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Keaton AA, Solomon BD, Kauvar EF, et al. TGIF Mutations in Human Holoprosencephaly: Correlation between Genotype and Phenotype. Mol Syndromol. 2011;1(5):211-222doi: 10.1159/000328203.
Keaton, A. A., Solomon, B. D., Kauvar, E. F., El-Jaick, K. B., Gropman, A. L., Zafer, Y., Meck, J. M., Bale, S. J., Grange, D. K., Haddad, B. R., Gowans, G. C., Clegg, N. J., Delgado, M. R., Hahn, J. S., Pineda-Alvarez, D. E., Lacbawan, F., Vélez, J. I., Roessler, E., & Muenke, M. (2010). TGIF Mutations in Human Holoprosencephaly: Correlation between Genotype and Phenotype. Molecular syndromology, 1(5), 211-222. https://doi.org/10.1159/000328203
Keaton, A A, et al. "TGIF Mutations in Human Holoprosencephaly: Correlation between Genotype and Phenotype." Molecular syndromology vol. 1,5 (2010): 211-222. doi: https://doi.org/10.1159/000328203
Keaton AA, Solomon BD, Kauvar EF, El-Jaick KB, Gropman AL, Zafer Y, Meck JM, Bale SJ, Grange DK, Haddad BR, Gowans GC, Clegg NJ, Delgado MR, Hahn JS, Pineda-Alvarez DE, Lacbawan F, Vélez JI, Roessler E, Muenke M. TGIF Mutations in Human Holoprosencephaly: Correlation between Genotype and Phenotype. Mol Syndromol. 2010;1(5):211-222. doi: 10.1159/000328203. Epub 2011 May 18. PMID: 22125506; PMCID: PMC3214944.
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Mol Syndromol. 2010;1(5):211-222. doi: 10.1159/000328203. Epub 2011 May 18.

TGIF Mutations in Human Holoprosencephaly: Correlation between Genotype and Phenotype.

Molecular syndromology

A A Keaton, B D Solomon, E F Kauvar, K B El-Jaick, A L Gropman, Y Zafer, J M Meck, S J Bale, D K Grange, B R Haddad, G C Gowans, N J Clegg, M R Delgado, J S Hahn, D E Pineda-Alvarez, F Lacbawan, J I Vélez, E Roessler, M Muenke

Affiliations

  1. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Md.

PMID: 22125506 PMCID: PMC3214944 DOI: 10.1159/000328203

Abstract

Holoprosencephaly (HPE), which results from failed or incomplete midline forebrain division early in gestation, is the most common forebrain malformation. The etiology of HPE is complex and multifactorial. To date, at least 12 HPE-associated genes have been identified, including TGIF (transforming growth factor beta-induced factor), located on chromosome 18p11.3. TGIF encodes a transcriptional repressor of retinoid responses involved in TGF-β signaling regulation, including Nodal signaling. TGIF mutations are reported in approximately 1-2% of patients with non-syndromic, non-chromosomal HPE. We combined data from our comprehensive studies of HPE with a literature search for all individuals with HPE and evidence of mutations affecting TGIF in order to establish the genotypic and phenotypic range. We describe 2 groups of patients: 34 with intragenic mutations and 21 with deletions of TGIF. These individuals, which were ascertained from our research group, in collaboration with other centers, and through a literature search, include 38 probands and 17 mutation-positive relatives. The majority of intragenic mutations occur in the TGIF homeodomain. Patients with mutations affecting TGIFrecapitulate the entire phenotypic spectrum observed in non-chromosomal, non-syndromic HPE. We identified a statistically significant difference between the 2 groups with respect to inheritance, as TGIF deletions were more likely to be de novo in comparison to TGIF mutations (χ(2) ((2)) = 6.97, p(permutated) = 0.0356). In addition, patients with TGIF deletions were also found to more commonly present with manifestations beyond the craniofacial and neuroanatomical features associated with HPE (p = 0.0030). These findings highlight differences in patients with intragenic mutations versus deletions affecting TGIF, and draw attention to the homeodomain region, which appears to be particularly relevant to HPE. These results may be useful for genetic counseling of affected patients.

References

  1. Teratology. 1995 Jun;51(6):398-403 - PubMed
  2. AJNR Am J Neuroradiol. 2010 Oct;31(9):1596-601 - PubMed
  3. Cell. 1999 Apr 2;97(1):29-39 - PubMed
  4. Arch Ophthalmol. 1991 Jan;109(1):136-7 - PubMed
  5. Brain Dev. 2006 Aug;28(7):413-9 - PubMed
  6. Nat Genet. 2000 Jun;25(2):205-8 - PubMed
  7. J Med Genet. 2006 Jun;43(6):496-500 - PubMed
  8. Am J Med Genet A. 2009 May;149A(5):919-25 - PubMed
  9. Dev Biol. 2004 Mar 15;267(2):374-86 - PubMed
  10. Brain Dev. 2008 Mar;30(3):203-5 - PubMed
  11. Am J Med Genet. 1989 Oct;34(2):237-45 - PubMed
  12. Clin Dysmorphol. 2007 Oct;16(4):247-52 - PubMed
  13. Eur J Pediatr. 1976 Aug 16;123(1):59-66 - PubMed
  14. Birth Defects Res A Clin Mol Teratol. 2008 Aug;82(8):585-91 - PubMed
  15. Curr Top Dev Biol. 2008;84:139-70 - PubMed
  16. Development. 2010 Jan;137(2):249-59 - PubMed
  17. Orphanet J Rare Dis. 2008 Feb 19;3:4 - PubMed
  18. Am J Med Genet A. 2007 Dec 15;143A(24):3088-99 - PubMed
  19. Nat Rev Neurosci. 2002 Nov;3(11):843-53 - PubMed
  20. J Med Genet. 2009 Jun;46(6):389-98 - PubMed
  21. Hum Mol Genet. 1999 Dec;8(13):2479-88 - PubMed
  22. Am J Med Genet C Semin Med Genet. 2010 Feb 15;154C(1):133-41 - PubMed
  23. Orphanet J Rare Dis. 2007 Feb 02;2:8 - PubMed
  24. Prenat Diagn. 2006 Mar;26(3):226-30 - PubMed
  25. Am J Med Genet A. 2004 Jul 15;128A(2):114-9 - PubMed
  26. Neurology. 2002 Oct 8;59(7):1058-66 - PubMed
  27. J Biol Chem. 1999 Dec 24;274(52):37105-10 - PubMed
  28. Am J Hum Genet. 2002 Nov;71(5):1017-32 - PubMed
  29. Mol Cell Biol. 2003 Apr;23(8):2969-80 - PubMed
  30. Hum Genet. 1988 Nov;80(3):219-23 - PubMed
  31. Am J Hum Genet. 1995 Nov;57(5):1080-5 - PubMed
  32. Hum Genet. 2003 Feb;112(2):131-4 - PubMed
  33. Am J Med Genet C Semin Med Genet. 2010 Feb 15;154C(1):93-101 - PubMed
  34. Am J Med Genet C Semin Med Genet. 2010 Feb 15;154C(1):52-61 - PubMed
  35. J Med Genet. 2010 Aug;47(8):513-24 - PubMed
  36. Mol Genet Metab. 2007 Jan;90(1):97-111 - PubMed
  37. AJNR Am J Neuroradiol. 1993 Mar-Apr;14(2):431-40 - PubMed
  38. J Ultrasound Med. 2009 Aug;28(8):1077-80 - PubMed
  39. Prenat Diagn. 2002 Jan;22(1):5-7 - PubMed
  40. Curr Opin Neurol. 2003 Apr;16(2):135-41 - PubMed
  41. Dev Dyn. 2006 Feb;235(2):547-53 - PubMed
  42. Nat Genet. 1996 Nov;14(3):357-60 - PubMed
  43. Hum Mutat. 2009 Aug;30(8):1175-82 - PubMed
  44. Am J Med Genet A. 2004 Aug 15;129A(1):21-4 - PubMed
  45. Hum Genet. 2010 Apr;127(4):421-40 - PubMed
  46. Am J Med Genet C Semin Med Genet. 2010 Feb 15;154C(1):120-32 - PubMed
  47. Teratology. 1977 Dec;16(3):261-72 - PubMed
  48. J Med Genet. 1981 Oct;18(5):396-8 - PubMed
  49. J Genet Hum. 1983 Sep;31(3):239-42 - PubMed
  50. J Inherit Metab Dis. 1998 Aug;21(5):481-97 - PubMed
  51. J Mol Evol. 2007 Aug;65(2):137-53 - PubMed
  52. Mol Genet Metab. 2011 Apr;102(4):470-80 - PubMed
  53. Mol Cell Biol. 2006 Feb;26(3):990-1001 - PubMed
  54. Dev Dyn. 2006 Jun;235(6):1482-90 - PubMed
  55. Hum Mutat. 2009 Oct;30(10):E921-35 - PubMed
  56. Am J Med Genet C Semin Med Genet. 2010 Feb 15;154C(1):183-90 - PubMed
  57. J Med Genet. 1991 Aug;28(8):530-2 - PubMed
  58. Genet Couns. 2001;12(3):287-98 - PubMed
  59. J Biol Chem. 2000 Dec 15;275(50):39762-6 - PubMed

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