Dominant paternal transmission of Cornelia de Lange syndrome: A new case and review of 25 previously reported familial recurrences

Russell, Karen; Ming, Jeffrey E.; Patel, Ketan; Jukofsky, Lori; Magnusson, Mark; Krantz, Ian D.

doi:10.1002/ajmg.10066

Cited by 62 publications

(53 citation statements)

References 41 publications

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“…This means that approximately one-third of the coding sequence was sampled in 45 individuals and more than one-half of the proximal intronic sequence was also sampled for splicing mutations. On the basis of observed relative frequencies of splice site mutations and other mutations in large multiexon genes, and assuming that all affected individuals are heterozygotes (as expected from the strong evidence for autosomal dominant transmission 26 ) and that there are no strong mutational hot spots in the coding sequence, the identification of 9 mutations in a panel of 45 individuals with CdLS ( Table 1) equates roughly to a detection rate >50%. The relatively low mutation detection rate could reflect limitations of the mutation screening protocol: only coding sequences and proximal intronic sequences were analyzed, and the gene is large and possibly prone to undetected large-scale mutations.…”

Section: Methodsmentioning

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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Section: Methodsmentioning

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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“…1 The majority of the cases are sporadic, but a few cases showing an autosomal-dominant inheritance have been reported. 2 Two recent studies reported mutations in the NIPBL gene to cause CdLS 3,4 and NIPBL mutations have previously been identified in 26 -56% of CdLS cases. 4 -8 NIPBL is located on chromosome 5p13, consists of 47 exons and encodes delangin, a 2804 amino-acid protein which is the homolog of fungal Scc2-type sister chromatid cohesion protein and the Drosophila Nipped-B developmental regulator.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive mutational analysis of a cohort of Swedish Cornelia de Lange syndrome patients

et al. 2006

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Cornelia de Lange syndrome (CdLS; OMIM 122470) is a rare multiple congenital anomaly/mental retardation syndrome characterized by distinctive dysmorphic facial features, severe growth and developmental delay and abnormalities of the upper limbs. About 50% of CdLS patients have been found to have heterozygous mutations in the NIPBL gene and a few cases were recently found to be caused by mutations in the X-linked SMC1L1 gene. We performed a mutation screening of all NIPBL coding exons by direct sequencing in 11 patients (nine sporadic and two familial cases) diagnosed with CdLS in Sweden and detected mutations in seven of the cases. All were de novo, and six of the mutations have not been previously described. Four patients without identifiable NIPBL mutations were subsequently subjected to multiplex ligation-dependent probe amplification analysis to exclude whole exon deletions/duplications of NIPBL. In addition, mutation analysis of the 5 0 untranslated region (5 0 UTR) of NIPBL was performed. Tiling resolution array comparative genomic hybridization analysis was carried out on these four patients to detect cryptic chromosome imbalances and in addition the boys were screened for SMC1L1 mutations. We found a de novo 9p duplication with a size of 0.6 Mb in one of the patients with a CdLS-like phenotype but no mutations were detected in SMC1L1. So far, two genes (NIPBL and SMC1L1) have been identified causing CdLS or CdLS-like phenotypes. However, in a considerable proportion of individuals demonstrating the CdLS phenotype, mutations in any of these two genes are not found and other potential loci harboring additional CdLS-causing genes should be considered.

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“…The low estimates for the general recurrence risk for sibs ( Jackson et al 1993 ) argues against recessive inheritance and, in some of the multicase pedigrees, there is strong evidence for autosomal dominant inheritance ( KrajewskaWalasek et al 1998 ;Kozma 1996 ;McKenney et al 1996 ;Russell et al 2001 ;McConnell et al 2003 ). In other multi-case pedigrees, the birth of more than one affected child to unaffected parents can be explained by gonadal mosaicism.…”

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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Dominant paternal transmission of Cornelia de Lange syndrome: A new case and review of 25 previously reported familial recurrences

Cited by 62 publications

References 41 publications

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

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

Comprehensive mutational analysis of a cohort of Swedish Cornelia de Lange syndrome patients

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

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