Variation in a Repeat Sequence Determines Whether a Common Variant of the Cystic Fibrosis Transmembrane Conductance Regulator Gene Is Pathogenic or Benign

Joshua D. Groman, Timothy W. Hefferon, Teresa Casals, Lluís Bassas, Xavier P. Estivill, Marie Des Georges, Caroline Guittard, Monika Koudova, M. Daniele Fallin, Krisztina Nemeth, Gyorgy Fekete, Ludovit Kadasi, Ken Friedman, Martin Schwarz, Cristina Bombieri, Pier Franco Pignatti, Emmanuel Kanavakis, Maria Tzetis, Marianne Schwartz, Giuseppe NovelliMaria Rosaria D'Apice, Agnieszka Sobczynska-Tomaszewska, Jerzy Bal, Manfred Stuhrmann, Milan Macek, Mireille Claustres, Garry R. Cutting

Research output: Contribution to journalArticle

180 Citations (Scopus)

Abstract

An abbreviated tract of five thymidines (5T) in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is found in ∼10% of individuals in the general population. When found in trans with a severe CFTR mutation, 5T can result in male infertility, nonclassic cystic fibrosis, or a normal phenotype. To test whether the number of TG repeats adjacent to 5T influences disease penetrance, we determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens, 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. Of the unaffected individuals, 78% (21 of 27) had 5T adjacent to 11 TG repeats, compared with 9% (10 of 107) of affected individuals. Conversely, 91% (97 of 107) of affected individuals had 12 or 13 TG repeats, versus only 22% (6 of 27) of unaffected individuals (P < .00001). Those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats (odds ratio 34.0, 95% CI 11.1-103.7, P < .00001). Thus, determination of TG repeat number will allow for more accurate prediction of benign versus pathogenic 5T alleles.

Original languageEnglish
Pages (from-to)176-179
Number of pages4
JournalAmerican Journal of Human Genetics
Volume74
Issue number1
DOIs
Publication statusPublished - Jan 2004
Externally publishedYes

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Cystic Fibrosis Transmembrane Conductance Regulator
Regulator Genes
Male Infertility
Phenotype
Mutation
Penetrance
Cystic Fibrosis
Thymidine
Introns
Alleles
Odds Ratio
Population

ASJC Scopus subject areas

  • Genetics

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Variation in a Repeat Sequence Determines Whether a Common Variant of the Cystic Fibrosis Transmembrane Conductance Regulator Gene Is Pathogenic or Benign. / Groman, Joshua D.; Hefferon, Timothy W.; Casals, Teresa; Bassas, Lluís; Estivill, Xavier P.; Des Georges, Marie; Guittard, Caroline; Koudova, Monika; Fallin, M. Daniele; Nemeth, Krisztina; Fekete, Gyorgy; Kadasi, Ludovit; Friedman, Ken; Schwarz, Martin; Bombieri, Cristina; Pignatti, Pier Franco; Kanavakis, Emmanuel; Tzetis, Maria; Schwartz, Marianne; Novelli, Giuseppe; D'Apice, Maria Rosaria; Sobczynska-Tomaszewska, Agnieszka; Bal, Jerzy; Stuhrmann, Manfred; Macek, Milan; Claustres, Mireille; Cutting, Garry R.

In: American Journal of Human Genetics, Vol. 74, No. 1, 01.2004, p. 176-179.

Research output: Contribution to journalArticle

Groman, JD, Hefferon, TW, Casals, T, Bassas, L, Estivill, XP, Des Georges, M, Guittard, C, Koudova, M, Fallin, MD, Nemeth, K, Fekete, G, Kadasi, L, Friedman, K, Schwarz, M, Bombieri, C, Pignatti, PF, Kanavakis, E, Tzetis, M, Schwartz, M, Novelli, G, D'Apice, MR, Sobczynska-Tomaszewska, A, Bal, J, Stuhrmann, M, Macek, M, Claustres, M & Cutting, GR 2004, 'Variation in a Repeat Sequence Determines Whether a Common Variant of the Cystic Fibrosis Transmembrane Conductance Regulator Gene Is Pathogenic or Benign', American Journal of Human Genetics, vol. 74, no. 1, pp. 176-179. https://doi.org/10.1086/381001
Groman, Joshua D. ; Hefferon, Timothy W. ; Casals, Teresa ; Bassas, Lluís ; Estivill, Xavier P. ; Des Georges, Marie ; Guittard, Caroline ; Koudova, Monika ; Fallin, M. Daniele ; Nemeth, Krisztina ; Fekete, Gyorgy ; Kadasi, Ludovit ; Friedman, Ken ; Schwarz, Martin ; Bombieri, Cristina ; Pignatti, Pier Franco ; Kanavakis, Emmanuel ; Tzetis, Maria ; Schwartz, Marianne ; Novelli, Giuseppe ; D'Apice, Maria Rosaria ; Sobczynska-Tomaszewska, Agnieszka ; Bal, Jerzy ; Stuhrmann, Manfred ; Macek, Milan ; Claustres, Mireille ; Cutting, Garry R. / Variation in a Repeat Sequence Determines Whether a Common Variant of the Cystic Fibrosis Transmembrane Conductance Regulator Gene Is Pathogenic or Benign. In: American Journal of Human Genetics. 2004 ; Vol. 74, No. 1. pp. 176-179.
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AU - Groman, Joshua D.

AU - Hefferon, Timothy W.

AU - Casals, Teresa

AU - Bassas, Lluís

AU - Estivill, Xavier P.

AU - Des Georges, Marie

AU - Guittard, Caroline

AU - Koudova, Monika

AU - Fallin, M. Daniele

AU - Nemeth, Krisztina

AU - Fekete, Gyorgy

AU - Kadasi, Ludovit

AU - Friedman, Ken

AU - Schwarz, Martin

AU - Bombieri, Cristina

AU - Pignatti, Pier Franco

AU - Kanavakis, Emmanuel

AU - Tzetis, Maria

AU - Schwartz, Marianne

AU - Novelli, Giuseppe

AU - D'Apice, Maria Rosaria

AU - Sobczynska-Tomaszewska, Agnieszka

AU - Bal, Jerzy

AU - Stuhrmann, Manfred

AU - Macek, Milan

AU - Claustres, Mireille

AU - Cutting, Garry R.

PY - 2004/1

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N2 - An abbreviated tract of five thymidines (5T) in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is found in ∼10% of individuals in the general population. When found in trans with a severe CFTR mutation, 5T can result in male infertility, nonclassic cystic fibrosis, or a normal phenotype. To test whether the number of TG repeats adjacent to 5T influences disease penetrance, we determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens, 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. Of the unaffected individuals, 78% (21 of 27) had 5T adjacent to 11 TG repeats, compared with 9% (10 of 107) of affected individuals. Conversely, 91% (97 of 107) of affected individuals had 12 or 13 TG repeats, versus only 22% (6 of 27) of unaffected individuals (P < .00001). Those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats (odds ratio 34.0, 95% CI 11.1-103.7, P < .00001). Thus, determination of TG repeat number will allow for more accurate prediction of benign versus pathogenic 5T alleles.

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