TGIF mutations in human holoprosencephaly

Correlation between genotype and phenotype

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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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 (χ2 (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.

Original languageEnglish (US)
Pages (from-to)211-222
Number of pages12
JournalMolecular Syndromology
Volume1
Issue number5
DOIs
StatePublished - May 2011

Fingerprint

Holoprosencephaly
Genetic Association Studies
Transforming Growth Factor beta
Mutation
Prosencephalon
Sequence Deletion
Genetic Counseling
Retinoids
Chromosomes

Keywords

  • 18p
  • 18p deletion
  • Holoprosencephaly
  • Monosomy 18p
  • TGIF

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Keaton, A. A., Solomon, B. D., Kauvar, E. F., El-Jaick, K. B., Gropman, A. L., Zafer, Y., ... Muenke, M. (2011). TGIF mutations in human holoprosencephaly: Correlation between genotype and phenotype. Molecular Syndromology, 1(5), 211-222. https://doi.org/10.1159/000328203

TGIF mutations in human holoprosencephaly : Correlation between genotype and phenotype. / 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.

In: Molecular Syndromology, Vol. 1, No. 5, 05.2011, p. 211-222.

Research output: Contribution to journalArticle

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 2011, 'TGIF mutations in human holoprosencephaly: Correlation between genotype and phenotype', Molecular Syndromology, vol. 1, no. 5, pp. 211-222. https://doi.org/10.1159/000328203
Keaton AA, Solomon BD, Kauvar EF, El-Jaick KB, Gropman AL, Zafer Y et al. TGIF mutations in human holoprosencephaly: Correlation between genotype and phenotype. Molecular Syndromology. 2011 May;1(5):211-222. https://doi.org/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. / TGIF mutations in human holoprosencephaly : Correlation between genotype and phenotype. In: Molecular Syndromology. 2011 ; Vol. 1, No. 5. pp. 211-222.
@article{7cb4d2be93c3432a9b31884120eea216,
title = "TGIF mutations in human holoprosencephaly: Correlation between genotype and phenotype",
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 (χ2 (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.",
keywords = "18p, 18p deletion, Holoprosencephaly, Monosomy 18p, TGIF",
author = "Keaton, {A. A.} and Solomon, {B. D.} and Kauvar, {E. F.} and El-Jaick, {K. B.} and Gropman, {A. L.} and Y. Zafer and Meck, {J. M.} and Bale, {S. J.} and Grange, {D. K.} and Haddad, {B. R.} and Gowans, {G. C.} and Clegg, {N. J.} and Delgado, {M. R.} and Hahn, {J. S.} and Pineda-Alvarez, {D. E.} and F. Lacbawan and V{\'e}lez, {J. I.} and E. Roessler and M. Muenke",
year = "2011",
month = "5",
doi = "10.1159/000328203",
language = "English (US)",
volume = "1",
pages = "211--222",
journal = "Molecular Syndromology",
issn = "1661-8769",
publisher = "S. Karger AG",
number = "5",

}

TY - JOUR

T1 - TGIF mutations in human holoprosencephaly

T2 - Correlation between genotype and phenotype

AU - Keaton, A. A.

AU - Solomon, B. D.

AU - Kauvar, E. F.

AU - El-Jaick, K. B.

AU - Gropman, A. L.

AU - Zafer, Y.

AU - Meck, J. M.

AU - Bale, S. J.

AU - Grange, D. K.

AU - Haddad, B. R.

AU - Gowans, G. C.

AU - Clegg, N. J.

AU - Delgado, M. R.

AU - Hahn, J. S.

AU - Pineda-Alvarez, D. E.

AU - Lacbawan, F.

AU - Vélez, J. I.

AU - Roessler, E.

AU - Muenke, M.

PY - 2011/5

Y1 - 2011/5

N2 - 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 (χ2 (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.

AB - 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 (χ2 (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.

KW - 18p

KW - 18p deletion

KW - Holoprosencephaly

KW - Monosomy 18p

KW - TGIF

UR - http://www.scopus.com/inward/record.url?scp=79957460595&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79957460595&partnerID=8YFLogxK

U2 - 10.1159/000328203

DO - 10.1159/000328203

M3 - Article

VL - 1

SP - 211

EP - 222

JO - Molecular Syndromology

JF - Molecular Syndromology

SN - 1661-8769

IS - 5

ER -