Constitutional and somatic deletions of the Williams-Beuren syndrome critical region in Non-Hodgkin Lymphoma

Here, we report and investigate the genomic alterations of two novel cases of Non-Hodgkin Lymphoma (NHL) in children with Williams-Beuren syndrome (WBS), a multisystem disorder caused by 7q11.23 hemizygous deletion. Additionally, we report the case of a child with NHL and a somatic 7q11.23 deletion. Although the WBS critical region has not yet been identified as a susceptibility locus in NHL, it harbors a number of genes involved in DNA repair. The high proportion of pediatric NHL reported in WBS is intriguing. Therefore, the role of haploinsufficiency of genes located at 7q11.23 in lymphomagenesis deserves to be investigated.     

Autistic disorder in patients with Williams-Beuren syndrome: a reconsideration of the Williams-Beuren syndrome phenotype

Background

Williams-Beuren syndrome (WBS), a rare developmental disorder caused by deletion of contiguous genes at 7q11.23, has been characterized by strengths in socialization (overfriendliness) and communication (excessive talkativeness). WBS has been often considered as the polar opposite behavioral phenotype to autism. Our objective was to better understand the range of phenotypic expression in WBS and the relationship between WBS and autistic disorder.

Methodology

The study was conducted on 9 French individuals aged from 4 to 37 years old with autistic disorder associated with WBS. Behavioral assessments were performed using Autism Diagnostic Interview-Revised (ADI-R) and Autism Diagnostic Observation Schedule (ADOS) scales. Molecular characterization of the WBS critical region was performed by FISH.

Findings

FISH analysis indicated that all 9 patients displayed the common WBS deletion. All 9 patients met ADI-R and ADOS diagnostic criteria for autism, displaying stereotypies and severe impairments in social interaction and communication (including the absence of expressive language). Additionally, patients showed improvement in social communication over time.

Conclusions

The results indicate that comorbid autism and WBS is more frequent than expected and suggest that the common WBS deletion can result in a continuum of social communication impairment, ranging from excessive talkativeness and overfriendliness to absence of verbal language and poor social relationships. Appreciation of the possible co-occurrence of WBS and autism challenges the common view that WBS represents the opposite behavioral phenotype of autism, and might lead to improved recognition of WBS in individuals diagnosed with autism.     

Investigation of deletions at 7q11.23 in 44 patients referred for Williams-Beuren syndrome,using FISH and four DNA polymorphisms

Williams syndrome (WS) is associated with a submicroscopic deletion of the elastin gene (ELN) at 7q11.23. The deletion encompasses closely linked DNA markers. We have investigated 44 patients referred for possible WS using fluorescence in situ hybridization (FISH) analysis with a P1 clone containing an insert from the ELN, as well as performing genotype analysis of patients and parents with four DNA polymorphisms. Twenty-four patients were found to have deletions, 19 of whom were found clinically to have typical WS. The facial features were especially characteristic. None of the patients without detectable deletions was reported to have typical WS features, although one had supravalvular aortic stenosis, hypercalcemia, and mental retardation. No evidence was found in this material for variability of the size of the deletion. Our study supports the usefulness of analysis of ELN deletion in WS patients, both for confirmation of diagnosis and for genetic counselling. Received: 2 August 1996     

Innate frequency-discrimination hyperacuity in Williams-Beuren syndrome mice

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Recurrent achalasia in a child with Williams-Beuren syndrome

Williams-Beuren syndrome is a multysistem genetic disorder caused by the 1.6Mb hemizygous deletion involving the elastin gene in the region q11.23 of chromosome 7. The phenotype of Williams-Beuren syndrome is extremelly variable but the most common findings include cardiovascular disease, distinctive facies, mental retardation, a specific congitive profile, endocrine abnormalities, growth retardation and connective tissue abnormalities. Although gastrointestinal difficulties are one of the most constant and prominent finding of the syndrome, including gastro-esophageal reflux (GER), poor suckling, vomiting, constipation, prolonged colic, rectal prolapse, inguinal, umbilical and hiatal hernia, there have been no reports of achalasia in association with Williams-Beuren syndrome in the literature. We present the case of a boy with Williams-Beuren syndrome, achalasia and recurrent postoperative stenosis of the cardia. After Heller myotomy, the boy developed severe restenosis of the cardia with abundant adhesions which repeated after every treatment, five times in periods shorter than one month. Eventually, he developed GER, errosive gastritis and hiatal hernia which led to severe malnutrition and failure to thrive. Although the genetic defect causing Williams-Beuren syndrome might not be the direct cause of achalasia we suggest that the frequent development of severe restenosis of cardia due to tight adhesions could be the consequence of elastin gene haploinsufficiency and altered structure and function of elastic fibers in esophageal connective tissue. This case highlights the importance of early diagnosis of esophageal motor disorders in childhood which should be included in the differential diagnosis when a child with Williams-Beuren syndrome presents with dysphagia and/or regurgitation.     

Williams-Beuren syndrome: a model of recurrent genomic mutation

Williams-Beuren syndrome is a segmental aneusomy syndrome with manifestations affecting the vascular, connective tissue, endocrine and central nervous systems. Most patients show a similar heterozygous approximately 1.5 Mb deletion at 7q11.23 that contains a number of reported genes. Deletion mapping in the few atypical patients with smaller deletions suggested that additive effects of haploinsufficiency for two or more genes might be necessary for the phenotype. Vascular stenoses are caused by haploinsufficiency at the elastin gene, while the genes responsible for the cognitive deficits are likely located at the telomeric edge of the deletion, including CYLN2 and GTF2I. Large region-specific segmental duplications predispose to misalignment and inter- or intrachromosomal unequal crossing-over causing the deletions. Atypical alleles at 7q11.23 such as inversions and deletions/insertions of large repeats, also generated through aberrant recombination between the local segmental duplications, are found in approximately 35% of transmitting parents. Genomic instability at 7q11.23 is directly related to the genomic structure of the region.     

Identification of additional transcripts in the Williams-Beuren syndrome critical region

Williams-Beuren syndrome (WBS) is a developmental disorder associated with haploinsufficiency of multiple genes at 7q11.23. Here, we report the characterization of WBSCR16, WBSCR17, WBSCR18, WBSCR20A, WBSCR20B, WBSCR20C, WBSCR21, WBSCR22, and WBSCR23, nine novel genes contained in the WBS commonly deleted region or its flanking sequences. They encode an RCC1-like G-exchanging factor, an N-acetylgalactosaminyltransferase, a DNAJ-like chaperone, NOL1/NOP2/sun domain-containing proteins, a methyltransferase, or proteins with no known homologies. Haploinsufficiency of these newly identified WBSCR genes may contribute to certain of the WBS phenotypical features.     

NMR assignments of the WBSCR27 protein related to Williams-Beuren syndrome

Williams-Beuren syndrome is a genetic disorder characterized by physiological and mental abnormalities, and is caused by hemizygous deletion of several genes in chromosome 7. One of the removed genes encodes the WBSCR27 protein. Bioinformatic analysis of the sequence of WBSCR27 indicates that it belongs to the family of SAM-dependent methyltransferases. However, exact cellular functions of this protein or phenotypic consequences of its deficiency are still unknown. Here we report nearly complete ¹H, ¹⁵N, and ¹³C chemical shifts assignments of the 26 kDa WBSCR27 protein from Mus musculus in complex with the cofactor S-adenosyl-l-methionine (SAM). Analysis of the assigned chemical shifts allowed us to characterize the protein’s secondary structure and backbone dynamics. The topology of the protein’s fold confirms the assumption that the WBSCR27 protein belongs to the family of class I methyltransferases.     

Elastin region deletions in Williams syndrome

Williams syndrome (WS) is considered a contiguous gene syndrome, with most patients having a 1.5-Mb deletion of chromosome 7q11.23 containing the elastin gene and flanking genes. Studies of the frequency, extent, and origin of these deletions are ongoing in many labs to discover ultimately the molecular and pathogenetic basis for WS. An analysis of 9 sporadic WS families with typical phenotypes was performed by genotyping polymorphisms in the region. This study revealed deletions in all 9 patients, with one showing a novel deletion extending much further centromeric than any other WS deletions yet reported.     

Growth assessment in children with Williams-Beuren syndrome: a systematic review

Journal of Applied Genetics - Williams-Beuren syndrome (WBS) is a rare genetic disease caused by a sporadic heterozygous microdeletion in 7q11.23. It is characterized by distinctive facial...     

Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome

In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17-74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS.     

Chromosome duplications and deletions and their mechanisms of origin.

Duplications and deletions of the same gene loci or chromosome regions are known to produce different clinical manifestations and are significant factors in human morbidity and mortality. Extensive cytogenetic and molecular cytogenetic studies with cosmid and YAC probes in two patients with unique mosaicism for reciprocal duplication-deletion allowed us to further understand the origin of these abnormalities. The first patient's mosaic karyotype was 46,XX, inv dup(11) (q23q13)/46,XX,del(11)(q13q23). The second patient had a 46,XY,dup(7)(p11.2p13)/46,XY,del(7)(p11.2p13)/46,XY karyotype. Fluorescence in situ hybridization studies on the first patient placed the two breakpoints near the folate-sensitive fragile sites FRA11A and FRA11B. The presence of repeated sequences responsible for these fragile sites may have been involved in the patient's duplication-deletion. Our investigation leads us to conclude that, in addition to known mechanisms (such as unequal crossovers between homologs, unequal sister chromatid exchanges, excision of intrachromatid loops, and meiotic recombination within a single chromatid), duplication-deletion can also arise by the formation of an overlying loop followed by an uneven crossover at the level of the DNA strand.     

The contribution of CLIP2 haploinsufficiency to the clinical manifestations of the Williams-Beuren syndrome

Williams-Beuren syndrome is a rare contiguous gene syndrome, characterized by intellectual disability, facial dysmorphisms, connective-tissue abnormalities, cardiac defects, structural brain abnormalities, and transient infantile hypercalcemia. Genes lying telomeric to RFC2, including CLIP2, GTF2I and GTF2IRD1, are currently thought to be the most likely major contributors to the typical Williams syndrome cognitive profile, characterized by a better-than-expected auditory rote-memory ability, a relative sparing of language capabilities, and a severe visual-spatial constructive impairment. Atypical deletions in the region have helped to establish genotype-phenotype correlations. So far, however, hardly any deletions affecting only a single gene in the disease region have been described. We present here two healthy siblings with a pure, hemizygous deletion of CLIP2. A putative role in the cognitive and behavioral abnormalities seen in Williams-Beuren patients has been suggested for this gene on the basis of observations in a knock-out mouse model. The presented siblings did not show any of the clinical features associated with the syndrome. Cognitive testing showed an average IQ for both and no indication of the Williams syndrome cognitive profile. This shows that CLIP2 haploinsufficiency by itself does not lead to the physical or cognitive characteristics of the Williams-Beuren syndrome, nor does it lead to the Williams syndrome cognitive profile. Although contribution of CLIP2 to the phenotype cannot be excluded when it is deleted in combination with other genes, our results support the hypothesis that GTF2IRD1 and GTF2I are the main genes causing the cognitive defects associated with Williams-Beuren syndrome.     

Submicroscopic deletion in patients with Williams-Beuren syndrome influences expression levels of the nonhemizygous flanking genes

Genomic imbalance is a common cause of phenotypic abnormalities. We measured the relative expression level of genes that map within the microdeletion that causes Williams-Beuren syndrome and within its flanking regions. We found, unexpectedly, that not only hemizygous genes but also normal-copy neighboring genes show decreased relative levels of expression. Our results suggest that not only the aneuploid genes but also the flanking genes that map several megabases away from a genomic rearrangement should be considered possible contributors to the phenotypic variation in genomic disorders.     

A macaque's-eye view of human insertions and deletions: differences in mechanisms

Insertions and deletions (indels) cause numerous genetic diseases and lead to pronounced evolutionary differences among genomes. The macaque sequences provide an opportunity to gain insights into the mechanisms generating these mutations on a genome-wide scale by establishing the polarity of indels occurring in the human lineage since its divergence from the chimpanzee. Here we apply novel regression techniques and multiscale analyses to demonstrate an extensive regional indel rate variation stemming from local fluctuations in divergence, GC content, male and female recombination rates, proximity to telomeres, and other genomic factors. We find that both replication and, surprisingly, recombination are significantly associated with the occurrence of small indels. Intriguingly, the relative inputs of replication versus recombination differ between insertions and deletions, thus the two types of mutations are likely guided in part by distinct mechanisms. Namely, insertions are more strongly associated with factors linked to recombination, while deletions are mostly associated with replication-related features. Indel as a term misleadingly groups the two types of mutations together by their effect on a sequence alignment. However, here we establish that the correct identification of a small gap as an insertion or a deletion (by use of an outgroup) is crucial to determining its mechanism of origin. In addition to providing novel insights into insertion and deletion mutagenesis, these results will assist in gap penalty modeling and eventually lead to more reliable genomic alignments.