Background-A genetic predisposition for progressive enlargement of thoracic aortic aneurysms leading to type A dissection (TAAD) is inherited in an autosomal-dominant manner in up to 19% of patients, and a number of chromosomal loci have been identified for the condition. Having mapped a TAAD locus to 3p24 -25, we sequenced the gene for transforming growth factor- receptor type II (TGFBR2) to determine whether mutations in this gene resulted in familial TAAD. Methods and Results-We sequenced all 8 coding exons of TGFBR2 by using genomic DNA from 80 unrelated familial TAAD cases. We found TGFBR2 mutations in 4 unrelated families with familial TAAD who did not have Marfan syndrome. Affected family members also had descending aortic disease and aneurysms of other arteries. Strikingly, all 4 mutations affected an arginine residue at position 460 in the intracellular domain, suggesting a mutation "hot spot" for familial TAAD. Despite identical mutations in the families, assessment of linked polymorphisms suggested that these families were not distantly related. Structural analysis of the TGFBR2 serine/threonine kinase domain revealed that R460 is strategically located within a highly conserved region of this domain and that the amino acid substitutions resulting from these mutations will interfere with the receptor's ability to transduce signals. Conclusion-Germline
Purpose: Our work is the first documentation, in real time, of workflow in a general genetics department including data on patient care, research, and other activities for both clinical geneticists and genetic counselors. Methods:All physician geneticists and genetic counselors in the medical genetics department used an electronic tool to record their activities in 15 minute increments during clinic hours, evenings, and weekends over a 10-week period.Results: The average work week was 54.1 hours for physicians and 43.5 hours for genetic counselors. During clinic hours physicians spent about one-fourth of their time on direct patient care, one-fourth on other patient-related activities, one-fourth on research unrelated to individual patient care, and the remaining fourth on all other activities. However, after hours and on weekends they spent most of their time on research. Genetic counselors spent half of their time on patient-related activities, one-fourth on direct patient care, and the remainder on all other activities. The total professional time averaged 7 hours per new patient and 3.5 hours per follow-up with nearly 60% of this time devoted to patient-related activities. Conclusions: The labor intensive nature of clinical genetics, the large amount of time devoted to patient-related activities, and continuing limitations on billing by genetic counselors all contribute to the financial challenges faced by genetics departments. Genet Med 2008:10(9):699 -706. Key Words: clinical genetics services, workforce, workflow, time study, reimbursement, genetic counselingProvision of medical genetics services is a time and labor intensive activity. 1,2 The detailed three generation pedigree not only takes far longer than the standard family history screening in primary care (which adds an average of only 3 min to a primary care visit 3 ), but frequently must be supplemented by acquisition and review of medical records of affected relatives, examination of parents and other relatives (who don't usually have their own appointments), and the review of family photographs when affected relatives are unavailable. Because of the complexity of modern genetic knowledge and the need to discuss implications for multiple family members, face-to-face genetic counseling is time-consuming. The ordering, insurance preauthorization, and follow-up of increasingly complex laboratory tests, literature review for rare diagnoses, and documentation of the visit (which is more extensive than in most disciplines due to the need to educate referring providers about rare disorders), as well as writing and reviewing of detailed summary letters for the family also contribute to the work of genetic counseling. Although some of these challenges exist in other fields, genetics remains unique in terms of dependence on family information. Furthermore, because most genetic disorders are rare, time savings through standardization of protocols, documentation tools, and patient education materials are rarely applicable. Rapid advances in genetic knowledge...
Fluorescent in situ hybridization (FISH) screening of subtelomeric rearrangements has resulted in the identification of previously unrecognized chromosomal causes of mental retardation with and without dysmorphic features. This article reports the phenotypic and molecular breakpoint characterization in a cohort of 12 patients with subtelomeric deletions of chromosome 9q34. The phenotypic findings are consistent amongst these individuals and consist of mental retardation, distinct facial features and congenital heart defects (primarily conotruncal defects). Detailed breakpoint mapping by FISH, microsatellite and single nucleotide polymorphism (SNP) genotyping analysis has narrowed the commonly deleted region to an approximately 1.2 Mb interval containing 14 known transcripts. The majority of the proximal deletion breakpoints fall within a 400 kb interval between SNP markers C12020842 proximally and C80658 distally suggesting a common breakpoint in this interval.
Newborn screening (NBS) protocols for cystic fibrosis (CF) are the first regional population-based programs to incorporate DNA analysis into their procedures. Research about these programs can inform policy and practice regarding how best to counsel families with abnormal NBS results. The grounded theory method guided interviews with 33 families whose infants had abnormal CF NBS results. A dimensional analysis of these interviews provided a theoretical framework describing parents' preferences regarding counseling during their infant's sweat test appointment. This framework describes the contexts and characteristics of the two main dimensions of parents' preferences: factual information and emotional support. Factual information included learning about the probability of a CF diagnosis, CF disease facts, sweat test procedure, and CF genetics. Social support consisted of offering parents a choice about the timing and amount of CF information, showing empathy for their distress, instilling hope, personalizing counseling, and providing hospitality. This framework also explains the consequences of counseling that matched versus mismatched parental preferences in these domains. Counseling that matched parents preferences reduced parents' distress while mismatched counseling tended to increase parents' worry about their infant.
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