Exclusion of linkage to chromosome 3q in some familial cases of the Cornelia deLange Syndrome

Abstract

The Cornelia deLange Syndrome (CDLS) (OMTM #122470 ) is a complex genetic developmental disorder consisting of characteristic facial features, hirsutism, various ophthalmologic abnormalities, abnormalities of the upper extremities, gastroesophageal dysfunction, growth and neurodevelopmental retardation. Most cases of CdLS appear to be sporadic. Familial cases are rare and demonstrate autosomal dominant inheritance.

Several patients with CdLS have had chromosomal abnormalities, suggesting potential genomic regions within which the disease gene(s) may lie. Partial phenotypic overlap between CdLS patients and patients with duplication of chromosome 3q26-27 has been noted. A patient described by Ireland et al (J Med Genet 28:639-640, 1991) with an apparently balanced translocation with a breakpoint within the dup3q critical region and classic CdLS phenotype added further support to the hypothesis that a CdLS gene lay within this chromosomal region. It has been postulated that a gene within the duplicated region on chromosome 3q is deleted or mutated in patients with CdLS and results in a different but mildly overlapping phenotype.

We have performed linkage analysis in 9 familial cases of CdLS to the minimal critical region for the dup3q syndrome that encompasses the translocation breakpoint on chromosome 3q. 12 markers spanning approximately 40 Mb (37 cM) were used to haplotype the nine families and linkage analysis performed. In 4/9 families (44%) the affected sib pairs did not share haplotypes to this region from either parent while in the remaining 5 families (56%) at least one parental allele was shared. These studies indicate that chromosome 3q26-27 does not segregate with the CdLS phenotype in all familial cases studied. This would imply that this region on chromosome 3 may not be associated with CdLS or may be associated with a subset of CdLS cases. Other candidate loci are being examined for linkage to CdLS which may prove to be a genetically heterogeneous disorder.