Exclusion of linkage to the CDL1 gene region on chromosome 3q26.3 in some familial cases of Cornelia de Lange syndrome

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.

Somatic mosaicism in Cornelia de Lange syndrome: a further contributor to the wide clinical expressivity?

“…In a few cases familial transmission has been inferred by the recurrence of affected sibs, from an apparently normal couple, both carrying the same mutation in NIPBL (4,11). Moreover, the report of an unaffected father with two daughters with CdLS, from two non-related spouses, suggested that gonadal mosaicism plays a role in the recurrence of CdLS (13). The germline mosaicism theory has been nicely demonstrated by Niu et al who found the same NIPBL mutation in the DNA of sperms from the father of two siblings (14).…”

Molecular analysis of a constitutional complex genome rearrangement with 11 breakpoints involving chromosomes 3, 11, 12, and 21 and a ∼0.5-Mb submicroscopic deletion in a patient with mild mental retardation

“…In the complex t(3;12), one of the breakpoints maps at 3q26.3, previously suggested as a candidate region for Cornelia de Lange syndrome, CdLS (Ireland et al 1991;Krantz et al 2001;Faas et al 2002). However, the causative gene for CdLS has been subsequently shown to be NIPBL initially identified by breakpoint mapping in a CdLS patient with a t(5;13)(p13.1;q12.2) (Borck et al 2004;Krantz et al 2004;Tonkin et al 2004b).…”

Cornelia de Lange Syndrome and the link between chromosomal function, DNA repair and developmental gene regulation

“…After collaborative linkage analyses excluded the 3q26-27 region in some rare multicase families [8], we prioritised the study of breakpoints in t(14;21)(q32;q11) and t(5;13)(p13.1;q11.2) translocation cases [9 ]. Following a report of a del(5)(p13.1p14.2) CdLS case, the 5p13 breakpoint was extensively characterised and found to sever intron 1 of a previously uncharacterised gene in which nine additional CdLS-specific mutations were found (five of them shown to arise de novo) [9 ].…”