Williams Syndrome Medline Alert - October 1998

From the Medical Literature - October 1998


Record  1

High level of unequal meiotic crossovers at the origin of the 22q11. 2 and 7q11.23 deletions. Baumer A; Dutly F; Balmer D; Riegel M; Tukel T; Krajewska-Walasek M; Schinzel AA Institute for Medical Genetics, University of Zurich, CH-8001 Zurich, Switzerland. [email protected] Hum Mol Genet (ENGLAND) May 1998, 7 (5) p887-94, ISSN 0964-6906 Languages: ENGLISH Document type: JOURNAL ARTICLE

Interstitial chromosomal deletions at 22q11.2 and 7q11.23 are detected in the vast majority of patients affected by CATCH 22 syndromes and the Williams-Beuren syndrome, respectively. In a group of 15 Williams-Beuren patients, we have shown previously that a large number of 7q11.23 deletions occur in association with an interchromosomal rearrangement, indicative of an unequal crossing-over event between the two homologous chromosomes 7. In this study, we show that a similar mechanism also underlies the formation of the 22q11.2 deletions associated with CATCH 22. In eight out of 10 families with a proband affected by CATCH 22, we were able to show that a meiotic recombination had occurred at the critical deleted region based on segregation analysis of grandparental haplotypes. The incidences of crossovers observed between the closest informative markers, proximal and distal to the deletion, were compared with the expected recombination frequencies between the markers. A significant number of recombination events occur at the breakpoint of deletions in CATCH 22 patients (P = 2.99x10(-7)). The segregation analysis of haplotypes in three-generation families was also performed on an extended number of Williams-Beuren cases (22 cases in all). The statistically significant occurrence of meiotic crossovers (P = 4.45x10(-9)) further supports the previous findings. Thus, unequal meiotic crossover events appear to play a relevant role in the formation of the two interstitial deletions. The recurrence risk for healthy parents in cases where such meiotic recombinations can be demonstrated is probably negligible. Such a finding is in agreement with the predominantly sporadic occurrence of the 22q11.2 and 7q11. 23 deletions. No parent-of-origin bias was observed in the two groups of patients with regard to the origin of the deletion and to the occurrence of inter- versus intrachromosomal rearrangements.


Record 2

Delineation of the common critical region in Williams syndrome and clinical correlation of growth, heart defects, ethnicity, and parental origin. Wu YQ; Sutton VR; Nickerson E; Lupski JR; Potocki L; Korenberg JR; Greenberg F; Tassabehji M; Shaffer LG Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. Am J Med Genet (UNITED STATES) Jun 16 1998, 78 (1) p82-9, ISSN 0148-7299 Languages: ENGLISH Document type: JOURNAL ARTICLE

Williams syndrome (WS) is a neurodevelopmental disorder with a variable phenotype. Molecular genetic studies have indicated that hemizygosity at the elastin locus (ELN) may account for the cardiac abnormalities seen in WS, but that mental retardation and hypercalcemia are likely caused by other genes flanking ELN. In this study, we defined the minimal critical deletion region in 63 patients using 10 microsatellite markers and 5 fluorescence in situ hybridization (FISH) probes on chromosome 7q, flanking ELN. The haplotype analyses showed the deleted cases to have deletions of consistent size, as did the FISH analyses using genomic probes for the known ends of the commonly deleted region defined by the satellite markers. In all informative cases deleted at ELN, the deletion extends from D7S489U to D7S1870. The genetic distance between these two markers is about 2 cM. Of the 51 informative patients with deletions, 29 were maternal and 22 were paternal in origin. There was no evidence for effects on stature by examining gender, ethnicity, cardiac status, or parental origin of the deletion. Heteroduplex analysis for LIMK1, a candidate gene previously implicated in the WS phenotype, did not show any mutations in our WS patients not deleted for ELN. LIMK1 deletions were found in all elastin-deletion cases who had WS. One case, who has isolated, supravalvular aortic stenosis and an elastin deletion, was not deleted for LIMK1. It remains to be determined if haploinsufficiency of LIMK1 is responsible in part for the WS phenotype or is simply deleted due to its close proximity to the elastin locus.


Record 3

Occurrence of cancer in a cohort of 183 persons with constitutional chromosome 7 abnormalities. Hasle H; Olsen JH; Hansen J; Friedrich U; Tommerup N Department of Pediatrics, Aarhus University Hospital, Denmark. Cancer Genet Cytogenet (UNITED STATES) Aug 1998, 105 (1) p39-42, ISSN 0165-4608 Languages: ENGLISH Document type: JOURNAL ARTICLE; REVIEW; REVIEW OF REPORTED CASES

Cytogenetic abnormalities in human malignancies frequently involve chromosome 7. The existence of several tumor suppressor genes on the long arm of chromosome 7 has been suggested in both epithelial and hematologic malignancies. From the Danish Cytogenetic Register, we identified 183 persons with constitutional abnormalities involving chromosome 7, including 16 patients with Williams syndrome. By linkage to the Danish Cancer Registry, we found five persons with cancer, including one thyroid carcinoma, three carcinomas of the digestive tract, and one malignant melanoma. There were no cases of leukemia. The overall risk of developing cancer was not increased. (28 Refs.)


Record 4

Verbal and nonverbal abilities in the Williams syndrome phenotype: evidence for diverging developmental trajectories. Jarrold C; Baddeley AD; Hewes AK Department of Experimental Psychology, University of Bristol, U.K. J Child Psychol Psychiatry (ENGLAND) May 1998, 39 (4) p511-23, ISSN 0021-9630 Languages: ENGLISH Document type: JOURNAL ARTICLE

One commonly cited feature of Williams syndrome is a characteristic dissociation between relatively spared language skills and severely impaired nonverbal abilities. However, the actual evidence for a dissociation between verbal and nonverbal abilities in Williams syndrome is equivocal. In two separate studies we examined these abilities in 16 individuals showing the Williams syndrome phenotype. When considered as a whole, the group did have significantly superior verbal abilities, but this difference was caused by a large discrepancy in abilities in only a small number of individuals. In both studies there was a clear, linear relation between individuals' verbal ability, and the magnitude of their verbal-nonverbal discrepancy. We suggest that these results are best explained in terms of verbal ability developing at a faster rate than nonverbal ability in this disorder. We discuss how this model of differential rates of development has the potential to reconcile the apparently inconsistent findings in this area.


Record 5

A highly polymorphic CA/GT repeat (LIMK1GT) within the Williams syndrome critical region. Mari A; Amati F; Conti E; Bengala M; Novelli G; Dallapiccola B Department of Public Health and Cell Biology Tor Vergata University and Institute C.S.S.-Mendel, Rome, Italy. Clin Genet (DENMARK) Mar 1998, 53 (3) p226-7, ISSN 0009-9163 Languages: ENGLISH Document type: JOURNAL ARTICLE


Record 6

Why should neurologists be interested in Williams syndrome? [editorial; comment] Rossen ML; Sarnat HB Neurology (UNITED STATES) Jul 1998, 51 (1) p8-9, ISSN 0028-3878 Comment on Neurology 1998 Jul;51(1):33-40 Languages: ENGLISH Document type: COMMENT; EDITORIAL


Record 7

Brain biochemistry in Williams syndrome: evidence for a role of the cerebellum in cognition? [see comments] Rae C; Karmiloff-Smith A; Lee MA; Dixon RM; Grant J; Blamire AM; Thompson CH; Styles P; Radda GK MRC Biochemical and Clinical Magnetic Resonance Unit, John Radcliffe Hospital, Oxford, UK. Neurology (UNITED STATES) Jul 1998, 51 (1) p33-40, ISSN 0028-3878 Comment in Neurology 1998 Jul;51(1):8-9 Languages: ENGLISH Document type: JOURNAL ARTICLE

OBJECTIVE: To determine what biochemical changes may occur in the brain in Williams syndrome (WS) and whether these changes may be related to the cognitive deficits. BACKGROUND: WS is a rare, congenital disorder with a characteristic physical, linguistic, and behavioral phenotype with known cognitive deficits. METHODS: We obtained 31P magnetic resonance spectra (MRS) from a region consisting of mostly frontal and parietal lobe of 14 patients with WS (age, 8 to 37 years) and 48 similarly-aged controls. 1H MRS (27 cm3) localized to the left cerebellum obtained from the WS cohort were compared with those from 16 chronological age- and sex-matched normal controls. A battery of cognitive tests were administered to all subjects undergoing 1H MRS. RESULTS: WS brains exhibited significant biochemical abnormalities. All 31P MRS ratios containing the phosphomonoester (PME) peak were significantly altered in WS, suggesting that PME is significantly decreased. Ratios of choline-containing compounds and creatine-containing compounds to N-acetylaspartate (Cho/NA and Cre/NA) were significantly elevated in the cerebellum in WS cf. controls, whereas the ratio of Cho/Cre was not altered. This suggests a decrease in the neuronal marker N-acetylaspartate in the cerebellum. Significant correlations were found between the cerebellar ratios Cho/NA and Cre/NA and the ability of all subjects at various neuropsychological tests, including Verbal and Performance IQ, British Picture Vocabulary Scale, Ravens Progressive Matrices, and Inspection Time. CONCLUSIONS: The correlations can be interpreted in two ways: 1) Our sampling of cerebellar biochemistry reflects a measure of "global" cerebral biochemistry and is unrelated to cerebellar function, or 2) The relations indicate that cerebellar neuronal integrity is a requirement (on a developmental time scale or in real-time) for ability on a variety of cognitive tests.


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