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, 101 (2), 120-9

Exclusion of Linkage to the CDL1 Gene Region on Chromosome 3q26.3 in Some Familial Cases of Cornelia De Lange Syndrome

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Exclusion of Linkage to the CDL1 Gene Region on Chromosome 3q26.3 in Some Familial Cases of Cornelia De Lange Syndrome

I D Krantz et al. Am J Med Genet.

Abstract

Cornelia de Lange Syndrome (CdLS) is a complex developmental disorder consisting of characteristic facial features, limb abnormalities, hirsutism, ophthalmologic involvement, gastroesophageal dysfunction, hearing loss, as well as growth and neurodevelopmental retardation. Most cases of CdLS appear to be sporadic. Familial cases are rare and indicate autosomal dominant inheritance. Several individuals with CdLS have been reported with chromosomal abnormalities, suggesting candidate genomic regions within which the causative gene(s) may lie. A CdLS gene location (CDL1) has been assigned to 3q26.3 based on phenotypic overlap with the duplication 3q syndrome (critical region 3q26.2-q27) and the report of a CdLS individual with a balanced de novo t(3;17)(q26.3;q23.1). It has been postulated that a gene within the dup3q critical region results in the CdLS when deleted or mutated. We have performed a linkage analysis to the minimal critical region for the dup3q syndrome (that encompasses the translocation breakpoint) on chromosome 3q in 10 rare familial cases of CdLS. Nineteen markers spanning a region of approximately 40 Mb (37 cM) were used. Results of a multipoint linkage analysis demonstrated total lod-scores that were negative across the chromosome 3q26-q27 region. In 4/10 families, lod-scores were less than -2 in the 2 cM region encompassing the translocation, while in the remaining 6/10 families, lod-scores could not exclude linkage to this region. These studies indicate that in some multicase families, the disease gene does not map to the CDL1 region at 3q26.3.

Figures

Fig. 1
Fig. 1
Region of chromosome 3q haplotyped in familial CdLS cases for this study. Markers used are indicated below the ideogram, with approximate spacing between markers in centimorgans. The dup3q critical region and t(3;17) breakpoint are indicated above the ideogram.
Fig. 2
Fig. 2
Facial features of individuals with CdLS from family II (A), XVII (B), XIII (C), I (D), GE (E), and XII (F).
Fig. 3
Fig. 3
A, B CdLS family pedigrees. Haplotypes with 19 polymorphic markers from across chromosome 3q encompassing the dup3q critical region and the t(3;17) breakpoint are indicated below each individual in the families. A darkened square or circle indicates an affected individual.
Fig. 3
Fig. 3
A, B CdLS family pedigrees. Haplotypes with 19 polymorphic markers from across chromosome 3q encompassing the dup3q critical region and the t(3;17) breakpoint are indicated below each individual in the families. A darkened square or circle indicates an affected individual.

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