Williams-Beuren Syndrome (WBS)

del(7)(q11.2)

Epidemiology and Etiology:

· Unequal crossing-over during meiosis in one parent

· M = F origin

· ~1/3 of cases the transmitting parent is heterozygous for an inversion between the centromeric and telomeric LCRs

· Postulated that the presence of the inversion loop during meiosis would predispose the (directly-oriented?) LCRs to pair up and have a recombination event (in the same chromatid or another chromatid / homolog

· De novo almost always

Common sites:

Gross features:

· Growth deficiency

· Facies:

· Periorbital fullness

· Bulbous nasal tip

· Long philtrum

· Wide mouth

· Full lips

· Full cheeks

· Small widely spaced teeth

· malocclusion

· Chronic otitis media

· Cardiovascular (80%):

· Supravalvular aortic stenosis

· Peripheral pulmonary stenosis

· Hernias

· Renal anomalies

· Musculoskeletal abnormalities

Histologic features:

·

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Molecular features:

· 1.55Mb deletion most often

· 3 large region-specific LCRs, each several hundred kb in length:

· Centromeric

· Medial

· Telomeric

· Each LCR is divided into discreet blocks A, B, C

· LCRs composed of transcriptionally active genes and pseudogenes

· Most (>95%) have a 1.55 Mb deletion caused by a recombination between centromeric and medial block B copies

· Hotspots of recombination:

· 12 kb region of the GTF2I gene

· Distal end of GTF2IRD2 gene

· A few (<5%) have a larger deletion (~1.84 Mb) caused by a recombination between centromeric and medial block A copies

· Genes deleted include:

· Elastin (ELN)

· Solely responsible for cardiovascular phenotype of the disease

· Contiguous brain and morphogenesis loci

· NCF1

· Those patients with deletion of NCF1 may have a reduced risk of HTN

· LIMK1

· Hypothesized to contribute to impairment in visuospatial constructive cognition (PMID: 14556246)

· GTF2I

· May be responsible for mental retardation phenotype (PMID: 14556246)

·

Other features:

· HTN

· Hypercalcemia

· diabetes

· constipation

· Visuospatial constructive cognition decreased

· Mild to moderate intellectual disability

· Anxiety

· ADHD

· Overfriendliness to strangers

· Lacking in social judgement

References:

· Gardner RJM, Sutherland GR. Chromosome Abnormalities and Genetic Counseling. 2nd ed. Oxford University Press, USA; 1996.

· Del Campo M, Antonell A, Magano LF, et al. Hemizygosity at the NCF1 gene in patients with Williams-Beuren syndrome decreases their risk of hypertension. Am. J. Hum. Genet. 2006;78(4):533-542.

· Morris CA, Mervis CB, Hobart HH, et al. GTF2I hemizygosity implicated in mental retardation in Williams syndrome: genotype-phenotype analysis of five families with deletions in the Williams syndrome region. Am. J. Med. Genet. A. 2003;123A(1):45-59.