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Epigenetic dysregulation has emerged as an important etiological mechanism of neurodevelopmental disorders (NDDs). Pathogenic variation in epigenetic regulators can impair deposition of histone post-translational modifications leading to aberrant spatiotemporal gene expression during neurodevelopment. The male-specific lethal (MSL) complex is a prominent multi-subunit epigenetic regulator of gene expression and is responsible for histone 4 lysine 16 acetylation (H4K16ac). Using exome sequencing, here we identify a cohort of 25 individuals with heterozygous de novo variants in MSL complex member MSL2. MSL2 variants were associated with NDD phenotypes including global developmental delay, intellectual disability, hypotonia, and motor issues such as coordination problems, feeding difficulties, and gait disturbance. Dysmorphisms and behavioral and/or psychiatric conditions, including autism spectrum disorder, and to a lesser extent, seizures, connective tissue disease signs, sleep disturbance, vision problems, and other organ anomalies, were observed in affected individuals. As a molecular biomarker, a sensitive and specific DNA methylation episignature has been established. Induced pluripotent stem cells (iPSCs) derived from three members of our cohort exhibited reduced MSL2 levels. Remarkably, while NDD-associated variants in two other members of the MSL complex (MOF and MSL3) result in reduced H4K16ac, global H4K16ac levels are unchanged in iPSCs with MSL2 variants. Regardless, MSL2 variants altered the expression of MSL2 targets in iPSCs and upon their differentiation to early germ layers. Our study defines an MSL2-related disorder as an NDD with distinguishable clinical features, a specific blood DNA episignature, and a distinct, MSL2-specific molecular etiology compared to other MSL complex-related disorders.

PURPOSE: Nonmuscle myosin II complexes are master regulators of actin dynamics that play essential roles during embryogenesis with vertebrates possessing 3 nonmuscle myosin II heavy chain genes, MYH9, MYH10, and MYH14. As opposed to MYH9 and MYH14, no recognizable disorder has been associated with MYH10. We sought to define the clinical characteristics and molecular mechanism of a novel autosomal dominant disorder related to MYH10. METHODS: An international collaboration identified the patient cohort. CAS9-mediated knockout cell models were used to explore the mechanism of disease pathogenesis. RESULTS: We identified a cohort of 16 individuals with heterozygous MYH10 variants presenting with a broad spectrum of neurodevelopmental disorders and variable congenital anomalies that affect most organ systems and were recapitulated in animal models of altered MYH10 activity. Variants were typically de novo missense changes with clustering observed in the motor domain. MYH10 knockout cells showed defects in primary ciliogenesis and reduced ciliary length with impaired Hedgehog signaling. MYH10 variant overexpression produced a dominant-negative effect on ciliary length. CONCLUSION: These data presented a novel genetic cause of isolated and syndromic neurodevelopmental disorders related to heterozygous variants in the MYH10 gene with implications for disrupted primary cilia length control and altered Hedgehog signaling in disease pathogenesis.

Although protein hydroxylation is a relatively poorly characterized posttranslational modification, it has received significant recent attention following seminal work uncovering its role in oxygen sensing and hypoxia biology. Although the fundamental importance of protein hydroxylases in biology is becoming clear, the biochemical targets and cellular functions often remain enigmatic. JMJD5 is a 'JmjC-only' protein hydroxylase that is essential for murine embryonic development and viability. However, no germline variants in JmjC-only hydroxylases, including JMJD5, have yet been described that are associated with any human pathology. Here we demonstrate that biallelic germline JMJD5 pathogenic variants are deleterious to JMJD5 mRNA splicing, protein stability, and hydroxylase activity, resulting in a human developmental disorder characterized by severe failure to thrive, intellectual disability, and facial dysmorphism. We show that the underlying cellular phenotype is associated with increased DNA replication stress and that this is critically dependent on the protein hydroxylase activity of JMJD5. This work contributes to our growing understanding of the role and importance of protein hydroxylases in human development and disease., Introduction The enzymatic incorporation of a single oxygen atom into an amino acid side chain is a relatively poorly characterized but emerging posttranslational modification (PTM) (1). Seminal work on the [...]

Background: The impacts of direct-to-consumer personal genomic testing (PGT) on health behaviors such as diet and exercise are poorly understood. Our investigation aimed to evaluate diet and exercise changes following PGT and to determine if changes were associated with genetic test results obtained from PGT. Methods: Customers of 23andMe and Pathway Genomics completed a web-based survey prior to receiving PGT results (baseline) and 6 months post-results. Fruit and vegetable intake (servings/day), and light, vigorous and strength exercise frequency (days/week) were assessed. Changes in diet and exercise were examined using paired t-tests and linear regressions. Additional analyses examined whether outcomes differed by baseline self-reported health (SRH) or content of PGT results. Results: Longitudinal data were available for 1,002 participants. Significant increases were observed for vegetable intake (mean Δ = 0.11 (95% CI = 0.05, 0.17), p = 0.0003) and strength exercise (Δ = 0.14 (0.03, 0.25), p = 0.0153). When stratified by SRH, significant increases were observed for all outcomes among lower SRH participants: fruit intake, Δ = 0.11 (0.02, 0.21), p = 0.0148; vegetable intake, Δ = 0.16 (0.07, 0.25), p = 0.0005; light exercise, Δ = 0.25 (0.03, 0.47), p = 0.0263; vigorous exercise, Δ = 0.23 (0.06, 0.41), p = 0.0097; strength exercise, Δ = 0.19 (0.01, 0.37), p = 0.0369. A significant change among higher SRH participants was only observed for light exercise, and in the opposite direction: Δ = -0.2468 (-0.06, -0.44), p = 0.0111. Genetic results were not consistently associated with any diet or exercise changes. Conclusions: The experience of PGT was associated with modest, mostly positive changes in diet and exercise. Associations were independent of genetic results from PGT. [ABSTRACT FROM AUTHOR]

Introduction: Direct-to-consumer personal genomic testing has the potential to influence health behaviors, including smoking. Critics of this testing highlight limited evidence to support positive behavioral benefits and caution that genomic results may provide false reassurance, leading to unhealthy behaviors. This study investigates interest in genetic risks of smoking-related diseases and changes in smoking behaviors among genomic testing consumers.Methods: From 2012 to 2013, a longitudinal series of web surveys was conducted. A total of 1464 customers of 23andMe and Pathway Genomics completed a survey prior to viewing genomic test results, of which 1002 participants provided data on smoking behaviors 6 months after receiving results.Results: At baseline, 64% of participants were never smokers, 29% were former smokers, and 7% were current smokers. Most baseline current smokers were very interested in genetic risk results for lung cancer (65%) and heart disease (72%). For lung cancer, this interest was significantly greater than former (50% very interested) and never smokers (37% very interested) (p < .0001). Even though participants were interested in smoking-related disease genetic risks, 96% reported the same smoking status at baseline and 6-month follow-up. Importantly, only 1% (n = 13/916) of former and never smokers became current smokers at 6 months and 22% (n = 14/64) of current smokers reported quitting.Conclusions: Overall, smokers show a high level of interest in genetic risks of smoking-related illnesses. The experience of receiving direct-to-consumer genomic health risks does not appear to have obvious harms related to smoking behaviors, with some potential benefits.Implications: In the setting of ongoing controversy surrounding direct-to-consumer genomic testing, this study provides evidence that consumers are interested in genetic risk results of smoking-related diseases. Receiving genomic testing results does not lead to smoking initiation among never smokers or reinitiation among former smokers and may be associated with a higher quit rate among current smokers at 6-month follow-up than the general population. These findings ease concerns that direct-to-consumer genomic testing could lead to false reassurance and unhealthy behaviors related to smoking. [ABSTRACT FROM AUTHOR]

Background: Direct access to genomic information has the potential to transform cancer risk counseling. We measured the impact of direct-to-consumer genomic risk information on changes to perceived risk (ΔPR) of breast, prostate, colorectal and lung cancer among personal genomic testing (PGT) customers. We hypothesized that ΔPR would reflect directionality of risk estimates, attenuate with time, and be modified by participant characteristics. Methods: Pathway Genomics and 23andMe customers were surveyed prior to receiving PGT results, and 2 weeks and 6 months post-results. For each cancer, PR was measured on a 5-point ordinal scale from "much lower than average" to "much higher than average. " PGT results, based on genotyping of common genetic variants, were dichotomized as elevated or average risk. The relationship between risk estimate and ΔPR was evaluated with linear regression; generalized estimating equations modeled this relationship over time. Results: With the exception of lung cancer (for which ΔPR was positive regardless of result), elevated risk results were significantly associated with positive ΔPR, and average risk results with negative ΔPR (e.g., prostate cancer, 2 weeks: least squares-adjusted ΔPR = 0.77 for elevated risk versus -0.21 for average risk; p-valuedifference < 0.0001) among 1154 participants. Large changes were rare: for each cancer, <4 % of participants overall reported a ΔPR of ±3 or more units. Effect modification by age, cancer family history, and baseline interest was observed for breast, colorectal, and lung cancer, respectively. A pattern of decreasing impact on ΔPR over time was consistently observed, but this trend was significant only in the case of colorectal cancer. Conclusions: We have quantified the effect on consumer risk perception of returning genetic-based cancer risk information directly to consumers without clinician mediation. Provided via PGT, this information has a measurable but modest effect on perceived cancer risk, and one that is in some cases modified by consumers' non-genetic risk context. Our observations of modest marginal effect sizes, infrequent extreme changes in perceived risk, and a pattern of diminishing impact with time, suggest that the ability of PGT to effect changes to cancer screening and prevention behaviors may be limited by relatively small changes to perceived risk. [ABSTRACT FROM AUTHOR]

Background: There is a widespread assumption that risk prediction is the major driver of customer interest in personal genomic testing (PGT). However, some customers may also be motivated by finding out whether their existing diseases have a genetic etiology. We evaluated the impact of an existing medical diagnosis on customer interest in condition-specific results from PGT. Methods: Using a prospective online survey of PGT customers, we measured customer interest prior to receiving PGT results for 11 health conditions, and examined the association between interest and personal medical history of these conditions using logistic regression. Results: We analyzed data from 1,538 PGT customers, mean age 48.7 years, 61 % women, 90 % White, and 47 % college educated. The proportion of customers who were 'very interested' in condition-specific PGT varied considerably, from 28 % for ulcerative colitis to 68% for heart disease. After adjusting for demographic and personal characteristics including family history, having a diagnosis of the condition itself was significantly associated with interest in genetic testing for risk of that condition, with odds ratios ranging from 2.07 (95 % CI 1.28-3.37) for diabetes to 19.99 (95 % CI 4.57-87.35) for multiple sclerosis. Conclusions: PGT customers are particularly interested in genetic markers for their existing medical conditions, suggesting that the value of genetic testing is not only predictive, but also explanatory. [ABSTRACT FROM AUTHOR]

Aim: To assess customer comprehension of health-related personal genomic testing (PGT) results. Methods: We presented sample reports of genetic results and examined responses to comprehension questions in 1,030 PGT customers (mean age: 46.7 years; 59.9% female; 79.0% college graduates; 14.9% non-White; 4.7% of Hispanic/Latino ethnicity). Sample reports presented a genetic risk for Alzheimer's disease and type 2 diabetes, carrier screening summary results for >30 conditions, results for phenylketonuria and cystic fibrosis, and drug response results for a statin drug. Logistic regression was used to identify correlates of participant comprehension. Results: Participants exhibited high overall comprehension (mean score: 79.1% correct). The highest comprehension (range: 81.1-97.4% correct) was observed in the statin drug response and carrier screening summary results, and lower comprehension (range: 63.6-74.8% correct) on specific carrier screening results. Higher levels of numeracy, genetic knowledge, and education were significantly associated with greater comprehension. Older age (≥60 years) was associated with lower comprehension scores. Conclusions: Most customers accurately interpreted the health implications of PGT results; however, comprehension varied by demographic characteristics, numeracy and genetic knowledge, and types and format of the genetic information presented. Results suggest a need to tailor the presentation of PGT results by test type and customer characteristics. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose To measure the frequency of prescription medication changes following direct-to-consumer personal genomic testing (DTC-PGT) and their association with the pharmacogenomic results received. Methods: New DTC-PGT customers were enrolled in 2012 and completed surveys prior to return of results and 6 months post-results; DTC-PGT results were linked to survey data. ‘Atypical response’ pharmacogenomic results were defined as those indicating an increase or decrease in risk of an adverse drug event or likelihood of therapeutic benefit. At follow-up, participants reported prescription medication changes and health care provider consultation. Results: Follow-up data were available from 961 participants, of which 54 (5.6%) reported changing a medication they were taking, or starting a new medication, due to their DTC-PGT results. Of these, 45 (83.3%) reported consulting with a health care provider regarding the change. Pharmacogenomic results were available for 961 participants, of which 875 (91.2%) received ≥1 atypical response result. For each such result received, the odds of reporting a prescription medication change increased 1.57 times (95% confidence interval = 1.17, 2.11). Conclusion: Receipt of pharmacogenomic results indicating atypical drug response is common with DTC-PGT, and associated with prescription medication changes; however, fewer than 1% of consumers report unsupervised changes at 6 months post-testing.

Purpose American adult adoptees may possess limited amounts of information about their biological families and turn to direct-to-consumer personal genomic testing (PGT) for genealogical and medical information. We investigated the motivations and outcomes of adoptees undergoing PGT using data from the Impact of Personal Genomics (PGen) Study. Methods: The PGen Study surveyed new 23andMe and Pathway Genomics customers prior to and 6 months after receiving PGT results. Exploratory analyses compared adoptees’ and non-adoptees’ PGT attitudes, expectations, and experiences. We evaluated the association of adoption status with motivations for testing and post-disclosure actions using logistic regression models. Results: Of 1607 participants, 80 (5%) were adopted. As compared to non-adoptees, adoptees were more likely to cite limited family health history knowledge (OR = 10.1; 95% CI = 5.7–19.5) and the opportunity to learn genetic disease risks (OR = 2.7; 95% CI = 1.6–4.8) as strong motivations for PGT. Of 922 participants who completed 6-month follow-up, there was no significant association between adoption status and PGT-motivated healthcare utilization or health behavior change. Conclusion: PGT allows adoptees to gain otherwise inaccessible information about their genetic disease risks and ancestry, helping them to fill the void of an incomplete family health history.

Purpose To measure changes to genetics knowledge and self-efficacy following personal genomic testing (PGT). Methods: New customers of 23andMe and Pathway Genomics completed a series of online surveys. Prior to receipt of results, and 6 months post-results, we measured genetics knowledge (9 true/false items) and genetics self-efficacy (5 Likert-scale items) and used paired methods to evaluate change over time. Correlates of change (e.g., decision regret) were identified using linear regression. Results: 998 PGT customers (59.9% female; 85.8% White; mean age 46.9±15.5 years) were included in our analyses. Mean genetics knowledge score out of 9 was 8.15±0.95 at baseline and 8.25±0.92 at 6 months (p = .0024). Mean self-efficacy score out of 35 was 29.06±5.59 at baseline and 27.7±5.46 at 6 months (p < .0001); on each item, 30–45% of participants reported lower self-efficacy following PGT. Change in self-efficacy was positively associated with health care provider consultation (p = .0042), impact of PGT on perceived control over one’s health (p < .0001), and perceived value of PGT (p < .0001), and negatively associated with decision regret (p < .0001). Conclusion: Lowered genetics self-efficacy following PGT may reflect an appropriate reevaluation by consumers in response to receiving complex genetic information.

Designed in collaboration with 23andMe and Pathway Genomics, the Impact of Personal Genomics (PGen) Study serves as a model for academic-industry partnership and provides a longitudinal dataset for studying psychosocial, behavioral, and health outcomes related to direct-to-consumer personal genomic testing (PGT). Web-based surveys administered at three time points, and linked to individual-level PGT results, provide data on 1,464 PGT customers, of which 71% completed each follow-up survey and 64% completed all three surveys. The cohort includes 15.7% individuals of non-white ethnicity, and encompasses a range of income, education, and health levels. Over 90% of participants agreed to re-contact for future research. Electronic supplementary material The online version of this article (doi:10.1186/s13073-014-0096-0) contains supplementary material, which is available to authorized users.