Expanding the spectrum of founder mutations causing isolated gonadotropin-releasing hormone deficiency

Jin Ho Choi, Ravikumar Balasubramanian, Phil H. Lee, Natalie D. Shaw, Janet E. Hall, Lacey Plummer, Cassandra L. Buck, Marie Laure Kottler, Katarzyna Jarzabek, Sławomir Wołczynski, Richard Quinton, Ana Claudia Latronico, Catherine Dode, Tsutomu Ogata, Hyung Goo Kim, Lawrence C Layman, James F. Gusella, William F. Crowley

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Context: Loss of function (LoF) mutations in more than 20 genes are now known to cause isolated GnRH deficiency (IGD) in humans. Most causal IGD mutations are typically private, ie, limited to a single individual/pedigree. However, somewhat paradoxically, four IGD genes (GNRH1, TAC3, PROKR2, and GNRHR) have been shown to harbor LoF founder mutations that are shared by multiple unrelated individuals. It is not known whether similar founder mutations occur in other IGD genes. Objective: The objective of the study was to determine whether shared deleterious mutations in IGD-associated genes represent founder alleles. Setting: This study was an international collaboration among academic medical centers. Methods: IGD patients with shared mutations, defined as those documented in three or more unrelated probands in 14 IGD-associated genes,wereidentifiedfromvarious academic institutions, the Human Gene Mutation Database, and literature reports by other international investigators. Haplotypes of single-nucleotide polymorphisms and short tandem repeats surrounding the mutations were constructed to assess genetic ancestry. Results: A total of eight founder mutations in five genes, GNRHR (Q106R, R262Q, R139H), TACR3 (W275X), PROKR2 (R85H), FGFR1 (R250Q, G687R), and HS6ST1 (R382W) were identified. Most founder alleles were present at low frequency in the general population. The estimated age of these mutant alleles ranged from 1925 to 5600 years and corresponded to the time of rapid human population expansion. Conclusions: We have expanded the spectrum of founder alleles associated with IGD to a total of eight founder mutations. In contrast to the approximately 9000-year-old PROKR2 founder allele that may confer a heterozygote advantage, the rest of the founder alleles are relatively more recent in origin, in keeping with the timing of recent human population expansion and any selective heterozygote advantage of these alleles requires further evaluation.

Original languageEnglish (US)
Pages (from-to)E1378-E1385
JournalJournal of Clinical Endocrinology and Metabolism
Volume100
Issue number10
DOIs
StatePublished - Oct 1 2015

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Gonadotropin-Releasing Hormone
Genes
Mutation
Alleles
Heterozygote
Population
Ports and harbors
Polymorphism
Microsatellite Repeats
Pedigree
Nucleotides
Haplotypes
Single Nucleotide Polymorphism
Research Personnel
Databases

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Choi, J. H., Balasubramanian, R., Lee, P. H., Shaw, N. D., Hall, J. E., Plummer, L., ... Crowley, W. F. (2015). Expanding the spectrum of founder mutations causing isolated gonadotropin-releasing hormone deficiency. Journal of Clinical Endocrinology and Metabolism, 100(10), E1378-E1385. https://doi.org/10.1210/jc.2015-2262

Expanding the spectrum of founder mutations causing isolated gonadotropin-releasing hormone deficiency. / Choi, Jin Ho; Balasubramanian, Ravikumar; Lee, Phil H.; Shaw, Natalie D.; Hall, Janet E.; Plummer, Lacey; Buck, Cassandra L.; Kottler, Marie Laure; Jarzabek, Katarzyna; Wołczynski, Sławomir; Quinton, Richard; Latronico, Ana Claudia; Dode, Catherine; Ogata, Tsutomu; Kim, Hyung Goo; Layman, Lawrence C; Gusella, James F.; Crowley, William F.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 100, No. 10, 01.10.2015, p. E1378-E1385.

Research output: Contribution to journalArticle

Choi, JH, Balasubramanian, R, Lee, PH, Shaw, ND, Hall, JE, Plummer, L, Buck, CL, Kottler, ML, Jarzabek, K, Wołczynski, S, Quinton, R, Latronico, AC, Dode, C, Ogata, T, Kim, HG, Layman, LC, Gusella, JF & Crowley, WF 2015, 'Expanding the spectrum of founder mutations causing isolated gonadotropin-releasing hormone deficiency', Journal of Clinical Endocrinology and Metabolism, vol. 100, no. 10, pp. E1378-E1385. https://doi.org/10.1210/jc.2015-2262
Choi, Jin Ho ; Balasubramanian, Ravikumar ; Lee, Phil H. ; Shaw, Natalie D. ; Hall, Janet E. ; Plummer, Lacey ; Buck, Cassandra L. ; Kottler, Marie Laure ; Jarzabek, Katarzyna ; Wołczynski, Sławomir ; Quinton, Richard ; Latronico, Ana Claudia ; Dode, Catherine ; Ogata, Tsutomu ; Kim, Hyung Goo ; Layman, Lawrence C ; Gusella, James F. ; Crowley, William F. / Expanding the spectrum of founder mutations causing isolated gonadotropin-releasing hormone deficiency. In: Journal of Clinical Endocrinology and Metabolism. 2015 ; Vol. 100, No. 10. pp. E1378-E1385.
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abstract = "Context: Loss of function (LoF) mutations in more than 20 genes are now known to cause isolated GnRH deficiency (IGD) in humans. Most causal IGD mutations are typically private, ie, limited to a single individual/pedigree. However, somewhat paradoxically, four IGD genes (GNRH1, TAC3, PROKR2, and GNRHR) have been shown to harbor LoF founder mutations that are shared by multiple unrelated individuals. It is not known whether similar founder mutations occur in other IGD genes. Objective: The objective of the study was to determine whether shared deleterious mutations in IGD-associated genes represent founder alleles. Setting: This study was an international collaboration among academic medical centers. Methods: IGD patients with shared mutations, defined as those documented in three or more unrelated probands in 14 IGD-associated genes,wereidentifiedfromvarious academic institutions, the Human Gene Mutation Database, and literature reports by other international investigators. Haplotypes of single-nucleotide polymorphisms and short tandem repeats surrounding the mutations were constructed to assess genetic ancestry. Results: A total of eight founder mutations in five genes, GNRHR (Q106R, R262Q, R139H), TACR3 (W275X), PROKR2 (R85H), FGFR1 (R250Q, G687R), and HS6ST1 (R382W) were identified. Most founder alleles were present at low frequency in the general population. The estimated age of these mutant alleles ranged from 1925 to 5600 years and corresponded to the time of rapid human population expansion. Conclusions: We have expanded the spectrum of founder alleles associated with IGD to a total of eight founder mutations. In contrast to the approximately 9000-year-old PROKR2 founder allele that may confer a heterozygote advantage, the rest of the founder alleles are relatively more recent in origin, in keeping with the timing of recent human population expansion and any selective heterozygote advantage of these alleles requires further evaluation.",
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AU - Choi, Jin Ho

AU - Balasubramanian, Ravikumar

AU - Lee, Phil H.

AU - Shaw, Natalie D.

AU - Hall, Janet E.

AU - Plummer, Lacey

AU - Buck, Cassandra L.

AU - Kottler, Marie Laure

AU - Jarzabek, Katarzyna

AU - Wołczynski, Sławomir

AU - Quinton, Richard

AU - Latronico, Ana Claudia

AU - Dode, Catherine

AU - Ogata, Tsutomu

AU - Kim, Hyung Goo

AU - Layman, Lawrence C

AU - Gusella, James F.

AU - Crowley, William F.

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N2 - Context: Loss of function (LoF) mutations in more than 20 genes are now known to cause isolated GnRH deficiency (IGD) in humans. Most causal IGD mutations are typically private, ie, limited to a single individual/pedigree. However, somewhat paradoxically, four IGD genes (GNRH1, TAC3, PROKR2, and GNRHR) have been shown to harbor LoF founder mutations that are shared by multiple unrelated individuals. It is not known whether similar founder mutations occur in other IGD genes. Objective: The objective of the study was to determine whether shared deleterious mutations in IGD-associated genes represent founder alleles. Setting: This study was an international collaboration among academic medical centers. Methods: IGD patients with shared mutations, defined as those documented in three or more unrelated probands in 14 IGD-associated genes,wereidentifiedfromvarious academic institutions, the Human Gene Mutation Database, and literature reports by other international investigators. Haplotypes of single-nucleotide polymorphisms and short tandem repeats surrounding the mutations were constructed to assess genetic ancestry. Results: A total of eight founder mutations in five genes, GNRHR (Q106R, R262Q, R139H), TACR3 (W275X), PROKR2 (R85H), FGFR1 (R250Q, G687R), and HS6ST1 (R382W) were identified. Most founder alleles were present at low frequency in the general population. The estimated age of these mutant alleles ranged from 1925 to 5600 years and corresponded to the time of rapid human population expansion. Conclusions: We have expanded the spectrum of founder alleles associated with IGD to a total of eight founder mutations. In contrast to the approximately 9000-year-old PROKR2 founder allele that may confer a heterozygote advantage, the rest of the founder alleles are relatively more recent in origin, in keeping with the timing of recent human population expansion and any selective heterozygote advantage of these alleles requires further evaluation.

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