Purpose: Down syndrome (DS) is a major cause of congenital heart disease (CHD) and the most frequent known cause of atrioventricular septal defects (AVSDs). Molecular studies of rare individuals with CHD and partial duplications of chromosome 21 established a candidate region that included D21S55 through the telomere. We now report human molecular and cardiac data that narrow the DS-CHD region, excluding two candidate regions, and propose DSCAM (Down syndrome cell adhesion molecule) as a candidate gene. Methods: A panel of 19 individuals with partial trisomy 21 was evaluated using quantitative Southern blot dosage analysis and fluorescence in situ hybridization (FISH) with subsets of 32 BACs spanning the region defined by D21S16 (21q11.2) through the telomere. These BACs span the molecular markers D21S55, ERG, ETS2, MX1/2, collagen XVIII and collagen VI A1/A2. Fourteen individuals are duplicated for the candidate region, of whom eight (57%) have the characteristic spectrum of DS-CHD. Results: Combining the results from these eight individuals suggests the candidate region for DS-CHD is demarcated by D21S3 (defined by ventricular septal defect), through PFKL (defined by tetralogy of Fallot). Conclusions: These data suggest that the presence of three copies of gene(s) from the region is sufficient for the production of subsets of DS-CHD. This region does not include genes located near D21S55, previously proposed as a "DS critical region," or the genes encoding collagens VI and XVIII. Of the potential gene candidates in the narrowed DS-CHD region, DSCAM is notable in that it encodes a cell adhesion molecule, spans more than 840 kb of the candidate region, and is expressed in the heart during cardiac development. Given these properties, we propose DSCAM as a candidate for DS-CHD. Genetics in Medicine, 2001:3(2):91-101.

Palindromic AT-rich repeats (PATRRs) on chromosomes 11q23 and 22q11 at the constitutional t(11;22) breakpoint are predicted to induce genomic instability, which mediates the translocation. A PCR-based translocation-detection system for the t(11;22) has been developed with PCR primers flanking the PATRRs of both chromosomes, to examine the involvement of the PATRRs in the recurrent rearrangement. Forty unrelated carriers of the t(11;22) balanced translocation, plus two additional, independent cases with the supernumerary-der(22) syndrome, were analyzed to compare their translocation breakpoints. Similar translocation-specific junction fragments were obtained from both derivative chromosomes in all 40 carriers of the t(11;22) balanced translocation and from the der(22) in both of the offspring with unbalanced supernumerary-der(22) syndrome, suggesting that the breakpoints in all cases localize within these PATRRs and that the translocation is generated by a similar mechanism. This PCR strategy provides a convenient technique for rapid diagnosis of the translocation, indicating its utility for prenatal and preimplantation diagnosis in families including carriers of the balanced translocation.

The t(11;22) is the only known recurrent, non-Robertsonian constitutional translocation. We have analyzed t(11;22) balanced-translocation carriers from multiple unrelated families by FISH, to localize the t(11;22) breakpoints on both chromosome 11 and chromosome 22. In 23 unrelated balanced-translocation carriers, the breakpoint was localized within a 400-kb interval between D22S788 (N41) and ZNF74, on 22q11. Also, 13 of these 23 carriers were tested with probes from chromosome 11, and, in each, the breakpoint was localized between D11S1340 and APOA1, on 11q23, to a region

The term Baller-Gerold syndrome was coined by Cohen [1979: Birth Defects 15(5B): 13-63] to designate the phenotype of craniosynostosis and radial aplasia. It is thought to be a rare autosomal recessive condition, which, in some patients, presents with additional abnormalities, such as polymicrogyria, mental retardation or anal atresia. A phenotypic overlap of Baller-Gerold and Roberts-SC phocomelia syndrome was noted when a patient with bicoronal synostosis and bilateral radial hypoplasia was found to have premature centromere separation, a finding characteristic of Roberts syndrome [Huson et al.,1990: J Med Genet 27:371-375]. Other cases of presumed Baller-Gerold syndrome were rediagnosed as Fanconi pancytopenia, Rothmund-Thomson syndrome or VACTERL association. These reports led to a narrowed redefinition of Baller-Gerold syndrome based on the exclusion of cytogenetic and hematopoetic abnormalities and the absence of additional malformations in patients with craniosynostosis and preaxial upper limb abnormalities. Here we report on a patient with unilateral radial aplasia and bicoronal synostosis without additional malformations and without chromosome breakage, who fits this narrow definition of Baller-Gerold syndrome. We identified a novel TWIST gene mutation in this patient, a Glu181Stop mutation predicting a premature termination of the protein carboxy-terminal to the helix 2 domain. This report provides further evidence that Baller-Gerold is of heterogeneous cause, and a thorough evaluation is indicated to identify a possibly more specific diagnosis, including Saethre-Chotzen syndrome. This differential diagnosis is of particular importance, as it is an autosomal dominant trait. Therefore, the recurrence risk for parents of an affected child can be 50% if one parent carries the mutation, as opposed to the 25% recurrence risk for autosomal recessive inheritance. Offspring of the affected patient also have a 50% risk to inherit the mutation, while the risk to bear an affected offspring for an autosomal recessive trait is very low.

We describe monozygotic twins with partially discordant phenotypes who were found to have a duplication of chromosome region 4q28.3-qter. The duplicated region of chromosome 4 resulted from an unbalanced segregation of a balanced maternal (4;22)(q28.3;p13) translocation. Duplication of the long arm of chromosome 4 has been described in >60 patients; however, it usually results from the unbalanced segregation of a parental balanced translocation and has an associated monosomy. Twenty cases of dup 4q without an associated monosomy have been reported, and this is the only case of dup 4q28. 3-qter. All cases of dup 4q are reviewed, and phenotypic aspects are analyzed. Issues of monozygotic twinning and other birth defects also are addressed.