The bead array approach is a rapid and reliable test for detecting aneuploidies and microdeletions. This assay has the potential to provide the benefit of expanded molecular cytogenetic testing to pregnant women undergoing invasive prenatal diagnosis. This approach may be especially useful in parts of the world where cytogenetic personnel and facilities may be limited.

Velo-cardio-facial syndrome (VCFS) is a congenital anomaly characterized by multiple dysmorphisms, cleft palate, cardiac anomalies, and learning disabilities, that results from a microdeletion of chromosome 22q11. An increased prevalence of psychiatric illness has been observed, with both schizophrenia and bipolar disorder commonly being diagnosed. For these reasons, the VCFS region is an interesting candidate region for bipolar disorder. We examined this region in 17 bipolar families from three populations: 13 families from the general North American population (University of California, San Diego/University of British Columbia, UCSD/UBC), three larger families from New York, and a portion of Old Order Amish pedigree 110. Three microsatellite markers spanning 13 cM around the VCFS region were genotyped in all the families. A maximum lod score of 2.51 was obtained in the UCSD/UBC families under a dominant model at D22S303. In the combined family set, maximum lod scores of 1.68 and 1.28 were obtained at this marker under dominant and recessive models, respectively. Four additional markers were subsequently typed in selected positive families, and yielded positive lods at 6 of 7 markers spanning 18 cM in this region. Nonparametric, multipoint analyses using the affected pedigree member (APM) method also yielded suggestive evidence for linkage in both the UCSD/UBC family set (P = 0.0024) and in the combined families (P = 0.017). Affected sibpair analyses were similarly positive in the UCSD/UBC families (P = 0.017), and in the combined families (P = 0.004). These results are suggestive of a possible locus for bipolar disorder near the VCFS region on chromosome 22.

By the principle of identity by descent, parental consanguinity in individuals with rare recessively transmitted disorders dictates homozygosity not just at the mutated disease-assoiated locus but also at sequences that flank that locus closely. In 25 of 26 individuals with Bloom syndrome examined whose parents were related, a polymorphic tetranucleotide repeat in an intron of the protooncogene FES was homozygous, far more often than expected (P < 0.0001 by x2). Therefore, BLM, the gene that when mutated gives rise to Bloom syndrome, is tightly linked to FES, a gene whose chromosome position Is known to be l5q26.1. This successful approach to the aignment ofthe Bloom syndrome locus to one short segment of the human genome simultaneously (i) demonstrates the power of homozygosity mapping and (it) becomes the first step in a "reverse" genetics defmition of the primary defect in Bloom syndrome.Bloom syndrome (BS) (1, 2) is a rare autosomal recessive disorder the predominating clinical feature of which is a well-proportioned smallness of the body. The locus mutated, here named BLM, has long been recognized to be of central importance in the maintenance of genomic stability because persons with BS, blm/blm, feature a remarkable degree of genomic instability. In somatic cells having such a mutator genotype, increased numbers of different types of spontaneous mutations arise at various sites, mutations that qualitatively are similar to those that arise spontaneously in normal individuals. In addition to locus-specific mutations, increased numbers of microscopically visible chromosome mutations at randomly distributed sites are present in metaphase chromosomes-gaps, breaks, and rearrangements. In particular, a striking excess ofchromatid exchanges occurs in BS, including homologous chromatid interchange which is cytogenetic evidence of somatic crossing-over (3); therefore, a mutation that does arise at any particular site in a BS somatic cell also is at an increased risk of becoming homozygous. Other than the generalized growth deficiency ofclinical BS, which itself may be the consequence of an excessive number oflethal mutations, the most important manifestation of the genomic instability of the somatic cells is neoplasia; cancers of a wide variety of sites and types emerge unusually early and frequently in persons with BS.The primary defect in BS is unknown, and this has limited its usefulness as a model for studying neoplastic transformation and progression. Results of many studies do point to a disturbance of DNA replication. (i) The cytogenetic abnormalities (4) are best explained on the basis of excessive exchange of chromatids via an error-prone mechanism activated during S-phase replication. (ii) Replication-fork progression is retarded (5), and an unusual size distribution of DNA replication intermediates is found (6). (iii) Some cultured BS cell lines exhibit hypersensitivity to certain DNAdamaging agents-e.g., mitomycin C, N-nitroso-N-ethylurea, and ethyl methanesulfonate (7)(8)(9). (iv) Altered activ...

Prenatal screening for single gene disorders, which include over 10,000 diverse diseases, presents a great challenge. The major approach to identifying high‐risk groups for diseases, from Tay Sachs Disease to sickle cell disease, has historically centered on ethnic‐based screening. A major concern in an ethnic‐based approach is that carriers belonging to less‐traditionally considered populations will be missed. In the United States, the paradigm for a more modern pan‐ethnic approach has become exemplified by cystic fibrosis (CF), although considerable debate about future directions remains. CF screening brings several additional issues to the forefront, including that the largest molecular prenatal genetic screening program is based on a single gene disorder that is not necessarily severely disabling. On the other hand, several devastating disorders where screening is indeed available remain relatively inaccessible to prenatal patients in the general population. Future candidates to consider for broad‐based screening programs include spinal muscular atrophy (SMA), fragile X, and inborn errors of metabolism. As prenatal screening for single gene disorders expands, issues to consider include inclusion criteria and risk versus benefit. © 2007 Wiley‐Liss, Inc.