Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care.

An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.

Bisphosphonate therapy for painless fracture: change of HSAN 1 clinical course with biphosphonate and Vitamin D therapy.

Hereditary Sensory and Autonomic Neuropathies comprise a set of 5 rare neurologic conditions, little known to radiologists as the neurologic and skin abnormalities precede the radiographic changes by months or even years. We report a Caucasian patient with a clinical history of HSAN, most consistent with subtype 1, whose progressive, destructive bone changes of the foot were not only controlled but to a degree reversed by the administration of bisphosphonates (Alendronate ) and vitamin D (Colecalciferol). The authors believe that combined bisphosphonate and vitamin D therapy is the treatment of choice for progressive bony changes in HSAN1. This therapy may be beneficial in other neuropathic osteoarthropathies and possibly osteolytic bone disorders.

46, XY gonadal dysgenesis: new SRY point mutation in two siblings with paternal germ line mosaicism.

Familial recurrence risks are poorly understood in cases of de novo mutations. In the event of parental germ line mosaicism, recurrence risks can be higher than generally appreciated, with implications for genetic counseling and clinical practice. In the course of treating a female with pubertal delay and hypergonadotropic hypogonadism, we identified a new missense mutation in the SRY gene, leading to somatic feminization of this karyotypically normal XY individual. We tested a younger sister despite a normal onset of puberty, who also possessed an XY karyotype and the same SRY mutation. Imaging studies in the sister revealed an ovarian tumor, which was removed. DNA from the father's blood possessed the wild type SRY sequence, and paternity testing was consistent with the given family structure. A brother was 46, XY with a wild type SRY sequence strongly suggesting paternal Y-chromosome germline mosaicism for the mutation. In disorders of sexual development (DSDs), early diagnosis is critical for optimal psychological development of the affected patients. In this case, preventive karyotypic screening allowed early diagnosis of a gonadal tumor in the sibling prior to the age of normal puberty. Our results suggest that cytological or molecular diagnosis should be applied for siblings of an affected DSD individual.

Novel mutations in the sacsin gene in ataxia patients from Maritime Canada.

We ascertained two families in Eastern Canada segregating a form of ataxia consistent with a recessive mode of inheritance. We performed a whole genome scan using dense SNP genotyping, and despite an absence of shared homozygosity in the families we defined linkage to a small region on chromosome 13. Direct DNA resequencing was employed to screen biologically relevant candidate genes in the interval, and two presumptive pathogenic mutations were found in the gene encoding sacsin. One variant is an obligate truncating mutation, the second is a missense variant in a highly conserved residue. Unexpectedly, one family was homozygous for the missense mutation, the other compound heterozygous for the two mutations. Our results expand the genotype phenotype correlation of mutations in the sacsin gene, and highlight the challenge of diagnosing genetically heterogeneous disorders on primarily clinical grounds. We demonstrate that whole genome genotyping on a modest scale can be productive in research, and potentially in a clinical context.

Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations.

Congenital indifference to pain (CIP) is a rare condition in which patients have severely impaired pain perception, but are otherwise essentially normal. We identified and collected DNA from individuals from nine families of seven different nationalities in which the affected individuals meet the diagnostic criteria for CIP. Using homozygosity mapping and haplotype sharing methods, we narrowed the CIP locus to chromosome 2q24-q31, a region known to contain a cluster of voltage-gated sodium channel genes. From these prioritized candidate sodium channels, we identified 10 mutations in the SCN9A gene encoding the sodium channel protein Nav1.7. The mutations completely co-segregated with the disease phenotype, and nine of these SCN9A mutations resulted in truncation and loss-of-function of the Nav1.7 channel. These genetic data further support the evidence that Nav1.7 plays an essential role in mediating pain in humans, and that SCN9A mutations identified in multiple different populations underlie CIP.

Child day care risks of common infectious diseases revisited.

BACKGROUND: The increased risk of common infectious diseases associated with child day care attendance may vary by age, health plan and parent educational level. This study determined quantitatively the risk of diarrhoeal illness and upper respiratory infection (URI) among day-care children in comparison with home-care children. It examined the extent of risks in day-care children under different conditions of three age groups, enrolled in two health plans, and from families of two levels of education. METHODS: The study subjects were recruited through two health plans: a Health Maintenance Organization (HMO) and the Medicaid program in Columbia, South Carolina of the USA. The sample was collected using a household survey of children, aged 5 years or younger. The participants were contacted bimonthly for 18 months with 435 attending out-of-home day care facilities and 753 being cared for at home. The potential confounding factors of family characteristics were controlled in examining the odds ratios for day care effect on common infections in children under different conditions. RESULTS: In general, risks of diarrhoeal illness and URI in day-care children are greater than in home-care children. Children younger than 1.5 years of age attending day care and covered by the Medicaid program are at the greatest risk. The difference in risks between day-care and home-care children, however, is reduced to an insignificant level for children older than 1.5 years of age and for children covered by the HMO health plan. Among day-care children, those who are covered by the Medicaid program are at a significantly higher risk than those who are covered by the HMO health plan. CONCLUSIONS: Although day-care children in general suffer a greater risk of common infectious diseases, the extent of day care effect on risks of diarrhoeal illness and URI varies significantly by age and type of health insurance plan.

A homozygous HAMP mutation in a multiply consanguineous family with pseudo-dominant juvenile hemochromatosis.

Juvenile hemochromatosis (JH) is an autosomal recessive condition that leads to significant morbidity due to early onset systemic iron overload. The majority of families with JH link to chromosome 1q and were recently found to have mutations in the HFE2 gene encoding hemojuvelin; however, several JH families have been reported to have mutations in the HAMP gene encoding hepcidin. Here, we report a multiply consanguineous family with a father and daughter showing iron overload consistent with JH. Sequence analysis of HAMP revealed homozygosity for amino acid substitution C78T due to a c.233G > A mutation. This mutation disrupts one of eight highly conserved cysteines that are believed to be critical for the function of the active enzyme. This finding adds support to the importance of the role of these conserved cysteines in the activity of hepcidin.

Identification of a common variant in the lipoprotein lipase gene in a large Utah kindred ascertained for coronary heart disease: the -93G/D9N variant predisposes to low HDL-C/high triglycerides.

Defects in the lipoprotein lipase (LPL) gene are associated with dyslipidemia in the general population. Several rare mutations in the gene, as well as two common coding region polymorphisms, D9N and N291S, exhibit deleterious effects on circulating lipid levels. Using a linkage-based approach, we have identified a large Utah kindred segregating the D9N variant in the LPL gene. The kindred was ascertained for premature coronary heart disease and was expanded based on familial dyslipidemia. A genomic scan identified a region of linkage including LPL, and mutation screening identified the segregating variant. In the kindred, the variant shows high penetrance for a hypoalphalipoproteinemia phenotype, but is also associated with hypertriglyceridemia and elevated insulin levels. The strength of linkage was dependent on the combination of phenotype definition and model parameters, favoring the use of a MOD score approach. Most other studies of LPL have proceeded by mutation screening of randomly chosen individuals or selected affected probands; this is the first example identifying a segregating LPL mutation using direct linkage.

A profile of women medical directors in community and migrant health centers.

This article looks at the nation's community and migrant health centers, where substantial numbers of female physicians are medical directors, the second highest executive position, in search of insights for managed care organizations for recruiting and retaining women medical directors. This paper provides the first comparative national profile of women and men community and migrant health center (C/MHC) medical directors in terms of their personal and work characteristics, as well as job satisfaction. The study findings indicate that, for the most part, female medical directors do not differ much from their male colleagues in issues of work characteristics or job satisfaction.

Genetic localization to chromosome 1p32 of the third locus for familial hypercholesterolemia in a Utah kindred.

Clinical familial hypercholesterolemia has been shown to result from mutations in 2 genes, the low density lipoprotein (LDL) receptor on chromosome 19 and apolipoprotein B on chromosome 2. However, we have recently described a Utah pedigree in which linkage to both genes was clearly excluded. A multipoint linkage analysis of 583 markers genotyped on 31 (18 affected) members of this pedigree was undertaken to localize a genetic region that may harbor a third gene that could result in clinical familial hypercholesterolemia. A multipoint log of the odds score of 6.8 was obtained for markers on 1p32. Haplotype carriers and affected status are completely concordant (18/18 persons). The phenotype is also expressed in young children (ages 4 and 9). Specific recombinant individuals in the pedigree restrict the region of linkage to an approximately 17 cM interval between polymorphic markers D1S2130 and D1S1596. This region appears to overlap the region found linked to severe hypercholesterolemia in French and Spanish families. The identification of the gene in this region may provide important pathophysiological insights into new mechanisms that may lead to highly elevated LDL cholesterol and other associated dyslipidemic phenotypes.

Patient characteristics associated with hospitalizations for ambulatory care sensitive conditions in South Carolina.

BACKGROUND: Data for this study came from South Carolina 1995 Hospital Inpatient Encounter Data Base. The population figures were 1995 South Carolina population estimates. METHODS: We examined patient sociodemographic characteristics and costs associated with adult and pediatric ambulatory care sensitive condition (ACSC) hospitalization in South Carolina. Bivariate statistical comparisons were done to test the differences between ACSC and non-ACSC groups in specific sociodemographic characteristics. Logistic regression determined the relative significance of individual characteristics to hospitalizations for ACSC. Cost/charge ratios were used to estimate costs associated with ACSC hospitalizations. RESULTS: Nonwhites, low-income individuals, and those residing in more rural areas had significantly more ACSC hospitalizations than their respective counterparts (i.e., whites, high-income individuals, and those residing in metropolitan statistical areas). Individuals without a primary care physician were more likely to be hospitalized with ACSC. Ambulatory care sensitive condition hospitalization charges were 12% of total hospital charges for adults and 20% for children. The average cost per ACSC hospitalization was $3,929 for adults and $1,818 for children. CONCLUSION: Providers can rapidly assess needs and barriers faced by vulnerable population groups by using regularly collected hospital discharge data at the national, state, and community level.

A profile of women CEOs/administrators in community and migrant health centers.

Most of the current research on women executives has focused on models in which few women achieve the highest position (e.g. hospital CEOs). This article looks at the nation's Community and Migrant Health Centers where substantial numbers of women hold the highest executive position. A national profile of women Community and Migrant Health Centers (C/MHCs) Chief Executive Officers/Administrators is provided in terms of their personal and work characteristics, as well as their values and beliefs regarding successful C/MHC attributes and important managerial practices. The study compares C/MHC Chief Executive Officers/Administrators based on gender. The study found that 41 percent of the CEO/Administrators were women and that they shared similar values and beliefs about functions/critical managerial factors and managerial characteristics of C/MHCs with their male colleagues. However, the study did find a comparable salary differential of over $11,000 in favor of male Chief Executive Officers/Administrators. The article reviews the literature of female executives in health care and concludes with recommendations for further study using the C/MHCs CEO/Administrators as a model study population.

Differences in the role and administrative relationships of medical directors in community and migrant health centers.

This study examined differences in medical directors of Community and Migrant Health Centers (C/MHCs) in the United States based on the size of the center, including demographics, job characteristics, roles, and their relationship with C/MHC administrators and governing boards. Data for this analysis came from a 1996 cross-sectional survey of Community and Migrant Health Centers medical directors. A total of 411 centers (68.3% surveyed) responded to the survey including 240 rural centers (67.4%) and 171 urban (68.7%) centers. Small centers were categorized as those with three or fewer physicians (n = 136), medium centers had more than three but less than eight ETE physicians (n = 14), and large centers had eight or more ETE physicians (n = 109). Several differences were found regarding the medical directors' roles and relationships with the administrator and governing boards on the size of the center. Large C/MHC medical directors had more autonomy than did small and medium C/MHC medical directors including in the areas of managing clinical staff, the budget, and strategic planning activities. They spent more time cultivating community resources than small and medium center counterparts and were more likely to possess the management skills needed in their role than do those in small and medium centers. They also reported a stronger working relationship with the C/MHC administrator and had more input with the C/MHC board than small or medium medical directors.

Economic impact of hospital closure on small rural counties, 1984 to 1988: demonstration of a comparative analysis approach.

Hospital closure in a rural community may affect the locale's economic prospects as well as the health of its residents. Studies of economic effects have primarily relied on modeling techniques rather than observation of actual change. This study demonstrates the use of a comparative analysis approach for estimating the economic effects of hospital closure on small rural counties. The experiences of 103 small rural counties at which a hospital closed between 1984 and 1988 was compared with a matched group of counties at which no closure took place. "Comparable" counties were selected based on seven scales measuring the similarity between a closure county and potential comparisons. Three scales examined population and economic characteristics in the year before closure; two scales measured change throughout a three-year period preceding closure; and two scales measured change throughout a five-year period preceding closure. Closure effects were measured through a multivariate analysis of the post-closure economic history of closure and comparison counties. The key assumption is that similar counties should have similar experiences over time. If an event occurs within some of these counties but not others, this event should have visible effects. Comparative analysis suggested that earned income in closure counties (excluding farming and mining income) was lower than in comparison counties subsequent to closure and that labor force growth was similarly affected. A comparative analysis approach produces results that parallel those obtained from economic modeling and should be considered for further research.

Physician practice characteristics and satisfaction: a rural-urban comparison of medical directors at U.S. Community and Migrant Health Centers.

For this study, the association between physician practice characteristics and satisfaction of medical directors at rural and urban Community and Migrant Health Centers (C/MHCs) was investigated. Data for this study came from a 1996 cross-sectional survey of C/MHCs' medical directors. A total of 411 centers (68.3 percent) responded to the survey, including 240 rural (67.4 percent) and 171 urban (68.7 percent) C/MHCs. Factor analysis was used to synthesize physician practice characteristics related to overall satisfaction. The resulting factors were entered as new variables in a predictive logistic regression model of overall satisfaction. Growing up in an inner-city community was significantly associated with practicing in an urban center; whereas, growing up in a rural or frontier community was more likely to result in practicing in a rural center. The majority of medical directors (82.3 percent) were either somewhat satisfied or very satisfied with their work. Satisfaction with work was most significantly associated with overall level of satisfaction, followed by satisfaction with administration, peers and patients. Recruitment efforts are more likely to succeed when they target individuals with prior exposure to underserved areas. Improving the working conditions and interactions with administrators would help sustain the high level of satisfaction experienced by medical directors at C/MHCs.

Practice environment and the employment of nurse practitioners, physician assistants, and certified nurse midwives by community health centers.

This report examines the relation between state variations in the regulation of nurse practitioners (NPs), physician assistants (PAs), and certified nurse midwives (CNMs), and the employment of these nonphysician providers (NPPs) by community health centers (CHCs). Data for this report came from a 1991-92 survey of CHCs assessing the employment of NPPs, and secondary available data. The dependent variables examined were the numbers of NPPs currently employed by CHCs. Independent variables included 1992 practice environment scores, CHC location, number of CHC physicians, and NPP-to-population ratios. The number of NPs and PAs employed by CHCs was significantly associated with practice environment for these practitioners. NPP-to-population ratios and the number of CHC physicians are also significantly associated with NPP employment by CHCs. State decision makers may reduce legislative and regulatory barriers to practice as a way to improve the practice environment for nonphysician primary care providers, particularly NPs and PAs. Thus, community health centers can employ adequate number of NPPs to fulfill their mission of serving the poor and underserved population.

African American administrators in community/migrant health centers.

Community and migrant health centers (CHC/MHCs) play a secondary role as avenues for the development of minority and women health care professionals, groups traditionally underrepresented in administrative and managerial positions within the health care system. This paper focuses on the role of CHC/MHCs in eliminating the barriers that typically limit the professional advancement of these groups. In a survey of both rural and urban CHC/MHC administrators, it was found that CHC/MHCs have higher percentages of minorities in top management positions than general management but do not necessarily reflect the minority composition of those being served. Of the CHC/MHC administrators, 20 percent were African American, less than the population served (31 percent) but greater than the percentage of African Americans in the general U.S. population (12 percent). This suggests that CHC/MHCs have partially met the original goal of upward mobility and that there is room for improvement.

Primary care physicians and barriers to providing care to persons with HIV/AIDS.

Primary care physicians play an increasingly important role in the care of persons with HIV/AIDS due to the rising number and changing geographic distribution of persons infected with HIV/AIDS. The study explored the relationship between barriers to health services and the experience and willingness of primary care physicians to care for persons with HIV/AIDS. The study was based on a random survey of primary care physicians in South Carolina. The results indicate that although primary care physicians' willingness to treat persons with HIV/AIDS is significantly associated with many self-reported barriers (i.e., financial, structural, knowledge, and attitudinal), their HIV/AID care experience was most significantly correlated with self-reported knowledge that overrides financial and structural barriers. The results emphasize the importance of programs and policy initiatives aimed at enhancing the primary care physicians' knowledge level and improving their attitudes related to HIV/AIDS.

How well trained are nursing home administrators?

Nursing home administrators represent wide variations in academic training. General education levels do not seem to affect administrative preparation in key domains of practice--specific academic fields of study are more relevant. Hence, sole emphasis on higher educational requirements for licensure appears to be a misdirected strategy for improving quality of care and enhancing management efficiencies in nursing homes. Educational paradigms studied have strengths and weakness in furnishing various job skills. These results are helpful in defining strategic actions for addressing both current deficiencies and future training needs. A specialized long-term care model that incorporates appropriate clinical and business skills is recommended. The roles of continuing education and executive educational offerings also need streamlining. These initiatives would require a joint effort from policymakers, academicians, and practitioners.