Clinical and molecular characterisation of 80 patients with 5p deletion: genotype-phenotype correlation

Pc, Mainardi; Perfumo, Chiara; Calı̀, Angelita; Coucourde, G; Pastore, Guido; Cavani, Simona; Zara, Federico; Overhauser, Joan; Pierluigi, Mauro; Fd, Bricarelli

doi:10.1136/jmg.38.3.151

Cited by 156 publications

(166 citation statements)

References 37 publications

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“…Cri-du-chat patients often exhibit difficulty swallowing and suckling, strabismus, and saliva control problems, which are likely caused by as-yet-undefined deficits in cranial nerve development. Thus, the 7-1 mutation will help elucidate specific cranial nerve deficits present in some cri-du-chat patients that heretofore may have been overshadowed by the more overwhelming symptoms (Church et al, 1995(Church et al, , 1997Cornish and Munir, 1998;Mainardi et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

A Genetic Screen for Mutations That Affect Cranial Nerve Development in the Mouse

Mar

Rivkin²,

Kim³

et al. 2005

J. Neurosci.

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Cranial motor and sensory nerves arise stereotypically in the embryonic hindbrain, act as sensitive indicators of general and regionspecific neuronal development, and are directly or indirectly affected in many human disorders, particularly craniofacial syndromes. The molecular genetic hierarchies that regulate cranial nerve development are mostly unknown. Here, we describe the first mouse genetic screen that has used direct immunohistochemical visualization methods to systematically identify genetic loci required for cranial nerve development. After screening 40 pedigrees, we recovered seven new neurodevelopmental mutations. Two mutations model human genetic syndromes. Mutation 7-1 causes facial nerve anomalies and a reduced lower jaw, and is located in a region of conserved synteny with an interval associated with the micrognathia and mental retardation of human cri-du-chat syndrome. Mutation 22-1 is in the Pax3 gene and, thus, models human Waardenburg syndrome. Three mutations cause global axon guidance deficits: one interferes with initial motor axon extension from the neural tube, another causes overall axon defasciculation, and the third affects general choice point selection. Another two mutations affect the oculomotor nerve specifically. Oculomotor nerve development, which is disrupted by six mutations, appears particularly sensitive to genetic perturbations. Phenotypic comparisons of these mutants identifies a "transition zone" that oculomotor axons enter after initial outgrowth and in which new factors govern additional progress. The number of interesting neurodevelopmental mutants revealed by this small-scale screen underscores the promise of similar focused genetic screens to contribute significantly to our understanding of cranial nerve development and human craniofacial syndromes.

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Section: Discussionmentioning

confidence: 99%

A Genetic Screen for Mutations That Affect Cranial Nerve Development in the Mouse

Mar

Rivkin²,

Kim³

et al. 2005

J. Neurosci.

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“…17 The location of another component in the ubiquitin-conjugating degradation pathway just next to the critical region for facial and mental retardation may further support that fact that the proposed UBC-E2 homologous gene FLJ25076 is involved in the cat-like cry phenotype. In addition, the finding of two genes presumably in the same ubiquitin proteosome- Markers (STS) and probes (P) g from Figure 4 used by Overhauser et al, 4 Gersh et al, 5 Church et al 6 and Mainardi et al, 7 and this study mapping the catlike cry 'critical region'. The cytogenetic bands (a) and positions (b) refer to NCBI Build 34 and July 2003 version in UCSC Genome Browser [20,21].…”

Section: Surveying Several Candidate Genesmentioning

confidence: 99%

“…The markers D5S23, D5S721, D5S769 and D5S791 delimit the CdCCR region. 4,5,7 A larger region including the CdCCR and additional childhood facial dysmorphism as well as moderate mental retardation is mapped to D5S24, D5S713, D5S755 and D5S706. 6 More detailed studies have identified the proximal part of 5p15.3 as the 'critical region' for cat-like cry and a segment within 5p15.2 as responsible for the 'critical region' for mental retardation.…”

Section: Introductionmentioning

confidence: 99%

Determination of the ‘critical region’ for cat-like cry of Cri-du-chat syndrome and analysis of candidate genes by quantitative PCR

Niebuhr

Yang

et al. 2005

Eur J Hum Genet

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Cri-du-chat (CDC, OMIM 123450) is a chromosomal syndrome that results from partial deletions on the short arm of chromosome 5. The clinical features of CDC normally include high-pitched cat-like cry, mental retardation, microcephaly, hypertelorism and epicanthic folds. The cat-like cry is the most prominent clinical characteristic in newborn children and is usually considered as diagnostic for the CDC syndrome. Using a strategy of 'phenotype dissection', the critical region for cat-like cry was mapped to the chromosomal segment 5p15.3 -5p15.2 in previous reports. In this study, the distal breakpoints of two interstitial deletions in two clinical distinctive CDC patients are analysed, one with and one without the catlike cry. Using PCR, the critical region for the cat-like cry is mapped to a short 640 kbp region on chromosome 5p. Genome analysis of this critical region reveals a gene-rich sequence containing five known genes, five putative genes and three spliced EST sequences, altogether 71 predicted exons. Three genes, FLJ25076, a homolog to a ubiquitin-conjugating enzyme UBC-E2, FLJ20303, a nucleolar protein NOP2, which may play a role in the regulation of the cell cycle and MGC5309, a protein with similarity to Nut2, a Drosophila transcriptional coactivator, have been characterized and expression profiles determined by quantitative PCR. These results suggest that one candidate gene, FLJ25076, encodes a ubiquitinconjugated enzyme E2 type, which is locally expressed in thoracic and scalp tissues. The other two genes are expressed uniformly in all tissues tested, which suggest that they are housekeeping genes.

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“…Recent molecular cytogenetic analyses have defined 5p15.3 and 5p15.2 as responsible for ''catlike cry'' and ''dysmorphism, microcephaly, and mental retardation,'' respectively (Gersh et al 1995). On the other hand, Mainardi et al (2001) reported that the region for cat-like cry was located between D5S13 and D5S731. We report here the detailed chromosomal analysis of six 5p-syndrome patients.…”

mentioning

confidence: 99%

“…Introduction 5p-syndrome, also called ''Cat cry syndrome'' or ''Cri du chat syndrome,'' varies clinically and genetically (Mainardi et al 2001). Recent molecular cytogenetic analyses have defined 5p15.3 and 5p15.2 as responsible for ''catlike cry'' and ''dysmorphism, microcephaly, and mental retardation,'' respectively (Gersh et al 1995).…”

mentioning

confidence: 99%

Genotype-phenotype correlation of 5p- syndrome: pitfall of diagnosis

et al. 2004

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To clarify the genotype-phenotype correlation of 5p-syndrome, FISH analyses were performed for six patients by using a series of probes spanning 5p13.1-p15.33. Genotypically, break points of deletion were quite different. Three of the six patients were diagnosed as interstitial deletion on chromosome 5p by G-banding method and FISH analysis; however, all of them proved to be entire distal deletions of 5p caused by unbalanced chromosomal translocations. Furthermore, one 5p-syndrome patient was diagnosed only by the FISH analysis using a single probe but not by ordinary chromosomal analyses. Therefore, when ordinary chromosomal analysis cannot detect any deletion in a patient who is phenotypically suspected of 5p-syndrome, multiple FISH analysis or parental chromosomal analysis would be needed for correct diagnosis. Interestingly, one patient with terminal deletion between 5p15.31-pter lacks mental retardation and cat-like crying, indicating that this region might not be responsible for those cardinal features of 5p-syndrome. Further studies on genotype-phenotype correlation will help us better understand 5p-syndrome and also determine functional mapping of the 5p region.

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Clinical and molecular characterisation of 80 patients with 5p deletion: genotype-phenotype correlation

Cited by 156 publications

References 37 publications

A Genetic Screen for Mutations That Affect Cranial Nerve Development in the Mouse

A Genetic Screen for Mutations That Affect Cranial Nerve Development in the Mouse

Determination of the ‘critical region’ for cat-like cry of Cri-du-chat syndrome and analysis of candidate genes by quantitative PCR

Genotype-phenotype correlation of 5p- syndrome: pitfall of diagnosis

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