Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations

Jill A. Rosenfeld, Kathleen Leppig, Blake C. Ballif, Heidi Thiese, Christine Erdie-Lalena, Erwati Bawle, Sujatha Sastry, J. Edward Spence, Anne Bandholz, Urvashi Surti, Jonathan (Jon) Zonana, Kory Keller, Wendy Meschino, Bassem A. Bejjani, Beth S. Torchia, Lisa G. Shaffer

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

PURPOSE: Pitt-Hopkins syndrome is characterized by severe mental retardation, characteristic dysmorphic features, and susceptibility to childhood-onset seizures and intermittent episodes of hyperventilation. This syndrome is caused by haploinsufficiency of TCF4, which encodes a basic helix-loop-helix transcription factor. Missense, nonsense, splice-site mutations, and gene deletions have been found in individuals with Pitt-Hopkins syndrome. Previous reports have suggested that the Pitt-Hopkins syndrome phenotype is independent of mutation or deletion type. METHODS: We screened 13,186 individuals with microarray-based comparative genomic hybridization. We also conducted a review of the literature and statistical analysis of the phenotypic features for all individuals with confirmed mutations or deletions of TCF4. RESULTS: We identified seven individuals with TCF4 deletions. All patients have features consistent with Pitt-Hopkins syndrome, although only three have breathing anomalies, and none has seizures. Our review of previously reported cases with TCF4 mutations and deletions showed that all patients with Pitt-Hopkins syndrome reported to date have severe psychomotor retardation, the onsets of seizures and hyperventilation episodes are limited to the first decade in most reported patients with Pitt-Hopkins syndrome, hyperventilation episodes are more common than seizures and are seen in the oldest patients, and individuals with missense TCF4 mutations are more likely to develop seizures. CONCLUSIONS: On the basis of an analysis of published cases, we propose a genotype-phenotype correlation of increased seizure activity with missense TCF4 mutations.

Original languageEnglish (US)
Pages (from-to)797-805
Number of pages9
JournalGenetics in Medicine
Volume11
Issue number11
DOIs
StatePublished - Nov 2009

Fingerprint

Missense Mutation
Seizures
Genotype
Phenotype
Mutation
Hyperventilation
Sequence Deletion
Basic Helix-Loop-Helix Transcription Factors
Haploinsufficiency
Comparative Genomic Hybridization
Gene Deletion
Genetic Association Studies
Intellectual Disability
Pitt-Hopkins syndrome
Respiration

Keywords

  • Array CGH
  • Deletion
  • Genotype-phenotype
  • Pitt-Hopkins syndrome
  • Seizures
  • TCF4

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Rosenfeld, J. A., Leppig, K., Ballif, B. C., Thiese, H., Erdie-Lalena, C., Bawle, E., ... Shaffer, L. G. (2009). Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations. Genetics in Medicine, 11(11), 797-805. https://doi.org/10.1097/GIM.0b013e3181bd38a9

Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations. / Rosenfeld, Jill A.; Leppig, Kathleen; Ballif, Blake C.; Thiese, Heidi; Erdie-Lalena, Christine; Bawle, Erwati; Sastry, Sujatha; Spence, J. Edward; Bandholz, Anne; Surti, Urvashi; Zonana, Jonathan (Jon); Keller, Kory; Meschino, Wendy; Bejjani, Bassem A.; Torchia, Beth S.; Shaffer, Lisa G.

In: Genetics in Medicine, Vol. 11, No. 11, 11.2009, p. 797-805.

Research output: Contribution to journalArticle

Rosenfeld, JA, Leppig, K, Ballif, BC, Thiese, H, Erdie-Lalena, C, Bawle, E, Sastry, S, Spence, JE, Bandholz, A, Surti, U, Zonana, JJ, Keller, K, Meschino, W, Bejjani, BA, Torchia, BS & Shaffer, LG 2009, 'Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations', Genetics in Medicine, vol. 11, no. 11, pp. 797-805. https://doi.org/10.1097/GIM.0b013e3181bd38a9
Rosenfeld, Jill A. ; Leppig, Kathleen ; Ballif, Blake C. ; Thiese, Heidi ; Erdie-Lalena, Christine ; Bawle, Erwati ; Sastry, Sujatha ; Spence, J. Edward ; Bandholz, Anne ; Surti, Urvashi ; Zonana, Jonathan (Jon) ; Keller, Kory ; Meschino, Wendy ; Bejjani, Bassem A. ; Torchia, Beth S. ; Shaffer, Lisa G. / Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations. In: Genetics in Medicine. 2009 ; Vol. 11, No. 11. pp. 797-805.
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AU - Rosenfeld, Jill A.

AU - Leppig, Kathleen

AU - Ballif, Blake C.

AU - Thiese, Heidi

AU - Erdie-Lalena, Christine

AU - Bawle, Erwati

AU - Sastry, Sujatha

AU - Spence, J. Edward

AU - Bandholz, Anne

AU - Surti, Urvashi

AU - Zonana, Jonathan (Jon)

AU - Keller, Kory

AU - Meschino, Wendy

AU - Bejjani, Bassem A.

AU - Torchia, Beth S.

AU - Shaffer, Lisa G.

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N2 - PURPOSE: Pitt-Hopkins syndrome is characterized by severe mental retardation, characteristic dysmorphic features, and susceptibility to childhood-onset seizures and intermittent episodes of hyperventilation. This syndrome is caused by haploinsufficiency of TCF4, which encodes a basic helix-loop-helix transcription factor. Missense, nonsense, splice-site mutations, and gene deletions have been found in individuals with Pitt-Hopkins syndrome. Previous reports have suggested that the Pitt-Hopkins syndrome phenotype is independent of mutation or deletion type. METHODS: We screened 13,186 individuals with microarray-based comparative genomic hybridization. We also conducted a review of the literature and statistical analysis of the phenotypic features for all individuals with confirmed mutations or deletions of TCF4. RESULTS: We identified seven individuals with TCF4 deletions. All patients have features consistent with Pitt-Hopkins syndrome, although only three have breathing anomalies, and none has seizures. Our review of previously reported cases with TCF4 mutations and deletions showed that all patients with Pitt-Hopkins syndrome reported to date have severe psychomotor retardation, the onsets of seizures and hyperventilation episodes are limited to the first decade in most reported patients with Pitt-Hopkins syndrome, hyperventilation episodes are more common than seizures and are seen in the oldest patients, and individuals with missense TCF4 mutations are more likely to develop seizures. CONCLUSIONS: On the basis of an analysis of published cases, we propose a genotype-phenotype correlation of increased seizure activity with missense TCF4 mutations.

AB - PURPOSE: Pitt-Hopkins syndrome is characterized by severe mental retardation, characteristic dysmorphic features, and susceptibility to childhood-onset seizures and intermittent episodes of hyperventilation. This syndrome is caused by haploinsufficiency of TCF4, which encodes a basic helix-loop-helix transcription factor. Missense, nonsense, splice-site mutations, and gene deletions have been found in individuals with Pitt-Hopkins syndrome. Previous reports have suggested that the Pitt-Hopkins syndrome phenotype is independent of mutation or deletion type. METHODS: We screened 13,186 individuals with microarray-based comparative genomic hybridization. We also conducted a review of the literature and statistical analysis of the phenotypic features for all individuals with confirmed mutations or deletions of TCF4. RESULTS: We identified seven individuals with TCF4 deletions. All patients have features consistent with Pitt-Hopkins syndrome, although only three have breathing anomalies, and none has seizures. Our review of previously reported cases with TCF4 mutations and deletions showed that all patients with Pitt-Hopkins syndrome reported to date have severe psychomotor retardation, the onsets of seizures and hyperventilation episodes are limited to the first decade in most reported patients with Pitt-Hopkins syndrome, hyperventilation episodes are more common than seizures and are seen in the oldest patients, and individuals with missense TCF4 mutations are more likely to develop seizures. CONCLUSIONS: On the basis of an analysis of published cases, we propose a genotype-phenotype correlation of increased seizure activity with missense TCF4 mutations.

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KW - Seizures

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