Chromosome rearrangements in cornelia de Lange syndrome (CdLS): report of a der(3)t(3;12)(p25.3;p13.3) in two half sibs with features of CdLS and review of reported CdLS cases with chromosome rearrangements

Abstract

Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited disorder characterized by multisystem involvement, cognitive delay, limb defects, and characteristic facial features. Recently, mutations in NIPBL have been found in approximately 50% of individuals with CdLS. Numerous chromosomal rearrangements have been reported in individuals with CdLS. These rearrangements may be causative of a CdLS phenotype, result in a phenocopy, or be unrelated to the observed phenotype. We describe two half siblings with a der(3)t(3;12)(p25.3;p13.3) chromosomal rearrangement, clinical features resembling CdLS, and phenotypic overlap with the del(3)(p25) phenotype. Region-specific BAC probes were used to fine-map the breakpoint region by fluorescence in situ hybridization (FISH). FISH analysis places the chromosome 3 breakpoint distal to RP11-115G3 on 3p25.3; the chromosome 12 breakpoint is distal to BAC RP11-88D16 on 12p13.3. A review of published cases of terminal 3p deletions and terminal 12p duplications indicates that the findings in these siblings are consistent with the del(3)(p25) phenotype. Given the phenotypic overlap with CdLS, we have reviewed the reported cases of chromosomal rearrangements involved in CdLS to better elucidate other potential loci that could harbor additional CdLS genes. Additionally, to identify chromosome rearrangements, genome-wide array comparative genomic hybridization (CGH) was performed on eight individuals with typical CdLS and without identifiable deletion or mutation of NIPBL. No pathologic rearrangements were identified.

Fig. 1

Photographs of Patient 1 (proband) and Patient 2 (half sister of the proband). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

Fig. 2

G-banded partial karyotypes (A, B) and FISH analysis (C–H) of Patients 1 and 2 and their mother. BAC probes (Green) and commercial probes (Red) show that in Patients 1 and 2, the chromosome 3p breakpoint is between RP11-115G3 (C), proximally and RP11-128A5 (D), distally; the chromosome 12p breakpoint is between RP11-88D16 (F), proximally and RP11-79K20 (G), distally. Patients 1 and 2 are monosomic for RP11-128A5 (D) on 3p25.3 and trisomic for RP11-79K20 (G) on 12p13.33. Their mother carries a t(3;12)(p25.3;p13.33) balanced translocation; RP11-128A5 has been translocated to 12p (E) and RP11-79K20 has been translocated to 3p (H).