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.

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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.

An analysis of PAX1 in the development of vertebral malformations. Due to the sporadic occurrence of congenital vertebral malformations, traditional linkage approaches to identify genes associated with human vertebral development are not possible. We therefore identified PAX1 as a candidate gene in vertebral malformations and congenital scoliosis due to its mutation in the undulated mouse. We performed DNA sequence analysis of the PAX1 gene in a series of 48 patients with congenital vertebral malformations, collectively spanning the entire vertebral column length. DNA sequence coding variants were identified in the heterozygous state in exon 4 in two male patients with thoracic vertebral malformations. One patient had T9 hypoplasia, T12 hemivertebrae and absent T10 pedicle, incomplete fusion of T7 posterior elements, ventricular septal defect, and polydactyly. This patient had a CCC (Pro)-->CTC (Leu) change at amino acid 410. This variant was not observed in 180 chromosomes tested in the National Institute of Environmental Health Sciences (NIEHS) single nucleotide polymorphism (SNP) database and occurred at a frequency of 0.3% in a diversity panel of 1066 human samples. The second patient had a T11 wedge vertebra and a missense mutation at amino acid 413 corresponding to CCA (Pro)-->CTA (Leu). This particular variant has been reported to occur in one of 164 chromosomes in the NIEHS SNP database and was found to occur with a similar frequency of 0.8% in a diversity panel of 1066 human samples. Although each patient's mother was clinically asymptomatic and heterozygous for the respective variant allele, the possibility that these sequence variants have clinical significance is not excluded.

22q11 deletion syndrome (22qDS) has recently been proposed for addition to the newborn screening panel in Wisconsin and it seems likely that it may soon be considered in other states as well. Input from patients with 22qDS and their family was gathered from 21 phone interviews. Cardiac, palate, hypocalcemia, and multiple anomalies were common reasons for involved patients to be diagnosed, though age at diagnosis ranged from birth to adulthood. Many commented on their struggles with 22qDS, including worries about the future and the patient's independence. In general, respondents favored newborn screening for 22qDS because it would help prevent some medical problems, increase access to services, explain existing problems, and identify mild cases. However, a minority expressed reservations, including concerns that it would disrupt bonding, could be too costly, and would not be useful for mild cases.

Abstract:The highly variable 22q11 deletion syndrome has been proposed for addition to newborn screening panels. A literature review investigated the incidence and prevalence, clinical features, and prognosis of 22q11 deletion syndrome and other issues related to newborn screening. Severe complications that could potentially be helped by screening include cardiac defects in 80% (with 20% having no outward signs to aid detection), hypocalcemia that can lead to seizures in 20% (though hypocalcemia is routinely investigated in sick newborns), and severe immune deficiency in Ͻ1% (which would be identified by some states' severe combined immunodeficiency screens). Other benefits that do not fit traditional goals of newborn screening include treatment for complications such as failure to thrive and developmental delay or preventing a "diagnostic odyssey." Although universal screening may prove the incidence to be Ͼ1:5000, undetected life-threatening effects occur in a minority of 22q11 deletion syndrome patients. Concerns include an untested screening technique, difficulty obtaining results in time for cardiac intervention, the chance of "vulnerable child syndrome" in mild cases, and possibly detecting congenital heart disease more efficiently by other means. Because addition of tests for highly variable conditions such as 22q11 deletion syndrome is likely to set a precedent for other syndromes, reevaluation of newborn screening criteria should be considered. Genet Med 2010:12(3):135-144.