High-Resolution Mapping of Genotype-Phenotype Relationships in Cri du Chat Syndrome Using Array Comparative Genomic Hybridization

Comprehensive Cancer Center and Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 03/2005; 76(2):312-26. DOI: 10.1086/427762
Source: PubMed


We have used array comparative genomic hybridization to map DNA copy-number changes in 94 patients with cri du chat syndrome who had been carefully evaluated for the presence of the characteristic cry, speech delay, facial dysmorphology, and level of mental retardation (MR). Most subjects had simple deletions involving 5p (67 terminal and 12 interstitial). Genotype-phenotype correlations localized the region associated with the cry to 1.5 Mb in distal 5p15.31, between bacterial artificial chromosomes (BACs) containing markers D5S2054 and D5S676; speech delay to 3.2 Mb in 5p15.32-15.33, between BACs containing D5S417 and D5S635; and the region associated with facial dysmorphology to 2.4 Mb in 5p15.2-15.31, between BACs containing D5S208 and D5S2887. These results overlap and refine those reported in previous publications. MR depended approximately on the 5p deletion size and location, but there were many cases in which the retardation was disproportionately severe, given the 5p deletion. All 15 of these cases, approximately two-thirds of the severely retarded patients, were found to have copy-number aberrations in addition to the 5p deletion. Restriction of consideration to patients with only 5p deletions clarified the effect of such deletions and suggested the presence of three regions, MRI-III, with differing effect on retardation. Deletions including MRI, a 1.2-Mb region overlapping the previously defined cri du chat critical region but not including MRII and MRIII, produced a moderate level of retardation. Deletions restricted to MRII, located just proximal to MRI, produced a milder level of retardation, whereas deletions restricted to the still-more proximal MRIII produced no discernible phenotype. However, MR increased as deletions that included MRI extended progressively into MRII and MRIII, and MR became profound when all three regions were deleted.

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Available from: Joe W Gray, Jun 15, 2014
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    • "The array-CGH analysis allowed more precise localization of the cat-like cry critical region between 6.0–7.5 Mb on 5p15.31 [6]. The region was further narrowed in the study by Wu et al. [5], using quantitative PCR, to a 640 kb small region on 5p15.31, "
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    ABSTRACT: Rearrangements involving chromosome 5p often result in two syndromes, Cri-du-chat (CdC) and Trisomy 5p, caused by a deletion and duplication, respectively. The 5p15.2 has been defined as a critical region for CdC syndrome; however, genotype-phenotype studies allowed isolation of particular characteristics such as speech delay, cat-like cry and mental retardation, caused by distinct deletions of 5p. A varied clinical outcome was also observed in patients with Trisomy 5p. Duplications of 5p10-5p13.1 manifest themselves in a more severe phenotype, while trisomy of regions distal to 5p13 mainly causes mild and indistinct features. Combinations of a terminal deletion and inverted duplication of 5p are infrequent in literature. Consequences of these chromosomal rearrangements differ, depending on size of deletion and duplication in particular cases, although authors mainly describe the deletion as the cause of the observed clinical picture. Here we present a 5-month-old Slovenian girl, with de novo terminal deletion and inverted duplication of chromosome 5p. Our patient presents features of both CdC and Trisomy 5. The most prominent features observed in our patient are a cat-like cry and severe malformations of the right ear. The cat-like cry, characteristic of CdC syndrome, is noted in our patient despite the fact that the deletion is not fully consistent with previously defined cat-like cry critical region in this syndrome. Features like dolichocephaly, macrocephaly and ear malformations, associated with duplication of the critical region of Trisomy 5p, are also present, although this region has not been rearranged in our case. Therefore, the true meaning of the described chromosomal rearrangements is discussed.
    Full-text · Article · Feb 2014 · BMC Medical Genetics
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    • "Comparison of the transmitted deletions in affected and unaffected families implicates a candidate gene region in 5p13.3 as the cause of the learning and/or behavioral difficulties in a 5p medial deletion syndrome that can also include microcephaly, facial dysmorphism, and short stature in some deletion carriers [Walker et al., 1984; Keppen et al., 1992; Johnson et al., 2000]. However, deletion of cadherin genes in both affected and unaffected families raises the possibility that variable penetrance of the cadherin cluster might account for the cognitive phenotype in this and other affected families as well as the additional severity of ID in distal cri-du-chat deletions that extend into the IDIII region [Zhang et al., 2005]. "
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    ABSTRACT: The central portion of the short arm of chromosome 5 is unusual in that large, cytogenetically visible interstitial deletions segregate in families with and without phenotypic consequences. Here we present a family in which a transmitted interstitial deletion of 5p13.3 to 5p14.3 co-segregated with learning and/or behavioral difficulties in six family members. Facial dysmorphism was not striking but a father and daughter both had lacrimal fistulae. The deletion was 12.23 Mb in size (chr5:20,352,535-32,825,775) and contained fifteen known protein coding genes. Five of these (GOLPH3; MTMR12; ZFR; SUB1; and NPR3) and an ultra-conserved microRNA (hsa-miR-579) were present in an 883 kb candidate gene region in 5p13.3 that was deleted in the present family but not in previously reported overlapping benign deletions. Members of the cadherin precursor gene cluster, with brain specific expression, were deleted in both affected and benign deletion families. The candidate genes in 5p13.3 may be sufficient to account for the consistent presence or absence of phenotype in medial 5p deletions. However, we consider the possibility of position effects in which CDH6, and/or other cadherin genes, become penetrant when adjacent genes, or modifiers of gene expression, are also deleted. This could account for the absence of intellectual disability in benign deletions of the cadherin cluster, the cognitive phenotype in medial 5p deletion syndrome and the greater severity of intellectual disability in patients with cri-du-chat syndrome and deletions of 5p15 that extend into the region deleted in the present family.
    Full-text · Article · Nov 2011 · American Journal of Medical Genetics Part A
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    • "; 4p [Maas et al., 2008]; 5p [Zhang et al., 2005]; 9p [Barbaro et al., 2009]; 11q [Coldren et al., 2008]; 13q [Kirchhoff et al., 2009]; 18q [Cody et al., 2009]; and 21 [Korbel et al., 2009]. Although these types of data identify regions and rarely identify singles genes, these data are never-the-less an important resource for information about potential annotation of specific genes. "
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    ABSTRACT: Nine out of 10 people has a chromosome copy number variation (CNV) of >1,000 bp of DNA. In some cases they are inconsequential, in other cases the variations cause disease or disability, and in most cases the relevance has not been elucidated. Several studies describe CNVs as "normal" biological variants while other studies suggest that CNVs may be associated with developmental disability. A concerted effort is needed to classify genes according to their dosage sensitivity, or to their lack of sensitivity. Over time, this effort will lead to the establishment of principles that permit the prediction of the consequence of any one genomic copy number change.
    Full-text · Article · Mar 2011 · American Journal of Medical Genetics Part A
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