Spinal muscular atrophy (SMA) is a leading inherited cause of infant death with a reported incidence of ∼1 in 10 000 live births and is second to cystic fibrosis as a common, life-shortening autosomal recessive disorder. The American College of Medical Genetics has recommended population carrier screening for SMA, regardless of race or ethnicity, to facilitate informed reproductive options, although other organizations have cited the need for additional large-scale studies before widespread implementation. We report our data from carrier testing (n=72 453) and prenatal diagnosis (n=121) for this condition. Our analysis of large-scale population carrier screening data (n=68 471) demonstrates the technical feasibility of high throughput testing and provides mutation carrier and allele frequencies at a level of accuracy afforded by large data sets. In our United States pan-ethnic population, the calculated a priori carrier frequency of SMA is 1/54 with a detection rate of 91.2%, and the pan-ethnic disease incidence is calculated to be 1/11 000. Carrier frequency and detection rates provided for six major ethnic groups in the United States range from 1/47 and 94.8% in the Caucasian population to 1/72 and 70.5% in the African American population, respectively. This collective experience can be utilized to facilitate accurate pre- and post-test counseling in the settings of carrier screening and prenatal diagnosis for SMA.

Marshall syndrome is a rare, autosomal dominant skeletal dysplasia that is phenotypically similar to the more common disorder Stickler syndrome. For a large kindred with Marshall syndrome, we demonstrate a splice-donor-site mutation in the COL11A1 gene that cosegregates with the phenotype. The G+1-->A transition causes in-frame skipping of a 54-bp exon and deletes amino acids 726-743 from the major triple-helical domain of the alpha1(XI) collagen polypeptide. The data support the hypothesis that the alpha1(XI) collagen polypeptide has an important role in skeletal morphogenesis that extends beyond its contribution to structural integrity of the cartilage extracellular matrix. Our results also demonstrate allelism of Marshall syndrome with the subset of Stickler syndrome families associated with COL11A1 mutations.

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BACKGROUND:The incidence of cystic fibrosis (CF) and the frequency of specific disease-causing mutations vary among populations. Affected individuals experience a range of serious clinical consequences, notably lung and pancreatic disease, which are only partially dependent on genotype.

Molecular characterization of subtle chromosomal aberrations can provide information to assist in predicting clinical outcome in cases involving genes known to have an effect due to haploinsufficiency or aberrant gene dosage.

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Chronic Myeloid Leukemia (CML) is diagnosed by the presence of the Philadelphia chromosome (Ph+). The number of cells containing the bcr/abl chromosomal translocation diminishes dramatically after current standard of care treatment. Patient progress is monitored quantitatively and long-term prognosis is favorable if the Ph+ cells are no longer detected by cytogenetic analysis or FISH (sensitivity of 20% and 2% respectively). Molecular monitoring of cDNA BCR/ABL transcripts is widely used to assess levels of minimal residual disease (MRD). In our laboratory, quantitative RT-PCR allows detection of BCR/ABL transcript down to 1 x 10−5 or one BCR/ABL transcript in 100,000 reference gene transcripts. Serial values from bone marrow (BM) and blood specimens are tracked over time and monitored for increases that may indicate unfavorable changes in disease status. Though the literature indicates that the levels of BCR/ABL transcript in BM and blood samples are comparable at the time of diagnosis, this may not be true in patients with MRD. To explore this question we compared BCR/ABL transcript levels in paired BM and blood samples that were either collected together or separately but within a short time frame. In 36% of these cases both specimen types had detectable low-level BCR/ABL transcript. The levels of transcript in bone marrow were consistently higher than the levels in the associated blood specimen, though there was a wide range of variability (3-50 fold). Additionally, when blood levels of transcript were near the lower limit of detection, we were more likely to observe a larger difference relative to bone marrow transcript levels than when blood levels of transcript were higher. These results indicate that while both BM and blood specimens are valuable for serial molecular monitoring, they may not be equivocal when sampled from patients with MRD. If a patient has been monitored using blood specimens, periodic concurrent testing of blood and bone marrow specimens can provide clinical utility.