Saethre-Chotzen/Williams-Beuren Combination LPU024 - Detail

One of the most frequent syndromes in congenital malformation: craniosynostosis (premature closure of one or more cranial sutures) is Saethre-Chotzen syndrome (acrocephalosyndactyly type III; ACS III). Saethre-Chotzen syndrome is characterized by craniofacial and limb abnormalities (Saethre M 1931, Chotzen F 1932) and the incidence of this rare syndrome is estimated at between 1 in 25-50,000 live births. This autosomal dominant disorder is one of the most difficult to diagnose and the identification of the TWIST1, a basic helix-loop-helix transcription factor on chromosome band 7p21.1, as a causative gene has proved invaluable for the diagnosis ^{1, 2}.

Williams-Beuren Syndrome (WBS) is a developmental disorder caused by a microdeletion within band 7q11.23³. Patients display connective tissue problems, typically supravalvular aortic stenosis (SVAS), growth retardation, renal anomalies, transient hypercalcaemia, hyperacusis and mental retardation⁴. Haploinsufficiency of the elastin (ELN) gene has been identified as being responsible for SVAS^{5, 6} however, of the remaining 15 genes identified within the WBS deletion none of the remaining clinical features have been conclusively attributed to any one of these genes.

The most recent work maps the WBS deletion region to be 1.6 Mb⁷ and flanked by highly homologous duplicons of 320-500 kb within which the common breakpoints cluster. The common WBS deletion results from non-homologous recombination between the GTF2I/NCF1 locus and the GTF2IP1/NCF1P1 locus or rare intrachromosomal exchange between the centromeric GTF2IP2/NCF1 and the telomeric GT2IP2/NCF1P2 duplicons.

Reference:/Bibliographie/Literatur/Bibliografia

1. Howard T, D et al. (1997) Nat Genet 15:36-41
2. El Ghouzzi V et al (1997) Nat Genet 15: 42-46
3. Francke U et al (1999) Hum Mol Genet 8: 1947-1954
4. Prober BR and Dykens EM (1996) Child Adolesc Psychiatr Clin North Am 5: 929-943
5. Li DY et al (1997) Hum Mol Genet 6: 1021-1028
6. Tassabehji M et al (1997) Hum Mol Genet 6: 1029-1036
7. Peoples R et al (2000) Am J Hum Genet 66: 47-68