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

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

Detailed Description
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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

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

Conditions
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Kallmann Syndrome, Hypogonadotropic Hypogonadism, Hypothalamic Amenorrhea, Polycystic Ovarian Syndrome, Precocious Puberty, Cleft Lip and Palate, Cleft Palate, Cleft Lip

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria:(any of the following conditions) hypogonadotropic hypogonadism Kallmann syndrome adult-onset hypogonadotropic hypogonadism hypothalamic amenorrhea polycystic ovarian syndrome primary gonadal failure precocious puberty cleft lip/palate family members of the above groups Exclusion Criteria: acute illness/hospitalization pituitary tumors iron overload (hemochromatosis) infiltrative diseases (sarcoidosis) chronic alcohol abuse illicit drug use anabolic steroid abuse
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients<br>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<br>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 | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| rare sequence variant(s) in gene(s) | The investigators aim to discover genes associated with reproductive disorders by identifying rare sequence variants (mutations) in patients | 1 year (ongoing if no variants are identified) | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GnRH deficiency, hypogonadism, anosmia, infertility, cleft lip, cleft palate, cryptorchidism, microphallus