Pathogenic significance of deletions distal to the currently described Wolf–Hirschhorn syndrome critical regions on 4p16.3

South, Sarah T.; Hannes, Femke; Fisch, Gene S.; Vermeesch, Joris Robert; Zollino, Marcella

doi:10.1002/ajmg.c.30188

Cited by 46 publications

(46 citation statements)

References 19 publications

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“…The separation of rodent Fgfrl1 from the WHSCRs may, therefore, be the result of a more recent event, perhaps involving an inversion. This complicates the interpretation of the large-scale mouse deletions, as described by Näf et al (Näf et al, 2001), since the emerging model of human WHS predicts that many mutations in this region are implicated in the syndrome: deletion of any of at least three non-overlapping regions in 4p16.3 can be pathogenic for the craniofacial features of WHS (South et al, 2008). Thus, it is likely that in humans, heterozygous mutations in both FGFRL1 and a homologue of an undefined gene that is eliminated in WHS mouse models with large-scale deletions that do not target Fgfrl1 (Näf et al, 2001), collectively contribute to the craniofacial features of WHS.…”

Section: Dmmbiologistsorg 288mentioning

confidence: 99%

Multiple congenital malformations of Wolf-Hirschhorn syndrome are recapitulated inFgfrl1null mice

Catela

Bilbao

Slonimsky

et al. 2009

Disease Models &Amp; Mechanisms

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SUMMARY Wolf-Hirschhorn syndrome (WHS) is caused by deletions in the short arm of chromosome 4 (4p) and occurs in about one per 20,000 births. Patients with WHS display a set of highly variable characteristics including craniofacial dysgenesis, mental retardation, speech problems, congenital heart defects, short stature and a variety of skeletal anomalies. Analysis of patients with 4p deletions has identified two WHS critical regions (WHSCRs); however, deletions targeting mouse WHSCRs do not recapitulate the classical WHS defects, and the genes contributing to WHS have not been conclusively established. Recently, the human FGFRL1 gene, encoding a putative fibroblast growth factor (FGF) decoy receptor, has been implicated in the craniofacial phenotype of a WHS patient. Here, we report that targeted deletion of the mouse Fgfrl1 gene recapitulates a broad array of WHS phenotypes, including abnormal craniofacial development, axial and appendicular skeletal anomalies, and congenital heart defects. Fgfrl1 null mutants also display a transient foetal anaemia and a fully penetrant diaphragm defect, causing prenatal and perinatal lethality. Together, these data support a wider role for Fgfrl1 in development, implicate FGFRL1 insufficiency in WHS, and provide a novel animal model to dissect the complex aetiology of this human disease.

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Section: Dmmbiologistsorg 288mentioning

confidence: 99%

Multiple congenital malformations of Wolf-Hirschhorn syndrome are recapitulated inFgfrl1null mice

Catela

Bilbao

Slonimsky

et al. 2009

Disease Models &Amp; Mechanisms

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“…[6][7][8] Of patients meeting the minimal diagnostic criteria, 9 the smallest terminal deletion identified was B1.9 Mb, 1, 9,10 suggesting that genes within this interval of 4p16.3 are responsible for the core features of WHS. 8,11 Beyond this region, the loss of additional critical genes appears to be responsible for variably present features, such as congenital malformations or hearing loss. 1,5,8 The identification of patients with atypical 4p deletions has provided key insight into which regions of 4p16.3 may (or may not) contribute to the pathogenesis of WHS.…”

Section: Introductionmentioning

confidence: 99%

“…For example, small terminal deletions (up to 400 kb) have been inherited from phenotypically normal individuals; [12][13][14] indicating that monosomy of this region is likely benign. 11 Between B1.8 and 2.0 Mb from the 4p terminus, two adjacent critical regions were proposed based on the smallest region of overlap (SRO) among the deletions of individuals with or without the core features of WHS. The more proximal critical region (WHSCR) was delineated first 15 and mapping within this 165-kb interval identified two genes, WHSC1 and WHSC2.…”

Section: Introductionmentioning

confidence: 99%

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

et al. 2013

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Wolf-Hirschhorn syndrome (WHS) is a complex genetic disorder caused by the loss of genomic material from the short arm of chromosome 4. Genotype-phenotype correlation studies indicated that the loss of genes within 4p16.3 is necessary for expression of the core features of the phenotype. Within this region, haploinsufficiency of the genes WHSC1 and LETM1 is thought to be a major contributor to the pathogenesis of WHS. We present clinical findings for three patients with relatively small (o400 kb) de novo interstitial deletions that overlap WHSC1 and LETM1. 3D facial analysis was performed for two of these patients. Based on our findings, we propose that hemizygosity of WHSC1 and LETM1 is associated with a clinical phenotype characterized by growth deficiency, feeding difficulties, and motor and speech delays. The deletion of additional genes nearby WHSC1 and LETM1 does not result in a marked increase in the severity of clinical features, arguing against their haploinsufficiency. The absence of seizures and typical WHS craniofacial findings in our cohort suggest that deletion of distinct or additional 4p16.3 genes is necessary for expression of these features. Altogether, these results show that although loss-offunction for WHSC1 and/or LETM1 contributes to some of the features of WHS, deletion of additional genes is required for the full expression of the phenotype, providing further support that WHS is a contiguous gene deletion disorder.

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“…Patients with small terminal deletions, that do not span the LETM1 gene, have been reported to experience seizures. 4,5 The current report in DMCN establishes a critical platform for the assessment of future cohorts of patients with microdeletions.…”

mentioning

confidence: 99%

“…Deterioration was significantly associated with older age, delayed walking debut, and severe neurological impairment. 4 Self-reported causes…”

mentioning

confidence: 99%

Distinctive EEG patterns in patients with Wolf‐Hirschhorn syndrome

Bergemann

2009

Develop Med Child Neuro

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It is vital that we develop appropriate means of screening children with epilepsy for the presence of psychopathology or behavioural problems to facilitate access to diagnosis and treatment. However, it is equally important that we utilize our knowledge of the aetiology of such psychopathology and its relationship with the primary symptoms of epilepsy when assessing the construct validity of behavioural assessment tools. , 1964-74. Psychol Med 1976 6: 313-32. 2. Rodenburg R, Stams G, Meijer A, Aldenkamp AP, Deković M.Psychopathology in children with epilepsy: a meta-analysis.

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Pathogenic significance of deletions distal to the currently described Wolf–Hirschhorn syndrome critical regions on 4p16.3

Cited by 46 publications

References 19 publications

Multiple congenital malformations of Wolf-Hirschhorn syndrome are recapitulated inFgfrl1null mice

Multiple congenital malformations of Wolf-Hirschhorn syndrome are recapitulated inFgfrl1null mice

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

Distinctive EEG patterns in patients with Wolf‐Hirschhorn syndrome

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