Mayada Tassabehji

Williams Syndrome: Use of Chromosomal Microdeletions as a Tool to Dissect Cognitive and Physical Phenotypes

In Williams syndrome (WS), a deletion of approximately 1.5 Mb on one copy of chromosome 7 causes specific physical, cognitive, and behavioral abnormalities. Molecular dissection of the phenotype may be a route to identification of genes important in human cognition and behavior. Among the genes known to be deleted in WS are ELN (which encodes elastin), LIMK1 (which encodes a protein tyrosine kinase expressed in the developing brain), STX1A (which encodes a component of the synaptic apparatus), and FZD3. Study of patients with deletions or mutations confined to ELN showed that hemizygosity for elastin is responsible for the cardiological features of WS. LIMK1 and STX1A are good candidates for cognitive or behavioral aspects of WS. Here we describe genetic and psychometric testing of patients who have small deletions within the WS critical region. Our results suggest that neither LIMK1 hemizygosity (contrary to a previous report) nor STX1A hemizygosity is likely to contribute to any part of the WS phenotype, and they emphasize the importance of such patients for dissecting subtle but highly penetrant phenotypes.

Delineation of the common critical region in Williams syndrome and clinical correlation of growth, heart defects, ethnicity, and parental origin.

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.

Using case study comparisons to explore genotype-phenotype correlations in Williams-Beuren syndrome

Williams-Beuren syndrome (WBS, MIM 194050) is a rare condition, with striking physical and behavioural features,1–3 which occurs in 1/20 000-1/50 000 live births. Cases are generally sporadic; however, familial cases with an autosomal dominant mode of inheritance have been reported. It results in a complex phenotype with physical, cognitive, and behavioural aspects that include an uneven cognitive profile (WBSCP), with verbal tasks outstripping spatial tasks, and overall IQs in the 50-60 range. Physically, WBS phenotypes include a dysmorphic face, congenital heart disease (typically supravalvular aortic stenosis (SVAS)), growth retardation, hyperacusis, premature ageing, and often infantile hypercalcaemia. These features are caused by deletion of the Williams-Beuren syndrome critical region (WBSCR) at chromosomal position 7q11.23 on either the maternal or paternal chromosome 7. The deletion is thought to arise from recombination between misaligned repeat sequences flanking the WBSCR during meiosis. The breakpoints cluster within these repeat regions, so that most WBS patients have similar deletions of approximately 1.5 Mb. A few WBS patients have, however, been reported with smaller deletions (<1 Mb).3,4 Patients with partial deletions of the WBSCR (that include the elastin gene) and SVAS as the only resulting phenotype have also been described.5 No credible cases of WBS without the deletion have so far been reported, suggesting that haploinsufficiency for a single gene will not explain the phenotype. Nineteen genes have so far been described in the WBSCR, yet only elastin hemizygosity has been confidently associated with any aspect of the WBS phenotype, namely SVAS, hernias, and possibly premature ageing. It would therefore appear that, alone or in combination, some of the remaining genes in the deleted region are responsible for the other features of WBS. Relations between genotype and phenotype in WBS are mainly studied at the group level with rather gross measures of …

Mutation of the MITF gene in albinism-deafness syndrome (Tietz syndrome).

A mother and her son with albinism and sensorineural deafness compatible with Tietz syndrome (MIM 103500) are reported. An in-frame deletion of the MITF gene that is identical at the molecular level to the mouse mi mutant allele has been found in this family. MITF gene mutations account for 20% of Waardenburg syndrome (WS) type II. These data, together with the wide spectrum of mutant alleles reported in mi mice (which have pigmentary disorders), suggest that MITF could be regarded as a candidate gene in various pigmentation disorders in man.

Spectrum of arterial obstructions caused by one elastin gene point mutation

The single-point mutation K176X causes the complete spectrum of arterial stenoses described in WilliamsBeuren syndrome (WBS); therefore, consistent genotype and phenotype correlations with respect to elastin gene mutations are not possible. Supravalvular aortic stenosis (SVAS) is a frequent feature of WBS caused by hemizygous microdeletion in the chromosomal region 7q11.23 encompassing, among others, the elastin gene [3]. In familial and sporadic cases of SVAS, gross deletions and widespread point mutations in the elastin gene have been described [5, 6, 8]. We report the clinical spectrum of arterial stenoses seen in a family with the nonsense point mutation K176X. At age 2.3 years, a long-segment severe SVAS was diagnosed in a boy by cardiac catheterization. The aortic arch distal to the innominate artery was of normal size. In addition, there were moderate bilateral peripheral pulmonary artery stenoses with systolic pressure gradients of 10–20 mmHg. The patient underwent surgical repair of SVAS by patch aortoplasty. At 7.1 years of age repeat aortic angiography revealed obstructions at the take-off of the carotid and subclavian arteries with systolic pressure gradients of 20–40 mmHg. In addition, we found a moderate stenosis of the left pulmonary artery, moderate obstructions of the renal and visceral arteries, and a diffuse narrowing of the infrarenal abdominal aorta. At 8.6 years, antihypertensive therapy with beta blocker was initiated to decrease elevated blood pressure (left arm 147/56/107 mmHg, right arm 92/47/ 60 mmHg). A 4.2-year-old girl had mild SVAS but significant peripheral stenoses and hypoplasia of both the right and left pulmonary artery. Cardiac catheterization revealed systolic pressure gradients across the SVAS of 17 mmHg and across the peripheral pulmonary artery stenoses of 50–60 mmHg. Repeat cardiac catheterization at the age of 6.4 years showed a decrease of both systolic pressure gradients (34–38 mmHg). There was no progression of the mild SVAS. Her brother underwent surgical patch aortoplasty because of severe SVAS at 5 months of age. Cardiac cartheterization at the age of 6.7 years showed mild hypoplasia of the ascending aorta as well as severe bilateral peripheral pulmonary artery stenoses. At 11.5 years of age aortic angiography showed a mild obstruction at the origin of the left subclavian artery (systolic gradient of 10 mmHg) and persisting severe stenoses to both pulmonary arteries (40–45 mmHg). Metcalfe et al. [6] reported a broad spectrum of elastin gene mutations in 35 patients with SVAS, one of which was the nonsense mutation K176X (exon 10 526A>T). This point mutation was detected in 2 patients (nos. 120 and 134) representing the first two patients in this report, who were initially thought to be unrelated [6]; however, we suspected a common ancestral link because both families originated from southern Germany, and the mutation K176X has not been reported elsewhere. Our third patient and other family members were screened for the K176X mutation by sequencing of PCR-amplified DNA from exon 10 as described previously [6]. K176X was detected in the mother of the first patient and in his younger brother, but not in his elder brother. The mother had a history of Eur J Pediatr (2003) 162: 53–54 DOI 10.1007/s00431-002-1111-9