Preconception Carrier Screening by Genome Sequencing: Results from the Clinical Laboratory.

Advances in sequencing technologies permit the analysis of a larger selection of genes for preconception carrier screening. The study was designed as a sequential carrier screen using genome sequencing to analyze 728 gene-disorder pairs for carrier and medically actionable conditions in 131 women and their partners (n = 71) who were planning a pregnancy. We report here on the clinical laboratory results from this expanded carrier screening program. Variants were filtered and classified using the latest American College of Medical Genetics and Genomics (ACMG) guideline; only pathogenic and likely pathogenic variants were confirmed by orthologous methods before being reported. Novel missense variants were classified as variants of uncertain significance. We reported 304 variants in 202 participants. Twelve carrier couples (12/71 couples tested) were identified for common conditions; eight were carriers for hereditary hemochromatosis. Although both known and novel variants were reported, 48% of all reported variants were missense. For novel splice-site variants, RNA-splicing assays were performed to aid in classification. We reported ten copy-number variants and five variants in non-coding regions. One novel variant was reported in F8, associated with hemophilia A; prenatal testing showed that the male fetus harbored this variant and the neonate suffered a life-threatening hemorrhage which was anticipated and appropriately managed. Moreover, 3% of participants had variants that were medically actionable. Compared with targeted mutation screening, genome sequencing improves the sensitivity of detecting clinically significant variants. While certain novel variant interpretation remains challenging, the ACMG guidelines are useful to classify variants in a healthy population.

Cell Sources for Cultivated Meat: Applications and Considerations throughout the Production Workflow.

Cellular agriculture is an emerging scientific discipline that leverages the existing principles behind stem cell biology, tissue engineering, and animal sciences to create agricultural products from cells in vitro. Cultivated meat, also known as clean meat or cultured meat, is a prominent subfield of cellular agriculture that possesses promising potential to alleviate the negative externalities associated with conventional meat production by producing meat in vitro instead of from slaughter. A core consideration when producing cultivated meat is cell sourcing. Specifically, developing livestock cell sources that possess the necessary proliferative capacity and differentiation potential for cultivated meat production is a key technical component that must be optimized to enable scale-up for commercial production of cultivated meat. There are several possible approaches to develop cell sources for cultivated meat production, each possessing certain advantages and disadvantages. This review will discuss the current cell sources used for cultivated meat production and remaining challenges that need to be overcome to achieve scale-up of cultivated meat for commercial production. We will also discuss cell-focused considerations in other components of the cultivated meat production workflow, namely, culture medium composition, bioreactor expansion, and biomaterial tissue scaffolding.

Development of a Synthetic Training Model for Canine Thoracocentesis.

Thoracocentesis, a procedure in which air or fluid is removed from the pleural space, is used to relieve respiratory distress, and as a diagnostic procedure in human and veterinary medicine. Veterinary students commonly learn and practice the procedure on canine cadavers which are in limited supply and are not amenable to long-term storage and use. Practicing thoracocentesis on a cadaveric model also provides limited feedback indicative of success and/or procedural complications. One commercial model for practicing canine thoracocentesis is available, but it costs over US$2000 and is excessively bulky. In order to improve the learning process for veterinary students, we have developed a reusable synthetic canine thorax model that accurately replicates the thoracocentesis procedure, provides immediate feedback to the students and reduces the need for canine cadavers. The low cost of our product provides an efficient alternative to cadavers for instruction in veterinary schools or hospitals.

Temporary Anosmia in Mice Following Nasal Lavage With Dilute Detergent Solution.

Olfactory sensory deprivation induces anosmia and reduces tyrosine hydroxylase and dopamine levels in the olfactory bulb. The behavioral consequences specific to the loss of olfactory bulb dopamine are difficult to determine because sensory deprivation protocols are either confounded by side effects or leave the animal anosmic. A new method to both induce sensory deprivation and to measure the behavioral and circuit consequences is needed. We developed a novel, recoverable anosmia protocol using nasal lavage with a dilute detergent solution. Detergent treatment did not damage the olfactory epithelium as measured by scanning electron microscopy, alcian blue histology, and acetylated tubulin immunohistochemistry. One treatment-induced anosmia that lasted 24 to 48 h. Three treatments over 5 days reduced olfactory bulb tyrosine hydroxylase and dopamine levels indicating that anosmia persists between treatments. Importantly, even with multiple treatments, olfactory ability recovered within 48 h. This is the first report of a sensory deprivation protocol that induces recoverable anosmia and can be paired with biochemical, histological, and behavioral investigations of olfaction.

Recommended care and care adherence following a diagnosis of Lynch syndrome: a mixed-methods study.

BACKGROUND: Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome. This study assesses trends in diagnosis of LS and adherence to recommended LS-related care in a large integrated healthcare organization (~ 575,000 members). METHODS: Electronic medical record (EMR) data (1999-2015) were examined to identify patients with a diagnosis of LS. We examined their LS-associated care recommendations and adherence to these recommendations. Qualitative patient and provider interviews were conducted with the aim of identifying opportunities for improved care delivery. RESULTS: We identified 74 patients with a diagnosis of LS; 64% were diagnosed with a LS-related malignancy prior to their diagnosis of LS. The time to LS diagnosis following development of a LS-related cancer decreased over time: before 2009 11% of individuals received a diagnosis of LS within 1 year of developing a LS-related cancer compared to 83% after 2009 (p < 0.0001). Colonoscopy recommendations were documented in the EMR for almost all patients with LS (96%). Documentation of other recommendations for cancer surveillance was less commonly found. Overall, patient adherence to colonoscopy was high (M = 81.5%; SD = 32.7%), and adherence to other recommendations varied. To improve care coordination, patients and providers suggested providing automated reminder prompts for LS-related surveillance, adding a LS-specific diagnosis code, and providing guidelines for LS-related surveillance in the EMR. CONCLUSIONS: We identified fewer than expected patients with LS in our large care system, indicating that there is still a diagnostic care gap. However, patients with LS were likely to receive and follow CRC surveillance recommendations. Recommendations for and adherence to extracolonic surveillance were variable. Improved care coordination and clearer documentation of the LS diagnosis is needed.

Time Costs for Genetic Counseling in Preconception Carrier Screening with Genome Sequencing.

Advances in technology and the promise of personalized health care are driving greater use of genome sequencing (GS) for a variety of clinical scenarios. As health systems consider adopting GS, they need to understand the impact of GS on the organization and cost of care. While research has documented a dramatic decrease in the cost of sequencing and interpreting GS, few studies have examined how GS impacts genetic counseling workloads. This study examined the time needed to provide genetic counseling for GS in the context of preconception carrier screening. Genetic counselors prospectively reported on the time spent in the results disclosure process with 107 study participants who were part of the NextGen study. We found that the median time for results disclosure was 64 min (ranged from 5 to 229 min). Preparation work was the most time-consuming activity. Qualitative data from journal entries, debrief interviews with genetic counselors, and detailed case conference notes provided information on factors influencing time for results disclosure and implications for practice. Results suggest that expanded carrier screening could require significant increases in genetic counseling time, unless we are able to generate new resources to reduce preparation work or develop other strategies such as the creation of new models to deliver this type of service.

Patient and provider perspectives on adherence to and care coordination of lynch syndrome surveillance recommendations: findings from qualitative interviews.

BACKGROUND: Patients with a genetic variant associated with Lynch syndrome (LS) are recommended to undergo frequent and repeated cancer surveillance activities to minimize cancer-related morbidity and mortality. Little is known about how patients and primary care providers (PCPs) track and manage these recommendations. We conducted a small exploratory study of patient and PCP experiences with recommended LS surveillance activities and communication with family members in an integrated health care system. METHODS: We used in-depth interviews with patients and providers to understand how surveillance is coordinated and monitored following confirmation of LS. We recruited patients with a range of ages/gender, and providers with at least at least one patient with a molecular diagnosis of LS. All interviews were recorded, transcribed, and content analyzed by a trained qualitative methodologist. RESULTS: Twenty-two interviews were completed with 12 patients and 10 providers. Most patients (10) had detailed knowledge of surveillance recommendations, but were less sure of time intervals. While all patients reported receiving initial education about their surveillance recommendations from a genetic counselor, seven did not follow-up with a genetic counselor in subsequent years. A third of patients described taking sole responsibility for managing their LS surveillance care. Lack of routine communication from the health system (e.g., prompts for surveillance activities), and provider engagement were surveillance barriers. PCPs were generally aware of LS, but had limited familiarity with surveillance recommendations. Most PCPs (7) viewed LS as rare and relied on patient and specialist expertise and support. Providers typically had 1 patient with LS in a panel of 1800 patients overall. Providers felt strongly that management of LS should be coordinated by a dedicated team of specialists. Most patients (92%) had at least one family member that sought LS testing, and common barriers for family members included lack of insurance, affordability, and fear of result. CONCLUSION: The maximal benefits of screening for confirmation of LS will only be realized with adherence to recommended preventive care. Important factors to ensure patients receive recommended LS care include a comprehensive and coordinated monitoring program that includes reminder prompts, and increased PCP education of LS and associated surveillance recommendations.

Genome sequencing and carrier testing: decisions on categorization and whether to disclose results of carrier testing.

PURPOSE: We investigated the use of genome sequencing for preconception carrier testing. Genome sequencing could identify one or more of thousands of X-linked or autosomal recessive conditions that could be disclosed during preconception or prenatal counseling. Therefore, a framework that helps both clinicians and patients understand the possible range of findings is needed to respect patient preferences by ensuring that information about only the desired types of genetic conditions are provided to a given patient. METHODS: We categorized gene-condition pairs into groups using a previously developed taxonomy of genetic conditions. Patients could elect to receive results from these categories. A Return of Results Committee (RORC) developed inclusion and exclusion criteria for each category. RESULTS: To date, the RORC has categorized 728 gene-condition pairs: 177 are categorized as life span-limiting, 406 are categorized as serious, 93 are categorized as mild, 41 are categorized as unpredictable, and 11 are categorized as adult-onset. An additional 64 gene-condition pairs were excluded from reporting to patients or put on a watch list, generally because evidence that a gene and condition were associated was limited. CONCLUSION: Categorization of gene-condition pairs using our taxonomy simplifies communication regarding patient preferences for carrier information from a genomic test.Genet Med advance online publication 12 January 2017.

Reasons for Declining Preconception Expanded Carrier Screening Using Genome Sequencing.

Genomic carrier screening can identify more disease-associated variants than existing carrier screening methodologies, but its utility from patients' perspective is not yet established. A randomized controlled trial for preconception genomic carrier screening provided an opportunity to understand patients' decisions about whether to accept or decline testing. We administered a survey to potential genomic carrier screening recipients who declined participation (N = 240) to evaluate their reasons for doing so. Two thirds of women declined participation. We identified major themes describing reasons these individuals declined to participate; the most common were time limitation, lack of interest, not wanting to know the information, and potential cause of worry or anxiety. Most women eligible for genomic carrier screening indicated that their reasons for opting out were due to logistical issues rather than opposing the rationale for testing. As expanded carrier screening and genomic sequencing become a more routine part of clinical care, it is anticipated there will be variable uptake from individuals for this testing. Thus, the advancement of clinical carrier screening from single genes, to expanded screening panels, to an exome- or genome-wide platform, will require approaches that respect individual choice to receive genetic testing for reproductive risk assessment.

Stakeholder perspectives on implementing a universal Lynch syndrome screening program: a qualitative study of early barriers and facilitators.

PURPOSE: Evidence-based guidelines recommend that all newly diagnosed colon cancer be screened for Lynch syndrome (LS), but best practices for implementing universal tumor screening have not been extensively studied. We interviewed a range of stakeholders in an integrated health-care system to identify initial factors that might promote or hinder the successful implementation of a universal LS screening program. METHODS: We conducted interviews with health-plan leaders, managers, and staff. Interviews were audio-recorded and transcribed. Thematic analysis began with a grounded approach and was also guided by the Practical Robust Implementation and Sustainability Model (PRISM). RESULTS: We completed 14 interviews with leaders/managers and staff representing involved clinical and health-plan departments. Although stakeholders supported the concept of universal screening, they identified several internal (organizational) and external (environment) factors that promote or hinder implementation. Facilitating factors included perceived benefits of screening for patients and organization, collaboration between departments, and availability of organizational resources. Barriers were also identified, including: lack of awareness of guidelines, lack of guideline clarity, staffing and program "ownership" concerns, and cost uncertainties. Analysis also revealed nine important infrastructure-type considerations for successful implementation. CONCLUSION: We found that clinical, laboratory, and administrative departments supported universal tumor screening for LS. Requirements for successful implementation may include interdepartmental collaboration and communication, patient and provider/staff education, and significant infrastructure and resource support related to laboratory processing and systems for electronic ordering and tracking.

Patients' ratings of genetic conditions validate a taxonomy to simplify decisions about preconception carrier screening via genome sequencing.

Advances in genome sequencing and gene discovery have created opportunities to efficiently assess more genetic conditions than ever before. Given the large number of conditions that can be screened, the implementation of expanded carrier screening using genome sequencing will require practical methods of simplifying decisions about the conditions for which patients want to be screened. One method to simplify decision making is to generate a taxonomy based on expert judgment. However, expert perceptions of condition attributes used to classify these conditions may differ from those used by patients. To understand whether expert and patient perceptions differ, we asked women who had received preconception genetic carrier screening in the last 3 years to fill out a survey to rate the attributes (predictability, controllability, visibility, and severity) of several autosomal recessive or X-linked genetic conditions. These conditions were classified into one of five taxonomy categories developed by subject experts (significantly shortened lifespan, serious medical problems, mild medical problems, unpredictable medical outcomes, and adult-onset conditions). A total of 193 women provided 739 usable ratings across 20 conditions. The mean ratings and correlations demonstrated that participants made distinctions across both attributes and categories. Aggregated mean attribute ratings across categories demonstrated logical consistency between the key features of each attribute and category, although participants perceived little difference between the mild and serious categories. This study provides empirical evidence for the validity of our proposed taxonomy, which will simplify patient decisions for results they would like to receive from preconception carrier screening via genome sequencing.

Generating a taxonomy for genetic conditions relevant to reproductive planning.

As genome or exome sequencing (hereafter genome-scale sequencing) becomes more integrated into standard care, carrier testing is an important possible application. Carrier testing using genome-scale sequencing can identify a large number of conditions, but choosing which conditions/genes to evaluate as well as which results to disclose can be complicated. Carrier testing generally occurs in the context of reproductive decision-making and involves patient values in a way that other types of genetic testing may not. The Kaiser Permanente Clinical Sequencing Exploratory Research program is conducting a randomized clinical trial of preconception carrier testing that allows participants to select their preferences for results from among broad descriptive categories rather than selecting individual conditions. This paper describes (1) the criteria developed by the research team, the return of results committee (RORC), and stakeholders for defining the categories; (2) the process of refining the categories based on input from patient focus groups and validation through a patient survey; and (3) how the RORC then assigned specific gene-condition pairs to taxonomy categories being piloted in the trial. The development of four categories (serious, moderate/mild, unpredictable, late onset) for sharing results allows patients to select results based on their values without separately deciding their interest in knowing their carrier status for hundreds of conditions. A fifth category, lifespan limiting, was always shared. The lessons learned may be applicable in other results disclosure situations, such as incidental findings.

"Is It Worth Knowing?" Focus Group Participants' Perceived Utility of Genomic Preconception Carrier Screening.

As genome sequencing technology advances, research is needed to guide decision-making about what results can or should be offered to patients in different clinical settings. We conducted three focus groups with individuals who had prior preconception genetic testing experience to explore perceived advantages and disadvantages of genome sequencing for preconception carrier screening, compared to usual care. Using a discussion guide, a trained qualitative moderator facilitated the audio-recorded focus groups. Sixteen individuals participated. Thematic analysis of transcripts started with a grounded approach and subsequently focused on participants' perceptions of the value of genetic information. Analysis uncovered two orientations toward genomic preconception carrier screening: "certain" individuals desiring all possible screening information; and "hesitant" individuals who were more cautious about its value. Participants revealed valuable information about barriers to screening: fear/anxiety about results; concerns about the method of returning results; concerns about screening necessity; and concerns about partner participation. All participants recommended offering choice to patients to enhance the value of screening and reduce barriers. Overall, two groups of likely users of genome sequencing for preconception carrier screening demonstrated different perceptions of the advantages or disadvantages of screening, suggesting tailored approaches to education, consent, and counseling may be warranted with each group.

Universal tumor screening for Lynch syndrome: Assessment of the perspectives of patients with colorectal cancer regarding benefits and barriers.

BACKGROUND: Universal tumor screening for Lynch syndrome, the most common form of hereditary colorectal cancer (CRC), has been recommended among all patients newly diagnosed with CRC. However, there is limited literature regarding patient perspectives of tumor screening for Lynch syndrome among patients with CRC who are not selected for screening based on family history criteria. METHODS: A total of 145 patients aged 39 to 87 years were administered surveys assessing perceived risk, patient perspectives, and potential benefits of and barriers to tumor screening for Lynch syndrome. Associations between patient-specific and cancer-specific factors and survey responses were analyzed. RESULTS: The majority of participants perceived their risk of developing Lynch syndrome as being low, with 9 participants (6.2%) anticipating an abnormal screening result. However, most participants endorsed the potential benefits of screening for themselves and their families, with 84.8% endorsing ≥6 benefits and 50.3% endorsing all 8 benefits. Participants also endorsed few potential barriers to screening, with 89.4% endorsing ≤4 of 9 potential barriers. A common barrier was worry about the cost of additional testing and surveillance, which was endorsed by 54.5% of participants. The level of distress associated with tumor screening for Lynch syndrome, which was very low, was not associated with age or CRC stage. CONCLUSIONS: The results of the current study indicate that patients with CRC overall have a positive attitude toward tumor screening for Lynch syndrome, endorse the benefits of screening, and experience low levels of distress. These findings provide insight into patient attitudes toward tumor screening for Lynch syndrome among unselected patients with CRC to inform educational approaches that assist in patient decision-making and guide the successful implementation of screening programs.

Nutrition counsellors' recommended eating patterns for individuals with type 2 diabetes in the USA.

Introduction: Multiple eating patterns can promote glycaemic control and weight loss among patients with type 2 diabetes mellitus (T2D). Clinical practice guidelines for T2D management encourage health professionals to guide patients' selection of a patient-centred eating pattern. This study aims to characterise beliefs about and recommendations for and against practice guideline-concordant eating patterns among registered dietitians (RDs) and other healthcare professionals who provide nutrition counselling to patients with T2D. Methods: This was a cross-sectional online survey. We invited 82 RDs affiliated with an academic health system in the midwestern USA to participate. We also invited health professionals who provide nutrition counselling to patients with T2D and are affiliated with 264 primary care practices within the Michigan Collaborative for Type 2 Diabetes. Participants were asked to select the eating pattern(s) that they commonly recommend or avoid for patients with T2D and why. Results: Survey respondents (n=81) most commonly recommend low-carbohydrate (77.8%); Mediterranean-style (52.8%) and energy-modified/calorie-restricted (36.1%) eating patterns. Survey respondents most commonly recommend avoiding very low-carbohydrate (51.0%) and very low-calorie (49.0%) eating patterns. Respondents who did not recommend very low-carbohydrate were most concerned about the eating pattern being too restrictive (93.0%). Conclusions: Survey respondents recommend a range of guideline-adherent eating patterns to patients with T2D but tend to recommend against very low-carbohydrate and very low-calorie eating patterns. Additional strategies are needed to increase patient-centred use of these evidence-based options in clinical practice settings.

Probability-Based Best Sample Selection for Acoustic Analysis of Normal and Disordered Voices.

PURPOSE: Acoustic analysis is a commonly used method for quantitatively measuring vocal fold function. The accuracy of acoustic analysis depends upon the operator selecting a stable segment of the voice sample to analyze. This paper proposes a novel method to more accurately and reliably select a stable voice segment. STUDY DESIGN: Four selection methods were implemented to evaluate each raw audio signal and determine the most stable segment of each signal: The proposed modal periodogram method, the moving window method, the midvowel method, and the whole vowel method. Acoustic parameters of interest-namely perturbation (jitter), correlation dimension (D2), and spectrum convergence ratio (SCR)-were calculated for 48 phonation samples to evaluate each method. METHODS: The proposed modal periodogram method utilizes a minimum mean-square error based approach to calculate a stable modal periodogram and obtain the most stable segment. The Wilcoxon Signed-Rank test was used to compare jitter, D2, and SCR values acquired using the modal periodogram method against the current standard segment selection methods. RESULTS: The modal periodogram method yielded significantly lower D2 values, and a significantly higher SCR for both normal and disordered voice samples (P < 0.01). This indicates that the modal periodogram method is more apt for selecting a stable audio segment than the other selection methods.

Changes in salivary biomarkers associated with periodontitis and diabetic neuropathy in individuals with type 1 diabetes.

The objective of this pilot clinical study was to identify salivary biomarkers that are associated with periodontal disease and measures of diabetic autonomic dysfunction. Saliva samples from 32 participants were obtained from 3 groups: healthy (H), type 1 diabetes mellitus (DM), and type 1 diabetes mellitus with neuropathy (DMN). Based on the periodontal examination, individuals' mean Periodontal Screening and Recording scores were categorized into two groups (periodontally healthy and gingivitis), and correlated to specific salivary inflammatory biomarkers assessed by a customized protein array and enzyme assay. The mean salivary IgA level in DM was 9211.5 ± 4776.4 pg/ml, which was significantly lower than H (17,182.2 ± 8899.3 pg/ml). IgA in DMN with healthy periodontium was significantly lower (5905.5 ± 3124.8 pg/ml) compared to H, although IgA levels in DMN patients with gingivitis (16,894. 6 ± 7084.3) were not. According to the result of a logistic regression model, IgA and periodontal condition were the indicators of the binary response given by H versus DM, and H versus DMN, respectively. These data suggest that selected salivary biomarkers, such as IgA, combined with a periodontal examination prior to obtaining salivary samples can offer a non-invasive method to assess risk for developing diabetic neuropathy.

Dapagliflozin and measures of cardiovascular autonomic function in patients with type 2 diabetes (T2D).

AIMS: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduce blood pressure without compensatory heart rate elevation, possibly by modulating sympathetic/parasympathetic activity. This may contribute to their cardiovascular benefits in type 2 diabetes (T2D). We evaluated the effects of dapagliflozin (DAPA) on measures of cardiovascular autonomic neuropathy (CAN), cardiac function, and glucose variability (GV) in T2D. METHODS: Pilot, randomized, two-period crossover trial comparing 12-week DAPA versus 12-week glimepiride treatment on CAN measures (cardiovascular autonomic reflex tests and heart rate variability), B-type natriuretic peptide (BNP), and GV (Abbott's Libre Pro devices) using signed rank tests and mixed models from baseline to 12 weeks within and between each period. RESULTS: Forty-five T2D participants on metformin monotherapy (mean age 57 ±â€¯8 years, duration 7 ±â€¯6 years, HbA1c 7.8 ±â€¯1.3%) were enrolled with 41 completing the trial. There were no differences in CAN indices or BNP with each drug compared to baseline and each other. Participants on DAPA demonstrated greater weight loss, reduced time in hypoglycemia, and improved GV compared to glimepiride. CONCLUSIONS: Short term treatment with DAPA did not affect CAN measures or BNP in uncomplicated and relatively healthy T2D participants. Longer prospective studies in patients with advanced disease are needed to better understand relationships between SGLT-2 inhibitors and CAN. CLINICAL TRIAL REGISTRATION: NCT02973477.

Deletion of an enhancer near DLX5 and DLX6 in a family with hearing loss, craniofacial defects, and an inv(7)(q21.3q35).

Precisely regulated temporal and spatial patterns of gene expression are essential for proper human development. Cis-acting regulatory elements, some located at large distances from their corresponding genes, play a critical role in transcriptional control of key developmental genes and disruption of these regulatory elements can lead to disease. We report a three generation family with five affected members, all of whom have hearing loss, craniofacial defects, and a paracentric inversion of the long arm of chromosome 7, inv(7)(q21.3q35). High resolution mapping of the inversion showed that the 7q21.3 breakpoint is located 65 and 80 kb centromeric of DLX6 and DLX5, respectively. Further analysis revealed a 5,115 bp deletion at the 7q21.3 breakpoint. While the breakpoint does not disrupt either DLX5 or DLX6, the syndrome present in the family is similar to that observed in Dlx5 knockout mice and includes a subset of the features observed in individuals with DLX5 and DLX6 deletions, implicating dysregulation of DLX5 and DLX6 in the family's phenotype. Bioinformatic analysis indicates that the 5,115 bp deletion at the 7q21.3 breakpoint could contain regulatory elements necessary for DLX5 and DLX6 expression. Using a transgenic mouse reporter assay, we show that the deleted sequence can drive expression in the inner ear and developing bones of E12.5 embryos. Consequently, the observed familial syndrome is likely caused by dysregulation of DLX5 and/or DLX6 in specific tissues due to deletion of an enhancer and possibly separation from other regulatory elements by the chromosomal inversion.

Heritability of serum iron measures in the hemochromatosis and iron overload screening (HEIRS) family study.

Heritability is the proportion of observed variation in a trait among individuals in a population that is attributable to hereditary factors. The Hemochromatosis and Iron Overload Screening family study estimated heritability of serum iron measures. Probands were HFE C282Y homozygotes or non-C282Y homozygotes with elevated transferrin saturation (TS > 50%, men; TS > 45%, women) and serum ferritin concentration (SF > 300 microg/L, men; SF > 200 microg/L, women). Heritability (h(2)) was estimated by variance component analysis of TS, natural logarithm (ln) of SF, and unsaturated iron-binding capacity (UIBC). Participants (N = 942) were 77% Caucasians, 10% Asians, 8% Hispanics, and 5% other race/ethnicities. Average age (SD) was 49 (16) years; 57% were female. For HFE C282Y homozygote probands and their family members, excluding variation due to HFE C282Y and H63D genotype and measured demographic and environmental factors, the residual h(2) (SE) was 0.21 (0.07) for TS, 0.37 (0.08) for ln SF, and 0.34 (0.08) for UIBC (all P < 0.0004 for comparisons with zero). For the non-C282Y homozygote proband group, residual h(2) was significant with a value of 0.64 (0.26) for ln SF (P = 0.0096). In conclusion, serum iron measures have significant heritability components, after excluding known genetic and nongenetic sources of variation.