Exome sequencing in multiplex families with left-sided cardiac defects has high yield for disease gene discovery.

Congenital heart disease (CHD) is a common group of birth defects with a strong genetic contribution to their etiology, but historically the diagnostic yield from exome studies of isolated CHD has been low. Pleiotropy, variable expressivity, and the difficulty of accurately phenotyping newborns contribute to this problem. We hypothesized that performing exome sequencing on selected individuals in families with multiple members affected by left-sided CHD, then filtering variants by population frequency, in silico predictive algorithms, and phenotypic annotations from publicly available databases would increase this yield and generate a list of candidate disease-causing variants that would show a high validation rate. In eight of the nineteen families in our study (42%), we established a well-known gene/phenotype link for a candidate variant or performed confirmation of a candidate variant's effect on protein function, including variants in genes not previously described or firmly established as disease genes in the body of CHD literature: BMP10, CASZ1, ROCK1 and SMYD1. Two plausible variants in different genes were found to segregate in the same family in two instances suggesting oligogenic inheritance. These results highlight the need for functional validation and demonstrate that in the era of next-generation sequencing, multiplex families with isolated CHD can still bring high yield to the discovery of novel disease genes.

Unfavorable social determinants of health and mortality risk by cardiovascular disease status: Findings from a National Study of United States Adults.

BACKGROUND: The association between cumulative burden of unfavorable social determinants of health (SDoH) and all-cause mortality has not been assessed by atherosclerotic cardiovascular disease (ASCVD) status on a population level in the United States. METHODS: We assessed the association between cumulative social disadvantage and all-cause mortality by ASCVD status in the National Health Interview Survey, linked to the National Death Index. RESULTS: In models adjusted for established clinical risk factors, individuals experiencing the highest level of social disadvantage (SDoH-Q4) had over 1.5 (aHR = 1.55; 95%CI = 1.22, 1.96) and 2-fold (aHR = 2.21; 95% CI = 1.91, 2.56) fold increased risk of mortality relative to those with the most favorable social profile (SDoH-Q1), respectively for adults with and without ASCVD; those experiencing co-occurring ASCVD and high social disadvantage had up to four-fold higher risk of mortality (aHR = 3.81; 95%CI = 3.36, 4.32). CONCLUSIONS: These findings emphasize the importance of a healthcare model that prioritizes efforts to identify and address key social and environmental barriers to health and wellbeing, particularly in individuals experiencing the double jeopardy of clinical and social risk.

Effects of core muscles strengthening exercises with routine physical therapy on trunk balance in stroke patients: A randomized controlled trial.

OBJECTIVE: To compare the effects of core muscle strengthening exercises with and without routine physical therapy on trunk balance in chronic stroke patients. METHODS: The randomised controlled trial was conducted at Mubarak Medical Complex, Sargodha, Pakistan, from October 28, 2021, to April 28, 2022, and comprised patients of either gender with chronic stroke aged 40-60 years. The subjects were randomised using the lottery method into group A that was managed with routine physical therapy, and group B which was further managed with core strengthening exercises. The intervention comprised 4 sessions per week for 8 weeks. Outcome was measured using Trunk Impairment Scale and Time Up and Go test. Data was collected at baseline, week 4 and post-intervention. Data was analysed using SPSS 23. RESULTS: Of the 80 individuals screened, 74(92.5%) were included. There were 37(50%) patients in group A; 30(81%) males and 7(19%) females with mean age 56.73±2.37 years. The remaining 37(50%) patients were in group B; 27(73%) males and 10(27%) females with mean age 55.65±2.88 years. Trunk balance and functional mobility improved significantly post-intervention in both groups (p<0.05), but group B values were significantly better compared to group A values (p<0.05). CONCLUSIONS: Core muscle strengthening exercises combined with routine physical therapy were found to be more effective compared to routine physical therapy alone in chronic stroke patients for improving trunk balance and functional mobility. Registration Number: IRCT20211116053070N1.

The role of breathing techniques in the management of asthma: A systematic review.

Objective: To determine the effectiveness of breathing techniques in the management of asthma. METHODS: The systematic review was conducted from July 2021 to August 2022, and comprised search on PubMed, Google Scholar, and MEDLINE databases using the population-intervention-control-outcomes format and Boolean operators. Relevant randomised controlled trials published in the English language in the preceding 10 years were included. The last literature search was done on January 15, 2022. To evaluate the bias in studies, the Cochrane risk of bias tool was used. PEDro scale was used to assess the quality of the trials analysed. RESULTS: Of the 250 studies initially identified, 11(4.4%) random controlled trials were analysed in detail. The quality of methodology was high, and the studies reported significant improvement with the use of breathing techniques in symptoms of asthma and quality of life along with a decrease in the use of bronchodilators. Conclusion: Literature supported the use of breathing techniques in the management of asthma.

Prevalence of De Quervain disease in infant caregivers and its association with risk factors.

De Quervain's disease (DQD) is commonly reported in mothers during pregnancy up to delayed postpartum period. A cross-sectional study was conducted to assess infant caregivers who visited the paediatric outpatient department or vaccination centre in two hospitals of Lahore, during the months of May and June, 2021. A total of 190 subjects were interviewed directly and assessed by applying Finkelstein's test on both hands. Data was collected using Numeric Pain Rating Scale (NPRS) and Patient Rated Wrist Evaluation (PRWE) from positive subjects. They were asked to report their pain and difficulty level of the affected hand with worsened symptoms. The results exhibited 26.8% prevalence of DQD in a sample size of 190. Infant's age, lifting frequency and hand dominance were proved significant risk factors. However, caregiver's age, history of wrist pain, infant weight and relationship with infant were proved insignificant. Mean PRWE pain and functional scores were 23.14±7.72 and 18.53±6.09, respectively.

A descriptive investigation of clinical practice models used by cardiovascular genetic counselors in North America.

Cardiovascular genetic counseling has expanded as an established genetic counseling specialty over the last 20 years. Despite guidelines recommending genetic counseling for heritable cardiac diseases, there have been limited descriptions of the practice model types used for different clinical indications seen in this genetic counseling subspecialty. We aimed to describe current clinical practice models used by cardiovascular genetic counselors and to document practice model strengths, challenges, and areas for improvement. Genetic counselor respondents (n = 63) who self-reported seeing cardiovascular indications were recruited through the National Society of Genetic Counselors and Twitter. They completed a survey describing the types of healthcare professionals with whom they collaborate to see common cardiovascular indications, the nature of their collaboration, and their qualitative experiences with their practice models. Clinical indications addressed in this survey were hypertrophic cardiomyopathy, dilated cardiomyopathy, all other cardiomyopathies, arrhythmias, aortopathies, dyslipidemias, pulmonary arterial hypertension, and congenital heart defects. Data were analyzed using descriptive statistics and thematic analysis. We found that the composition of multidisciplinary provider practice models varies by indication, though general cardiologists were the most common collaborative provider reported. Practice models including geneticists were most common for aortopathy indications. Overall, the majority of respondents were satisfied with the practice models they reported. While a wide variety of successes, challenges, and areas for improvement of practice models were reported, collaboration, communication, and access to appropriate providers for patient care were consistent themes across these three questions. To our knowledge, this is the first description of practice models used by cardiovascular genetic counselors. The results of this study add to the knowledge of this specialty of genetic counseling and assist in understanding the needs and challenges for developing cardiovascular genetics programs and clinics.

Genetic counselors and congenital heart disease: Clinical roles, genetic testing practices, and perceived genetic testing utility.

Genetic counseling and genetic testing are essential for individuals with congenital heart disease/defects (CHD/CHDs). However, the clinical practices of genetic counselors (GCs) and their preferences for different CHD genetic testing strategies are previously unexplored. To address these gaps, GCs (n = 112) representing diverse specialties completed an online survey regarding their counseling and testing practices for syndromic CHD and apparently isolated/non-syndromic CHDs (iCHD). We found practice variability around family screening recommendations, with prenatal respondents reporting lower prevalence of this practice for iCHDs (p = 0.0004). We found that all specialties considered chromosomal microarray (CMA) the most common prioritized genetic test for syndromic and iCHD, while more prenatal respondents considered FISH and karyotype useful for iCHDs compared to postnatal respondents (p = 0.0002 and p = 0.002, respectively). Among postnatal respondents, a higher proportion considered exome/genome sequencing as useful compared to prenatal respondents (p = 0.0159); specifically, postnatal respondents' preference for exome/genome sequencing for iCHDs was ~2.6-fold higher than prenatal respondents. We estimated participants' assessment of utility for different genetic testing modalities for iCHDs and found that prenatal respondents assigned higher mean utility to FISH (p = 0.0002), karyotype (p = 0.0006), and CMA (p < 0.0001). There were relatively moderate to decreased utility scores for gene panels and exome/genome sequencing for iCHDs compared to cytogenetic testing, across all specialties. Overall, these results provide insight into GC practices and use of various genetic testing strategies for syndromic CHDs and iCHDs. Findings may help inform and/or standardize clinical practices for CHD genetic testing, though additional studies are warranted.

Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterized by thickening of the ventricular muscle without dilation and is often associated with dominant pathogenic variants in cardiac sarcomeric protein genes. Here, we report a family with two infants diagnosed with infantile-onset HCM and mitral valve dysplasia that led to death before one year of age. Using exome sequencing, we discovered that one of the affected children had a homozygous frameshift variant in Myosin light chain 2 (MYL2:NM_000432.3:c.431_432delCT: p.Pro144Argfs*57;MYL2-fs), which alters the last 20 amino acids of the protein and is predicted to impact the most C-terminal of the three EF-hand domains in MYL2. The parents are unaffected heterozygous carriers of the variant and the variant is absent in control cohorts from gnomAD. The absence of the phenotype in carriers and the infantile presentation of severe HCM is in contrast to HCM associated with dominant MYL2 variants. Immunohistochemical analysis of the ventricular muscle of the deceased patient with the MYL2-fs variant showed a marked reduction of MYL2 expression compared to an unaffected control. In vitro overexpression studies further indicate that the MYL2-fs variant is actively degraded. In contrast, an HCM-associated missense variant (MYL2:p.Gly162Arg) and three other MYL2 stop-gain variants (p.E22*, p.K62*, p.E97*) that result in loss of the EF domains are stably expressed but show impaired localization. The degradation of the MYL2-fs can be rescued by inhibiting the cell's proteasome function supporting a post-translational effect of the variant. In vivo rescue experiments with a Drosophila MYL2-homolog (Mlc2) knockdown model indicate that neither the MYL2-fs nor the MYL2:p.Gly162Arg variant supports normal cardiac function. The tools that we have generated provide a rapid screening platform for functional assessment of variants of unknown significance in MYL2. Our study supports an autosomal recessive model of inheritance for MYL2 loss-of-function variants in infantile HCM and highlights the variant-specific molecular differences found in MYL2-associated cardiomyopathy.

Can probiotics prevent dental caries?

DATA SOURCES: This study was a systematic review conducted in accordance with the Transparent Reporting of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search was undertaken using eleven databases including PubMed, Embase, Web of Sciences, The Cochrane Library, Ovid, Scopus, Sinomed, Sciencedirect, China National Knowledge Infrastructure (CNKI), Wanfang and Technology Periodicals Database (VIP). Additional studies were identified by searching the references of these studies. The search time was from inception to April 2022. STUDY SELECTION: The population, intervention, comparison and outcomes were considered. The level of evidence was limited to relevant randomised control trials (RCT) that answered the questions defined in this review. DATA EXTRACTION AND SYNTHESIS: Screening of eligible studies was conducted by two independent reviewers. Data was extracted using a standardised form which included information about the type of research, population, sample size of experimental group and control group, outcome measurements and results. Bias risk and evidence quality assessment were also assessed. Where appropriate, standard meta-analysis techniques were used to pool study results. The statistical analysis was performed using the RevMan5.4 software and the Stata16. Sensitivity analysis was performed on the combined analysis results. RESULTS: A total of 17 RCTs were identified to meet the eligibility criteria. The trials lasted between 2 and 24 weeks and were published after 2000. The studies encompassed 3781 preschool children divided into an experimental group (n = 2047) and a control group (n = 1734). The meta-analysis highlighted that incidence of dental caries could be prevented by probiotics. Caries incidence in preschool children was reduced in the Lactobacillus rhamnosus group. Streptococcus Mutans (S.mutans) count in saliva could be reduced however, probiotics could not reduce the number of S.mutans in dental plaque. CONCLUSIONS: The authors conclude that probiotics could prevent dental caries. Lactobacillus rhamnosus was identified as the more effective than other probiotics to reduce dental caries in preschool children.

The Responsibility to Recontact Research Participants after Reinterpretation of Genetic and Genomic Research Results.

The evidence base supporting genetic and genomic sequence-variant interpretations is continuously evolving. An inherent consequence is that a variant's clinical significance might be reinterpreted over time as new evidence emerges regarding its pathogenicity or lack thereof. This raises ethical, legal, and financial issues as to whether there is a responsibility to recontact research participants to provide updates on reinterpretations of variants after the initial analysis. There has been discussion concerning the extent of this obligation in the context of both research and clinical care. Although clinical recommendations have begun to emerge, guidance is lacking on the responsibilities of researchers to inform participants of reinterpreted results. To respond, an American Society of Human Genetics (ASHG) workgroup developed this position statement, which was approved by the ASHG Board in November 2018. The workgroup included representatives from the National Society of Genetic Counselors, the Canadian College of Medical Genetics, and the Canadian Association of Genetic Counsellors. The final statement includes twelve position statements that were endorsed or supported by the following organizations: Genetic Alliance, European Society of Human Genetics, Canadian Association of Genetic Counsellors, American Association of Anthropological Genetics, Executive Committee of the American Association of Physical Anthropologists, Canadian College of Medical Genetics, Human Genetics Society of Australasia, and National Society of Genetic Counselors.

Delayed medical care due to transportation barriers among adults with atherosclerotic cardiovascular disease.

BACKGROUND: In patients with atherosclerotic cardiovascular disease (ASCVD), barriers related to transportation may impair access to care, with potential implications for prognosis. Although few studies have explored transportation barriers among patients with ASCVD, the correlates of delayed care due to transportation barriers have not been examined in this population. We aimed to examine this in U.S. patients with ASCVD using nationally representative data. METHODS: Using data from the 2009-2018 National Health Interview Survey, we estimated the self-reported prevalence of delayed medical care due to transportation barriers among adults with ASCVD, overall and by sociodemographic characteristics. Logistic regression was used to examine the association between various sociodemographic characteristics and delayed care due to transportation barriers. RESULTS: Among adults with ASCVD, 4.5% (95% CI; 4.2, 4.8) or ∼876,000 annually reported delayed care due to transportation barriers. Income (low-income: odds ratio [OR] 4.43, 95% CI [3.04, 6.46]; lowest-income: OR 6.35, 95% CI [4.36, 9.23]) and Medicaid insurance (OR 4.53; 95% CI [3.27, 6.29]) were strongly associated with delayed care due to transportation barriers. Additionally, younger individuals, women, non-Hispanic Black adults, and those from the U.S. South or Midwest, had higher odds of reporting delayed care due to transportation barriers. CONCLUSIONS: Approximately 5% of adults with ASCVD experience delayed care due to transportation barriers. Vulnerable groups include young adults, women, low-income people, and those with public/no insurance. Future studies should analyze the feasibility and potential benefits of interventions such as use of telehealth, mobile clinics, and provision of transportation among patients with ASCVD in the U.S.

Management of amended variant classification laboratory reports by genetic counselors in the United States and Canada: An exploratory study.

For the past two decades, the guidelines put forth by the American College of Medical Genetics and Genomics (ACMG) detailing providers' clinical responsibility to recontact patients have remained mostly unchanged, despite evolving variant interpretation practices which have yielded substantial rates of reclassification and amended reports. In fact, there is little information regarding genetic counselors' roles in informing patients of reclassified variants, or the process by which these amended reports are currently being handled. In this study, we developed a survey to measure current experiences with amended variant reports and preferences for ideal management, which was completed by 96 genetic counselors from the United States and Canada. All respondents indicated they were the individuals responsible for disclosing initial positive genetic testing results and any clinically actionable reclassified variant reports, and over half (56%) received at least a few amended variant reports each year. Nearly a quarter (20/87) of respondents reported having a standard operating procedure (SOP) for managing amended reports and all were very satisfied (12/20) or satisfied (8/20) with the SOP. Of those without a protocol, 76% (51/67) would prefer to have an SOP implemented. Respondents reported a preference for (1) laboratories to send amended variant reports directly to the genetic counselor or ordering physician through email or an online portal, and (2) notification to patients ideally occurring through a phone call. In the event that the original genetic counselor is inaccessible, respondents reported a preference for reports to be sent directly to another genetic counselor (36%) on the team or the clinic in general (27%). Information from this study provides insight into the current practices of genetic counselors as applied to amended reports and what improvements may increase the efficiency of the reporting process. Moreover, these results suggest a need for an updated statement addressing duty to recontact, specifically as it applies to amended variant reports.

Assessing genetic counselors' graduate school education and training in congenital heart defects.

Genetic counselors are one of the many providers involved in caring for patients with congenital heart defects (CHDs); however, little is known about the cardiovascular genetics training they receive by their graduate programs. To explore the recalled education experiences regarding CHDs by practicing genetic counselors, we surveyed graduates of programs primarily accredited by the American Council on Genetic Counseling (ACGC) about their graduate training in this area, the depth of CHD-specific education they received, and whether CHDs are a substantial referral indication in their current practice. Genetic counselors were recruited from the National Society of Genetic Counselors and Twitter (n = 112), and participants reflecting multiple specialties and 35 graduate programs completed an online survey which included questions about fieldwork placements and lectures in cardiovascular genetics, exposure to classification schemes regarding cardiac embryology, and education in counseling strategies for CHDs and CHD-related topics during their graduate training. When asked whether CHDs are a substantial referral indication seen in their current practice, 55% (62/112) responded yes. Most participants (79%, 88/112) recalled receiving some education about CHDs, but 91% (80/88) reported receiving little to no education regarding embryologic classification of CHDs and how to apply classification schemes to their counseling. Both participating prenatal and pediatric GCs reported that CHDs can be a common referral indication, yet they reported receiving limited education on teratogens associated with CHDs, family screening recommendations, and recurrence risk counseling for CHDs. Based on participant responses, the majority of respondents reported receiving sufficient education on syndromes with CHDs which can be beneficial in specialties such as pediatrics. This exploratory study provides insight into opportunities to further support genetic counseling educational opportunities for CHDs. These findings suggest genetic counseling graduate programs could consider implementing education on CHD counseling strategies as a standardized component of the curriculum and that practicing genetic counselors could benefit from educational opportunities and resources with updated information on this topic.

Genetic counseling for congenital heart disease - Practice resource of the National Society of Genetic Counselors.

Congenital heart disease (CHD) is an indication which spans multiple specialties across various genetic counseling practices. This practice resource aims to provide guidance on key considerations when approaching counseling for this particular indication while recognizing the rapidly changing landscape of knowledge within this domain. This resource was developed with consensus from a diverse group of certified genetic counselors utilizing literature relevant for CHD genetic counseling practice and is aimed at supporting genetic counselors who encounter this indication in their practice both pre- and postnatally.

Assessing dentist and dental student knowledge of and attitudes towards shared decision-making in the United Kingdom.

INTRODUCTION: Shared decision-making (SDM) is a partnership between healthcare professionals and patients when choosing care. AIM: To measure knowledge of, and attitudes to, SDM amongst undergraduate dental students and dentists in the UK. DESIGN AND SETTING: Cross-sectional online questionnaire for 4th and 5th year dental students and dentists in the UK. MATERIALS AND METHODS: The questionnaire included attitudinal questions, knowledge of SDM relative to the evidence base and preferred approach to decision-making. The questionnaire identified perceived learning needs and preferred method for SDM teaching for dentists and dental students. Respondents were invited to participate via social media, mailing lists and CPD courses. RESULTS: Respondents included 266 undergraduates and 130 dentists. SDM was defined by the people involved, components of the discussion, approach to decision-making and expected outcome. Attitudes to SDM were generally positive although concerns were expressed about patients wanting professionals to make the decision, straying from the professionals' preferred option and compatibility with clinical guidelines. Respondents reported a preference for decision-making to involve patients, but this tended to be an informative rather than deliberative approach. Respondents were least sure of the evidence about the impact of SDM on adherence, choices and health outcomes, and the best approach to risk communication. Respondents from both groups reported an interest in learning more about SDM and its integration into clinical practice. CONCLUSION: Knowledge of, and attitude to, SDM in UK dentists and dental undergraduates is generally positive; however, a demand for further SDM training was identified.

Reclassification of Variants of Uncertain Significance in Children with Inherited Arrhythmia Syndromes is Predicted by Clinical Factors.

Genetic testing is important to augment clinical diagnosis and inform management of inherited arrhythmias syndromes (IAS), but variants of uncertain significance (VUS) are common and remain a challenge in clinical practice. In 2015, American College of Medical Genetics (ACMG) published updated guidelines for interpretation of genetic results. Despite increasing understanding of human genomic variation, there are no guidelines for reinterpretation of prior genetic test results. Patients at a single tertiary children's hospital with genetic testing for an IAS that demonstrated a VUS were re-evaluated using 2015 ACMG guidelines, clinical information, and publically available databases. Search of the electronic medical record identified 116 patients with genetic testing results available, and 24/116 (21%) harbored a VUS for an IAS. 23 unique VUS were evaluated from 12 genes. Over half of the VUS (12/23 (52%)) were reclassified using 2015 criteria, and 8 (35%) changed to pathogenic and 4 (17%) to benign. Relative risk of reclassification of VUS to a pathogenic variant in a patient with confirmed clinical diagnosis was 4.1 (95% CI 1.23-15.4). Reclassification was not associated with initial testing year. These data demonstrate 52% of VUS in children with IAS are reclassified with application of 2015 ACMG guidelines. Strength of phenotyping is associated with eventual pathogenic classification of genetic variants and periodic re-evaluation of VUS identified on genetic testing for IAS is warranted.

A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20.

Congenital heart defects involving left-sided lesions (LSLs) are relatively common birth defects with substantial morbidity and mortality. Previous studies have suggested a high heritability with a complex genetic architecture, such that only a few LSL loci have been identified. We performed a genome-wide case-control association study to address the role of common variants using a discovery cohort of 778 cases and 2756 controls. We identified a genome-wide significant association mapping to a 200 kb region on chromosome 20q11 [P= 1.72 × 10-8 for rs3746446; imputed Single Nucleotide Polymorphism (SNP) rs6088703 P= 3.01 × 10-9, odds ratio (OR)= 1.6 for both]. This result was supported by transmission disequilibrium analyses using a subset of 541 case families (lowest P in region= 4.51 × 10-5, OR= 1.5). Replication in a cohort of 367 LSL cases and 5159 controls showed nominal association (P= 0.03 for rs3746446) resulting in P= 9.49 × 10-9 for rs3746446 upon meta-analysis of the combined cohorts. In addition, a group of seven SNPs on chromosome 1q21.3 met threshold for suggestive association (lowest P= 9.35 × 10-7 for rs12045807). Both regions include genes involved in cardiac development-MYH7B/miR499A on chromosome 20 and CTSK, CTSS and ARNT on chromosome 1. Genome-wide heritability analysis using case-control genotyped SNPs suggested that the mean heritability of LSLs attributable to common variants is moderately high ([Formula: see text] range= 0.26-0.34) and consistent with previous assertions. These results provide evidence for the role of common variation in LSLs, proffer new genes as potential biological candidates, and give further insight to the complex genetic architecture of congenital heart disease.

A cohort study of multiple families with FBN1 p.R650C variant, ectopia lentis, and low but not absent risk for aortopathy.

Marfan syndrome is a multisystem disease with cardiovascular, ophthalmologic, and skeletal features. Diagnosis is made clinically with emphasis on presence of aortic root dilation and ectopia lentis (EL). Most individuals meeting these criteria have a pathogenic variant in FBN1, usually unique or observed rarely. Individuals with EL alone may also have FBN1 pathogenic variants, and the risk for aortic disease is not well known. We identified a unique cohort of 31 individuals (mean age 29, range 2-78) from nine families ascertained by a proband with EL alone, who had the same FBN1 p.R650C variant. Comparison was made to individuals with Marfan syndrome (n = 103 from 97 families) at our institution. Those with the p.R650C variant had few skeletal features of Marfan syndrome. Age of onset of EL was later compared to others with cysteine variant changes. Aortic root dilation occurred in 4/16 (25%) of the p.R650C group versus 71/83 (86%) in the comparator group (p < 0.001) and dissection or replacement in 1/31 (3%) versus 20/103 (19%; p < 0.04). Aortic root Z scores were much lower in the p.R650C (0.34 ± 1.70) versus the comparator (2.99 ± 2.54; p < 0.0002). Kaplan-Meier failure curves for aortic root dilation demonstrated later age of onset and differed significantly for incidence rate ratio (comparator vs. p.R650C = 5.35, CI 1.84-21.17; p = 0.0001). Individuals with p.R650C predominantly have EL, but do have risk for aortic dilation at ages later than typical for Marfan syndrome in general and for cysteine changes specifically. Surveillance for aortic dilation is required but may occur less frequently.

Assessment of large copy number variants in patients with apparently isolated congenital left-sided cardiac lesions reveals clinically relevant genomic events.

Congenital left-sided cardiac lesions (LSLs) are a significant contributor to the mortality and morbidity of congenital heart disease (CHD). Structural copy number variants (CNVs) have been implicated in LSL without extra-cardiac features; however, non-penetrance and variable expressivity have created uncertainty over the use of CNV analyses in such patients. High-density SNP microarray genotyping data were used to infer large, likely-pathogenic, autosomal CNVs in a cohort of 1,139 probands with LSL and their families. CNVs were molecularly confirmed and the medical records of individual carriers reviewed. The gene content of novel CNVs was then compared with public CNV data from CHD patients. Large CNVs (>1 MB) were observed in 33 probands (∼3%). Six of these were de novo and 14 were not observed in the only available parent sample. Associated cardiac phenotypes spanned a broad spectrum without clear predilection. Candidate CNVs were largely non-recurrent, associated with heterozygous loss of copy number, and overlapped known CHD genomic regions. Novel CNV regions were enriched for cardiac development genes, including seven that have not been previously associated with human CHD. CNV analysis can be a clinically useful and molecularly informative tool in LSLs without obvious extra-cardiac defects, and may identify a clinically relevant genomic disorder in a small but important proportion of these individuals.

At the Heart of the Pregnancy: What Prenatal and Cardiovascular Genetic Counselors Need to Know about Maternal Heart Disease.

In the last decade, an increasing number of cardiac conditions have been shown to have a genetic basis. Cardiovascular genetic counseling has emerged as a subspecialty aiming to identify unaffected at-risk individuals. An important sector of this at-risk population also includes expectant mothers, in whom unique clinical challenges may arise. Genetic counselors, especially those in cardiovascular and prenatal settings, have an opportunity to identify and assist women who may benefit from cardiovascular care during pregnancy. This paper provides basic management and genetic evaluation principles for affected women, as well as guidance on identifying those who are at risk. We provide considerations for cardiac surveillance in pregnancy and the post-partum period. Finally, key psychosocial issues that appraise how to best provide support to at risk women as they make informed decisions are discussed. We propose that a team approach including cardiology, maternal fetal medicine, and genetic counseling best serves this patient population. Ongoing questions addressing an evidence based approach to cardiovascular genetic conditions in pregnancy still remain. Thus, well-designed research protocols are essential to mark progress in this area.