

CHH is due to GnRH deficiency (incidence 1: 4,000-10,000) and result in the failure of sexual maturation and infertility. It is genetically heterogeneous, with multiple patterns of inheritance and several associated loci. In the clinical spectrum of GnRH deficiency, CHH may also be associated with a cleft lip/palate (CL/P) in 5 to 7% of cases. However, this prevalence increases up to 40% in CHH patients carrying a mutation in a CL/P gene, suggesting a genetic overlap between CHH and CL/P.

Disorders of puberty have provided insight into the biology of reproduction and genetic technologies have enabled us to deepen understanding in this field. The focus of this study is to better understand the genetic control of puberty and human reproduction as well as its link with CL/P.

Increasing understanding of the molecular basis (genes) of inherited reproductive disorders and CL/P may enable investigators to:

improve diagnostic testing and treatments for these problems
develop new diagnostic tests and therapies for patients
enhance counseling for patients and families with reproductive disorders
enhance counseling for patients and families with cleft lip/palate

Study Design

Study Type:

Observational

Anticipated Enrollment :

2000 participants

Observational Model:

Case-Control

Time Perspective:

Other

Official Title:

The Genetics of Neuroendocrine Reproductive Disorders and of the Cleft Lip and/or Palate

Study Start Date :

Mar 1, 2012

Anticipated Primary Completion Date :

Mar 1, 2025

Anticipated Study Completion Date :

Mar 1, 2030

Arms and Interventions

Arm	Intervention/Treatment
Patients Patients with reproductive disorders with or without cleft lip/palate will be recruited for: completion of medical questionnaire and review of medical records family tree (including questions on reproductive disorders and cleft lip/palate) specimen collection (DNA/RNA) from: serum/plasma/saliva/urine/buccal swab/hair follicles/sperm/skin biopsy smell testing hearing test bone density brain MRI kidney, testicular/ovarian ultrasound
Family members Family members of Patients will be recruited for: completion of medical questionnaire specimen collection (DNA/RNA) from: serum/plasma/saliva/urine/buccal swab/hair follicles/sperm/skin biopsy smell testing

Arm

Intervention/Treatment

Patients

Patients with reproductive disorders with or without cleft lip/palate will be recruited for: completion of medical questionnaire and review of medical records family tree (including questions on reproductive disorders and cleft lip/palate) specimen collection (DNA/RNA) from: serum/plasma/saliva/urine/buccal swab/hair follicles/sperm/skin biopsy smell testing hearing test bone density brain MRI kidney, testicular/ovarian ultrasound

Family members

Family members of Patients will be recruited for: completion of medical questionnaire specimen collection (DNA/RNA) from: serum/plasma/saliva/urine/buccal swab/hair follicles/sperm/skin biopsy smell testing

Outcome Measures

Primary Outcome Measures

rare sequence variant(s) in gene(s) [1 year (ongoing if no variants are identified)]
The investigators aim to discover genes associated with reproductive disorders by identifying rare sequence variants (mutations) in patients

Secondary Outcome Measures

functionality of identified rare sequence variants (mutations) [1 year (following variant identification)]
The investigators will use a variety of scientific approaches to assess the functional impact of the identified rare sequence variants (mutations)
mode of inheritance [1 year (following variant identification)]
The investigators will examine family pedigrees and study family members to determine the inheritance patterns (how the disorder is transmitted in the family)
genotype-phenotype correlation [1 year (following variant identification)]
The investigators will study the phenotypic spectrum (how the disorder presents clinically) in patients with identified rare sequence variants (mutations)