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Mol. Hum. Reprod. Advance Access published online on May 7, 2008
Molecular Human Reproduction, doi:10.1093/molehr/gan027
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
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The Prevalence of Intragenic Deletions in Patients with Idiopathic Hypogonadotropic Hypogonadism and Kallmann Syndrome

Jennifer R. Pedersen-White1, Lynn P. Chorich2,3,4,5, David P. Bick6, Richard J. Sherins7 and Lawrence C. Layman2,3,4,5

1Section of Endocrinology and Metabolism Department of Internal Medicine 2Section of Reproductive Endocrinology, Infertility & Genetics Department of Obstetrics & Gynecology 3Reproductive Medicine Program 4 Developmental Neurobiology Program The Institute of Molecular Medicine and Genetics 5 Neuroscience Program The Medical College of Georgia, Augusta, GA 6Department of Pediatrics and Department of Obstetrics & Gynecology Medical College of Wisconsin, Milwaukie, WI 7Director of Andrology, Columbia Fertility Associates, Washington, DC

Corresponding Author: Lawrence C. Layman, M.D. Section of Reproductive Endocrinology, Infertility, & Genetics Department of Obstetrics & Gynecology The Medical College of Georgia 1120 15th Street Augusta, GA 30912-3360 Phone: (706) 721-3832 FAX: (706) 721-6830 E mail: Llayman{at}mcg.edu

Idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS) are clinically and genetically heterogeneous disorders caused by a deficiency of gonadotropin-releasing hormone (GnRH). Mutations in three genes—KAL1, GNRHR, and FGFR1 - account for 15-20% of all causes of IHH/KS. Nearly all mutations are point mutations identified by traditional PCR-based DNA sequencing. The relatively new method of multiplex ligation-dependent probe amplification (MLPA) has been successful for detecting intragenic deletions in other genetic diseases. We hypothesized that MLPA would detect intragenic deletions in ~15-20% of our cohort of IHH/KS patients. Fifty-four IHH/KS patients were studied for KAL1 deletions and 100 were studied for an autosomal panel of FGFR1, GNRH1, GNRHR, GPR54, and NELF gene deletions. Of all male and female subjects screened, 4/54 (7.4%) had KAL1 deletions. If only anosmic males were considered, 4/33 (12.1%) had KAL1 deletions. No deletions were identified in any of the autosomal genes in 100 IHH/KS patients. We believe this to be the first study to use MLPA to identify intragenic deletions in IHH/KS patients. Our results indicate ~12% of KS males have KAL1 deletions, but intragenic deletions of the FGFR1, GNRH1, GNRHR, GPR54, and NELF genes are uncommon in IHH/KS.

Key Words: Kallmann syndrome/KAL1 gene/hypogonadotropic hypogonadism/idiopathic hypogonadotropic hypogonadism/MLPA

Disclosure summary: The authors have no conflicts of interest to disclose.

Submitted on February 16, 2008; resubmitted on April 11, 2008; accepted on April 23, 2008.


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