The role of the TCF4 gene in the phenotype of individuals with 18q segmental deletions

Hasi, Minire; Soileau, Bridgette; Sebold, Courtney; Hill, Annice; Hale, Daniel E.; O’Donnell, Louise; Cody, Jannine D.

doi:10.1007/s00439-011-1020-y

Cited by 38 publications

(47 citation statements)

References 26 publications

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“…Recurrent mutations have been observed in exon 18. The deletions are each unique and no clustering of breakpoints has been observed, which is in accordance with what is known of 18q deletions in general [Heard et al, 2009;Hasi et al, 2011].…”

Section: Mutation Spectrum and Genotype-phenotype Correlationsupporting

confidence: 88%

“…As to the 18q deletion patients, hemizygosity for TCF4 appears to confer a major impact with regard to motor and cognitive development: in one study, children with larger regions of hemizygosity, including many other genes, were not more developmentally delayed than children with hemizygosity for the TCF4 gene alone. In contrast, patients with large deletions but haplosufficient for TCF4 had milder symptoms and longer survival [Hasi et al, 2011].…”

Section: Mutation Spectrum and Genotype-phenotype Correlationmentioning

confidence: 87%

“…Altogether 78 PTHS patients with alterations in the TCF4 gene have been published (summarized in Marangi et al [2011]; in addition, 1 patient in Hasi et al [2011]; and 2 patients in Lehalle et al [2011]). Of these, 18 are chromosome deletions encompassing the whole TCF4 gene, 6 partial gene deletions, 25 frameshift mutations including premature stop codons, 7 nonsense mutations, 5 splice site mutations, and 17 missense mutations.…”

Section: Mutation Spectrum and Genotype-phenotype Correlationmentioning

confidence: 99%

“…In addition, 27 patients not designated as PTHS cases but with 18q deletions of various sizes and encompassing the TCF4 gene have been published [Hasi et al, 2011]. Of these, 13 individuals had large terminal deletions (24-30 Mb), 8 had small interstitial deletions (5-16 Mb) and 6 had large interstitial deletions (24-27 Mb).…”

Section: Mutation Spectrum and Genotype-phenotype Correlationmentioning

confidence: 99%

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Pitt-Hopkins Syndrome

Peippo

Ignatius

2011

Mol Syndromol

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a Pitt-Hopkins-like phenotype has been assigned to autosomal recessive mutations of the CNTNAP2 gene at 7q33q36 and the NRXN1 gene at 2p16.3. Copyright © 2011 S. Karger AG, Basel History of the SyndromeIn 1978, pediatrician David Pitt and pediatric neurologist Ian Hopkins at the Royal Children's Hospital in Melbourne described 2 unrelated children with severe intellectual disability who while awake had spells of rapid overbreathing followed by holding of breath until cyanosis [Pitt and Hopkins, 1978]. Both patients had almost identical facial features with a wide mouth and palate, thick fleshy lips and a broad beaked nose with flared nostrils, and both also had clubbing of fingers and toes. The patients had been ascertained as a part of an etiological survey of 782 intellectually disabled individuals [Pitt and Roboz, 1965]. Over the next 28 years, only 4 sporadic patients [Singh 1993;Van Balkom et al., 1998;Peippo et al., 2006] and 1 pair of sibs [Orrico et al., 2001] supposed to have the same syndrome were published.In 2007, 2 independent groups using molecular karyotyping identified a microdeletion at 18q21.2 in 2 PittHopkins syndrome (PTHS) patients and subsequently haploinsufficiency of the TCF4 gene was found to cause the syndrome [Amiel et al., 2007;Zweier et al., 2007]. The original patients of Pitt and Hopkins [1978] and the one described by Singh [1993] were no longer available for Key WordsApnea ؒ Constipation ؒ Deletion of 18q ؒ Epilepsy ؒ Happy disposition ؒ Hyperpnea ؒ Myopia ؒ Pitt-Hopkins syndrome ؒ Stereotypic movements ؒ TCF4 Abstract Pitt-Hopkins syndrome (PTHS, MIM #610954) is characterized by severe intellectual disability, typical facial features and tendency to epilepsy, panting-and-holding breathing anomaly, stereotypic movements, constipation, and high myopia. Growth is normal or only mildly retarded, but half of the patients have postnatal microcephaly. Remarkably, congenital malformations are practically nonexistent. The cause of PTHS is de novo haploinsufficiency of the TCF4 gene (MIM * 602272) at 18q21.2. Altogether 78 PTHS patients with abnormalities of the TCF4 gene have been published since 2007 when the etiology of PTHS was revealed. In addition, 27 patients with 18q deletion encompassing the TCF4 gene but without given PTHS diagnosis have been published, and thus, the number of reported patients with a TCF4 abnormality exceeds 100. The mutational spectrum includes large chromosomal deletions encompassing the whole TCF4 gene, partial gene deletions, frameshift (including premature stop codon), nonsense, splice site, and missense mutations. So far, almost all patients have a private mutation and only 2 recurrent mutations are known. There is no evident genotype-phenotype correlation. No familial cases have been reported. Diagnosis of PTHS is based on the molecular confirmation of the characteristic clinical features. Recently,

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Section: Mutation Spectrum and Genotype-phenotype Correlationsupporting

confidence: 88%

Section: Mutation Spectrum and Genotype-phenotype Correlationmentioning

confidence: 87%

Section: Mutation Spectrum and Genotype-phenotype Correlationmentioning

confidence: 99%

Section: Mutation Spectrum and Genotype-phenotype Correlationmentioning

confidence: 99%

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Pitt-Hopkins Syndrome

Peippo

Ignatius

2011

Mol Syndromol

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“…We have previously published data regarding the consequences of TCF4 hemizygosity on the 18q- phenotype (Hasi et al 2011). Individuals with deletions inclusive of TCF4 have several features overlapping with those of Pitt-Hopkins syndrome.…”

Section: Introductionmentioning

confidence: 99%

Establishing a reference group for distal 18q-: clinical description and molecular basis

Cody¹,

Hasi

Soileau

et al. 2013

Hum Genet

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Although constitutional chromosome abnormalities have been recognized since the 1960s, clinical characterization and development of treatment options have been hampered by their obvious genetic complexity and relative rarity. Additionally, deletions of 18q are particularly heterogeneous, with no two people having the same breakpoints. We identified sixteen individuals with deletions that, despite unique breakpoints, encompass the same set of genes within a 17.6 Mb region. This group represents the most genotypically similar group yet identified with distal 18q deletions. As the deletion is of average size when compared with other 18q deletions, this group can serve as a reference point for the clinical and molecular description of this condition. We performed a thorough medical record review as well as a series of clinical evaluations on 14 of the 16 individuals. Common functional findings included developmental delays, hypotonia, growth hormone deficiency, and hearing loss. Structural anomalies included foot anomalies, ear canal atresia/stenosis, and hypospadias. The majority of individuals performed within the low normal range of cognitive ability but had more serious deficits in adaptive abilities. Of interest, the hemizygous region contains 38 known genes, 26 of which are sufficiently understood to tentatively determine dosage sensitivity. Published data suggest that 20 are unlikely to cause an abnormal phenotype in the hemizygous state and five are likely to be dosage sensitive: TNX3, NETO1, ZNF407, TSHZ1, and NFATC. A sixth gene, ATP9B, may be conditionally dosage sensitive. Not all distal 18q- phenotypes can be attributed to these six genes; however, this is an important advance in the molecular characterization of 18q deletions.

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