<scp>W</scp>olf‐<scp>H</scp>irschhorn (4<scp>p</scp>‐) Syndrome

Battaglia, A.; Carey, John C.; Wright, Tracy J.

doi:10.1002/0471695998.mgs055

Cited by 59 publications

(61 citation statements)

References 60 publications

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“…4J,K). The affected laryngeal cartilage elements in Fgfrl1 -/-mice also provide an explanation for the problems in swallowing and speech development in infants with WHS (Battaglia et al, 2001) and, in combination with the diaphragm phenotype, might contribute to respiratory distress (van Dooren et al, 2004).…”

Section: Skeletal Malformations In Fgfrl1 Null Micementioning

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: Skeletal Malformations In Fgfrl1 Null Micementioning

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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“…Variable clinical findings include feeding difficulties, congenital malformations including orofacial cleft, cardiac, renal and urogenital malformations, skeletal and dental anomalies, hearing loss, recurrent infections and other complications. [2][3][4] The broad clinical spectrum of WHS can be attributed to variability in both the mechanism and genomic content of 4p deletions. WHS is most often caused by terminal deletions, however, interstitial deletions, unbalanced translocations and complex genomic rearrangements account for a significant proportion of cases.…”

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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“…Variable clinical manifestations include severe feeding difficulties, seizures, antibody deficiency, and major congenital anomalies such as skeletal anomalies, heart lesions, oral facial clefts, sensoineural deafness, and genitourinary tract defects. 1 WHS is caused by deletions involving 4p16.3. Different mechanisms leading to the deletion of 4p16.3 include cytogenetically visible de novo 4p terminal and interstitial deletions (50 -60%), de novo microdeletions detected by fluorescence in situ hybridization (FISH) using a probe for the critical region (25 -30%), or an unbalanced translocation either de novo or inherited from a familial balanced translocation (approximately 15%).…”

Section: Introductionmentioning

confidence: 99%

“…Different mechanisms leading to the deletion of 4p16.3 include cytogenetically visible de novo 4p terminal and interstitial deletions (50 -60%), de novo microdeletions detected by fluorescence in situ hybridization (FISH) using a probe for the critical region (25 -30%), or an unbalanced translocation either de novo or inherited from a familial balanced translocation (approximately 15%). 1,2 A portion of the clinical variation appears to be due to differences in the size of the deletion on 4p. 3 -5 However, many patients do not fit into a strict correlation between size of the deletion and severity of the syndrome.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of Wolf–Hirschhorn syndrome using array CGH indicates a high prevalence of translocations

et al. 2007

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Wolf-Hirschhorn syndrome (WHS) is caused by deletions involving chromosome region 4p16.3. The minimal diagnostic criteria include mild-to-severe mental retardation, hypotonia, growth delay and a distinctive facial appearance. Variable manifestations include feeding difficulties, seizures and major congenital anomalies. Clinical variation may be explained by variation in the size of the deletion. However, in addition to having a deletion involving 4p16.3, previous studies indicate that approximately 15% of WHS patients are also duplicated for another chromosome region due to an unbalanced translocation. It is likely that the prevalence of unbalanced translocations resulting in WHS is underestimated since they can be missed using conventional chromosome analyses such as karyotyping and WHS-specific fluorescence in situ hybridization (FISH). Therefore, we hypothesized that some of the clinical variation may be due to an unrecognized and unbalanced translocation. Array comparative genomic hybridization (aCGH) is a new technology that can analyze the entire genome at a significantly higher resolution over conventional cytogenetics to characterize unbalanced rearrangements. We used aCGH to analyze 33 patients with WHS and found a much higher than expected frequency of unbalanced translocations (15/33, 45%). Seven of these 15 cases were cryptic translocations not detected by a previous karyotype combined with WHS-specific FISH. Three of these 15 cases had an unbalanced translocation involving the short arm of an acrocentric chromosome and were not detected by either aCGH or subtelomere FISH. Analysis of clinical manifestations of each patient also revealed that patients with an unbalanced translocation often presented with exceptions to some expected phenotypes.

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Wolf‐Hirschhorn (4p‐) Syndrome

Cited by 59 publications

References 60 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

Comprehensive analysis of Wolf–Hirschhorn syndrome using array CGH indicates a high prevalence of translocations

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