A de novo translocation t(3;17)(q26.3;q23.1) in a child with Cornelia de Lange syndrome.

Ireland, Mark T.; English, C; Cross, I; Houlsby, W T; Burn, John

doi:10.1136/jmg.28.9.639

Cited by 58 publications

(42 citation statements)

References 6 publications

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“…One such case is that of a child with a de novo balanced 14;21 translocation (karyotype, 46,XX,t(14;21)(q32;q11.2)) in whom a NIPBL mutation (S1459) was identified; this translocation was not related to the CdLS phenotype . Similarly, a de novo, balanced 3;17 translocation [Ireland et al, 1991] has been extensively studied [Tonkin et al, 2001] with no clear identification of a causative gene disrupted at the breakpoint. Conversely, however, in two cases with deletions in 5p13 [Taylor and Josifek, 1981;Hulinsky et al, 2003] (Table I), the chromosome abnormality is directly responsible for causing the CdLS phenotype in these individuals.…”

Section: Discussionmentioning

confidence: 99%

Chromosome rearrangements in Cornelia de Lange syndrome (CdLS): Report of a der(3)t(3;12)(p25.3;p13.3) in two half sibs with features of CdLS and review of reported CdLS cases with chromosome rearrangements

DeScipio

Kaur

Yaeger

et al. 2005

American J of Med Genetics Pt A

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Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited disorder characterized by multisystem involvement, cognitive delay, limb defects, and characteristic facial features. Recently, mutations in NIPBL have been found in ∼50% of individuals with CdLS. Numerous chromosomal rearrangements have been reported in individuals with CdLS. These rearrangements may be causative of a CdLS phenotype, result in a phenocopy, or be unrelated to the observed phenotype. We describe two half siblings with a der(3)t(3;12)(p25.3;p13.3) chromosomal rearrangement, clinical features resembling CdLS, and phenotypic overlap with the del(3)(p25) phenotype. Region‐specific BAC probes were used to fine‐map the breakpoint region by fluorescence in situ hybridization (FISH). FISH analysis places the chromosome 3 breakpoint distal to RP11‐115G3 on 3p25.3; the chromosome 12 breakpoint is distal to BAC RP11‐88D16 on 12p13.3. A review of published cases of terminal 3p deletions and terminal 12p duplications indicates that the findings in these siblings are consistent with the del(3)(p25) phenotype. Given the phenotypic overlap with CdLS, we have reviewed the reported cases of chromosomal rearrangements involved in CdLS to better elucidate other potential loci that could harbor additional CdLS genes. Additionally, to identify chromosome rearrangements, genome‐wide array comparative genomic hybridization (CGH) was performed on eight individuals with typical CdLS and without identifiable deletion or mutation of NIPBL. No pathologic rearrangements were identified. © 2005 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Chromosome rearrangements in Cornelia de Lange syndrome (CdLS): Report of a der(3)t(3;12)(p25.3;p13.3) in two half sibs with features of CdLS and review of reported CdLS cases with chromosome rearrangements

DeScipio

Kaur

Yaeger

et al. 2005

American J of Med Genetics Pt A

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“…A lymphoblastoid cell line was generated from a blood sample from the t(3;17)(q26.3;q23.1) case previously described by Ireland et al (1991) . Chromosome-specific centromere probes obtained from Appligene Oncor were used to identify chromosomes 3 and 17.…”

Section: Mapping the Translocation Breakpoints In The T(3;17) Translomentioning

confidence: 99%

“…Clues to subchromosomal location have, however, been suggested from associated chromosomal abnormalities. A variety of abnormalities have been reported (for a review, see Kousseff et al 1994 ) but much attention has been focused on distal 3q as a result of (1) phenotypic overlap between the duplication 3q syndrome and mild CdLS ( Steinbach et al 1981 ;Wilson et al 1985 ) and (2) the identification of a balanced de novo translocation t(3;17)(q26.3;q23.1) in a patient with classical CdLS, some time after the original reports of phenotypic similarity between mild CdLS and the duplication 3q syndrome ( Ireland et al 1991 ). The significance of the 3q26.3 breakpoint appeared to be enhanced when the 3q26.3-q27 interval was suggested as the critical region for the dup 3q syndrome ( Aqua et al 1995 ;Ireland et al 1995 ;Rizzu et al 1997 ); individuals trisomic for regions immediately proximal or distal to this region were reported not to resemble CdLS ( Rizzu et al 1997 ;Lopez-Rangel et al 1993 ).…”

Section: Introductionmentioning

confidence: 99%

A giant novel gene undergoing extensive alternative splicing is severed by a Cornelia de Lange-associated translocation breakpoint at 3q26.3

et al. 2004

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Cornelia de Lange syndrome (CdLS) is a rare developmental malformation syndrome characterised by mental handicap, growth retardation, distinctive facial features and limb reduction defects. The vast majority of CdLS cases are sporadic. We carried out a high density bacterial artificial chromosome (BAC) microarray comparative genome hybridisation screen but no evidence was found for a consistent pattern of microdeletion/micro-duplication. As an alternative, we focused on identifying chromosomal regions spanning associated translocation breakpoints. We prioritised the distal 3q region because of the occurrence, in a classical CdLS patient, of a de novo balanced translocation with a breakpoint at 3q26.3 and of reports of phenotypic overlap between cases of mild CdLS and individuals trisomic for the 3q26-q27 region. We show that the 3q26.3 breakpoint severs a previously uncharacterised giant gene, NAALADL2, containing at least 32 exons spanning 1.37 Mb. Northern blot analysis identified up to six different transcripts in the 1-10 kb range with strongest expression in kidney and placenta; embryonic expression was largely confined to duodenal and stomach endoderm, mesonephros, metanephros and pancreas. Transcript analysis identified extensive alternative splicing leading to multiple 5′ and 3′ untranslated regions and variable coding sequences. Multiple protein isoforms were defined by different N-terminal regions (with at least four alternative initiating methionine codons), and by differential protein truncation/use of alternative C-terminal sequences attributable to alternative splicing/polyadenylation. Outside the N-terminal regions, the predicted proteins showed significant homology to N-acetylated alpha-linked acidic dipeptidase and transferrin receptors. Mutation screening of NAALADL2 in a panel of CdLS patient DNA samples failed to identify patient-specific mutations. We discuss the possibility that the 3q26.3 translocation could nevertheless contribute to pathogenesis. Tonkin et al.

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“…Because CdLS is rare and most cases are sporadic, genome-wide linkage screens are problematic. As an alternative, we analyzed chromosomal breakpoints associated with CdLS, focusing first on three classical cases with de novo balanced translocations, including the previously described translocations t(3;17)(q26.3;q23.1) 4 and t(14;21)(q32;q11) 5 . We first analyzed the 3q26.3 breakpoint because of NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome Fig.…”

mentioning

confidence: 99%

NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome

et al. 2004

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Cornelia de Lange syndrome (CdLS) is a multiple malformation disorder characterized by dysmorphic facial features, mental retardation, growth delay and limb reduction defects 1,2 . We indentified and characterized a new gene, NIPBL, that is mutated in individuals with CdLS and determined its structure and the structures of mouse, rat and zebrafish homologs. We named its protein product delangin. Vertebrate delangins have substantial homology to orthologs in flies, worms, plants and fungi, including Scc2-type sister chromatid cohesion proteins, and D. melanogaster Nipped-B. We propose that perturbed delangin function may inappropriately activate DLX genes, thereby contributing to the proximodistal limb patterning defects in CdLS. Genome analyses typically identify individual delangin or Nipped-Blike orthologs in diploid animal and plant genomes. The evolution of an ancestral sister chromatid cohesion protein to acquire an additional role in developmental gene regulation suggests that there are parallels between CdLS and Roberts syndrome.The multisystem nature of the CdLS phenotype suggests that it is caused by a microdeletion or microduplication affecting several genes or by a single gene that regulates various target genes. A high-density BAC microarray comparative genome hybridization screen found no evidence for a consistent pattern of microdeletion or microduplication 3 . Because CdLS is rare and most cases are sporadic, genome-wide linkage screens are problematic. As an alternative, we analyzed chromosomal breakpoints associated with CdLS, focusing first on three classical cases with de novo balanced translocations, including the previously described translocations t(3;17)(q26.3;q23.1) 4 and t(14;21)(q32;q11) 5 . We first analyzed the 3q26.3 breakpoint because of NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome Arrows indicate the normal chromosome 5 and the der(5) t(5;13)(p13.1;q12.1) and der(13) t(5;13)(p13.1;q12.1) chromosomes. In occasional metaphases a weak G248P84262B4 signal can be detected on the der(5) chromosome as well as a strong signal on the der(13). The combined data suggest that the most likely location for the breakpoint is close to the proximal end of the region of overlap for inserts of G248P84262B4 and G248P8840C10 (Fig. 2a).

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A de novo translocation t(3;17)(q26.3;q23.1) in a child with Cornelia de Lange syndrome.

Abstract: A female infant with Cornelia de

Cited by 58 publications

References 6 publications

Chromosome rearrangements in Cornelia de Lange syndrome (CdLS): Report of a der(3)t(3;12)(p25.3;p13.3) in two half sibs with features of CdLS and review of reported CdLS cases with chromosome rearrangements

Chromosome rearrangements in Cornelia de Lange syndrome (CdLS): Report of a der(3)t(3;12)(p25.3;p13.3) in two half sibs with features of CdLS and review of reported CdLS cases with chromosome rearrangements

A giant novel gene undergoing extensive alternative splicing is severed by a Cornelia de Lange-associated translocation breakpoint at 3q26.3

NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome

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