Deletion of chromosome region 18q21.1 → 18q21.3 in a patient without clinical features of the 18q‐ phenotype

Engelen, J. J. M.; Moog, Ute; Weber, Jacobiene W.; Haagen, A. A. M.; Uum, Chris M.J. van; Hamers, A.J.H.

doi:10.1002/ajmg.a.10266

Cited by 8 publications

(10 citation statements)

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“…Behaviour will also be influenced by interactions within social and learning environments and by reactions from that environment to the individual's tempera- [6][7][8][9][10][11]13,14,[30][31][32][33][34][35] Published cases with proven TCF4 mutations [6][7][8][9][10][11]13,14,[30][31][32][33][34][35] Present study ment, external features, and neuropsychological deficits. Studying phenotypes of rare and ultra-rare genetic syndromes associated with severe intellectual disability has made it clear that, although individual outcomes may arise from genetic differences, the expression of genes affecting structure, development and function of the brain is also influenced by the interplay between genes, learning, and social context, and too much emphasis on biological determinants should be avoided.…”

Section: Discussionmentioning

confidence: 95%

Development, cognition, and behaviour in Pitt–Hopkins syndrome

Balkom

Vuijk²,

Franssens

et al. 2012

Develop Med Child Neuro

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ABBREVIATIONSASD Autism spectrum disorder PTHS Pitt-Hopkins syndrome AIM The aim of the study was to collect detailed data on behavioural, adaptive, and psychological functioning in 10 individuals with Pitt-Hopkins syndrome (PTHS), with specific attention to manifestations of autism spectrum disorder (ASD).METHOD The participants (four females, six males), residing in the Netherlands and Belgium, were ascertained through the Dutch national PTHS support group. Median age of participants was 10 years, the age range was between 32 and 289 months. They underwent psychiatric examinations and neuropsychological measurements using a comprehensive assessment battery. Additionally, parental information was gathered through standardized interviews and questionnaires. Findings were compared with those from the literature.RESULTS All participants showed profound intellectual disability, amiable demeanour with minimal maladaptive behaviours, severe impairments of communication and language, and intense, frequent motor stereotypies. Impairments in all participants were beyond what would be expected for cognitive abilities, fitting a classification of ASD.INTERPRETATION Patients with PTHS are characterized not only by specific physical and genetic manifestations but also by specific behavioural and cognitive characteristics. Studying behaviour and cognition may improve diagnosis and prognosis, allows recognition of comorbidities, and contributes to adequate counselling of families.Pitt-Hopkins syndrome (PTHS) is characterized by intellectual disability, distinctive facial characteristics, breathing abnormalities, and repetitive behaviours. It is caused by genetic deletions ⁄ mutations resulting in TCF4 haploinsufficiency. To date, some 66 patients with confirmed TCF4 changes have been studied worldwide, mainly investigating somatic and genetic aspects.Early descriptions of PTHS in individuals with intellectual disability emphasized an abnormal breathing pattern, distinctive facial features, and postnatal microcephaly. Further definition of the PTHS phenotype in later publications included severe developmental delays in motor and speech ⁄ language development, episodic diurnal hyperventilation with apnoea, and frequent epilepsy.1-5 Three causes of PTHS have been identified. The dominant form of PTHS is caused by deletions ⁄ mutations in Transcription Factor 4 (TCF4) on chromosome 18 at 18q21. [6][7][8][9][10][11][12][13][14] Recessive forms of a PTHS-like disorder are caused by mutations in NeuReXiN1 (NRXN1) on chromosome 2 and CoNTactiN Associated Protein-like 2 (CNT-NAP2) on chromosome 7. 15,16 As studies of the syndrome have accumulated, it has become clear that not all individuals with molecularly confirmed alterations show intermittent overbreathing. Most studies of individuals with PTHS have reported severe developmental delay and intellectual disability, motor abnormalities (late or absent walking, repetitive movements of hands and head), and behavioural traits such as autistic symptoms; a quiet, friendly disposition in ...

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Section: Discussionmentioning

confidence: 95%

Development, cognition, and behaviour in Pitt–Hopkins syndrome

Balkom

Vuijk²,

Franssens

et al. 2012

Develop Med Child Neuro

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“…In addition, 12 cases of terminal or interstitial deletions of 18q specifically involving 18q21.2 have been described, although the inclusion of TCF4 in these deletions has not been confirmed. [15][16][17][18][19][20] Therefore, these cytogenetically described deletions were excluded from further comparison.…”

Section: Review Of Cases With Tcf4 Mutations or Deletions In The Litementioning

confidence: 99%

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

Rosenfeld

Leppig

Ballif

et al. 2009

Genetics in Medicine

101

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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, splicesite mutations, and gene deletions have been found in individuals with Pitt-Hopkins syndrome. Previous reports have suggested that the PittHopkins 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 PittHopkins 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. itt-Hopkins syndrome (PTHS, OMIM 610954) was first described in 1978 1 in two individuals and is characterized by specific dysmorphic features (deep-set eyes, broad-beaked nose, wide mouth with bow-shaped upper lip, and widely spaced teeth), childhood-onset hyperventilation episodes, childhood-onset seizures, microcephaly, and severe psychomotor retardation with a happy disposition. It is an autosomal dominant condition caused by haploinsufficiency for TCF4 (transcription factor 4, OMIM 602272) on 18q21.2. [2][3][4] The etiology of PTHS was determined when two groups concurrently screened individuals with PTHS for chromosomal deletions using microarray technology, one with arraybased comparative genomic hybridization (aCGH) 5 and the other with single-nucleotide polymorphism-based molecular karyotyping. 3 Each group described a patient with a de novo deletion involving this gene. Further screening of individuals with PTHS or phenotypic overlap with PTHS found individuals with de novo missense and nonsense mutations in TCF4. 3,5 Subsequently, more individuals have been published with disruptions, deletions, and mutations in TCF4, most with typical PTHS features. 4,6 -10 TCF4 is a transcription factor that belongs to the class I basic helix-loop-helix (bHLH) protein family, also known as the "E-protein" family. These proteins form homo-and heterodimers with other heli...

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“…1,2 Most deletions are terminal, encompassing as much as 36 Mb, but interstitial deletions have also been reported. [2][3][4][5][6][7][8][9] Over the past 20 years, a broad phenotypic spectrum has been reported -from the time in the mid-20th century when 18q deletion syndrome was usually recognized as deGrouchy syndrome until now in the early 21st centurywhere comparative genomic hybridization (CGH) array analysis helps define and narrow critical deletions of chromosomal regions of 18q and how this may or may not correlate with clinical findings.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4][5][6][7][8][9][10][11][12] Regarding specific ocular and adnexal abnormalities, features include hypertelorism, ptosis, microophthalmia, microcornea, corneal opacities, iris malformations and hypoplasia, colobomas, amblyopia, nystagmus and strabismus. 4,5,7,10,12,13 In general, many researchers believe that the size of the deletion can be correlated with the severity of the phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…7 Ten years later, in 2003, Engelen and colleagues reported an interstitial deletion from 18q21.1!18q21.3 in a 16-month-old patient with mild craniofacial asymmetry, moderate developmental delay and no ocular abnormalities. 8 In 2007, with the use of new chromosomal mapping techniques, an updated phenotypic map of chromosome 18 was created based on information from 29 patients -defining critical regions for microcephaly, cognitive delay, short stature, white matter disorders, growth hormone insufficiency, and congenital aural atresia. 6 From this research, 1 of the 29 patients was identified with strabismus as well as having a 18q21.2 deletion with severe cognitive delay, epilepsy, and low IgA levels.…”

Section: Discussionmentioning

confidence: 99%

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Mosaic Chromosome 18q Partial Deletion Syndrome with Bilateral Full-thickness Corneal Disease: Surgical Intervention and Histopathology

Galvin

LeBoyer

Michelotti

et al. 2013

Ophthalmic Genetics

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A 2-month-old boy diagnosed with a mosaic chromosome 18q partial deletion syndrome was referred for bilateral cloudy corneas. The abnormal metaphases had a terminal deletion of the long arm of chromosome 18 as clonal abnormality. The cytogenetics findings were 46,XY, del (18)(q21.2)[12]/46,XY[20]. Ocular findings included bilateral microcornea with dense opacification and unilateral iris and chorioretinal coloboma. Penetrating keratoplasty (PK) was performed on both eyes. Histopathology of the host corneal button showed complete loss of Bowman's layer, hyperkeratosis of the epithelium, stromal neovascularization, and leukocyte infiltration. Descemet's membrane and endothelium were irregular in both specimens. CD45 stain for leukocytes confirmed perivascular and epithelial leukocytes infiltration. Mosaic chromosome 18q deletion syndrome is a rare genetic abnormality with a variable phenotype - including ocular findings - and hence, warrants an ophthalmic evaluation and genetic counseling.

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Deletion of chromosome region 18q21.1 → 18q21.3 in a patient without clinical features of the 18q‐ phenotype

Cited by 8 publications

References 10 publications

Development, cognition, and behaviour in Pitt–Hopkins syndrome

Development, cognition, and behaviour in Pitt–Hopkins syndrome

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

Mosaic Chromosome 18q Partial Deletion Syndrome with Bilateral Full-thickness Corneal Disease: Surgical Intervention and Histopathology

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