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Objective: Persons with congenital heart disease (CHD) are at increased risk of neurodevelopmental disabilities, including impairments to executive function. Sulcal pattern features correlate with executive function in adolescents with single‐ventricle heart disease and tetralogy of Fallot. However, the interaction of sulcal pattern features with genetic and participant factors in predicting executive dysfunction is unknown. Methods: We studied sulcal pattern features, participant factors, and genetic risk for executive function impairment in a cohort with multiple CHD types using stepwise linear regression and machine learning. Results: Genetic factors, including predicted damaging de novo or rare inherited variants in neurodevelopmental disabilities risk genes, apolipoprotein E genotype, and principal components of sulcal pattern features were associated with executive function measures after adjusting for age at testing, sex, mother's education, and biventricular versus single‐ventricle CHD in a linear regression model. Using regression trees and bootstrap validation, younger participant age and larger alterations in sulcal pattern features were consistently identified as important predictors of decreased cognitive flexibility with left hemisphere graph topology often selected as the most important predictor. Inclusion of both sulcal pattern and genetic factors improved model fit compared to either alone. Interpretation: We conclude that sulcal measures remain important predictors of cognitive flexibility, and the model predicting executive outcomes is improved by inclusion of potential genetic sources of neurodevelopmental risk. If confirmed, measures of sulcal patterning may serve as early imaging biomarkers to identify those at heightened risk for future neurodevelopmental disabilities. [ABSTRACT FROM AUTHOR]

Treatment‐resistant epilepsy is among the most serious complications of cardiofaciocutaneous syndrome (CFCS), a rare disorder caused by germline variants in the RAS‐MAPK signaling pathway. This study analyzed the clinical characteristics of epilepsy and response to anti‐seizure medications (ASMs) in a multinational CFCS cohort. A caregiver survey provided data regarding seizure history, use of ASMs and other treatment approaches, adverse effects, caregiver perception of treatment response, and neurological disease burden impact among individuals with CFCS. Results from 138 survey responses were quantitatively analyzed in conjunction with molecular genetic results and neurological records. The disease burden impact of CFCS was higher among individuals with epilepsy (n = 74/138), especially those with more severe seizure presentation. Oxcarbazepine, a sodium‐channel blocker, had the best seizure control profile with relatively infrequent adverse effects. The most commonly prescribed ASM, levetiracetam, demonstrated comparatively poor seizure control. ASM efficacy was generally similar for individuals with BRAF and MAP2K1 gene variants. The high proportion of patients with CFCS who experienced poor seizure control despite use of multiple ASMs highlights a substantial unmet treatment need. Prospective study of ASM efficacy and clinical trials of therapies to attenuate RAS‐MAPK signaling may improve avenues for clinical management. [ABSTRACT FROM AUTHOR]

Purpose: This study presents an analysis of language skills in individuals with Noonan syndrome (NS), an autosomal dominant genetic disorder. We investigated whether the language impairments affecting some individuals arise from deficits specifically within the linguistic system or whether they are associated with cognitive, perceptual, and motor factors. Comparisons of language abilities among the different NS genotypes were also conducted. Method: Sixty-six children and adolescents with NS were evaluated using standardized speech, language, and literacy assessments. Additional cognitive, perceptual, and motor tasks were administered to examine the relation of these factors to language development. Genotype was noted for those who underwent genetic testing. Results: Language impairments were more frequent in NS than in the general population and were associated with higher risk for reading and spelling difficulties. Language was significantly correlated with nonverbal cognition, hearing ability, articulation, motor dexterity, and phonological memory. Genotype analyses suggest that the higher performance of "SOS1"-positive than "PTPN11"-positive individuals on language tasks was largely mediated by differences in cognitive ability. Conclusions: Our results indicate that variation in language skill in NS is closely related to cognitive, perceptual, and motor factors. It does not appear that specific aspects of language are selectively affected in this syndrome.

Two Dartmouth Medical School (New Hampshire) medical students and their faculty sponsor collaborated to develop an elective course in women's health. Development and implementation of this course and the process by which it was later made part of the required curriculum are described. The success of the effort highlights the crucial role students can play in reforming medical curricula. (Author/MSE)

Study of monogenic mitochondrial cardiomyopathies may yield insights into mitochondrial roles in cardiac development and disease. Here, we combined patient-derived and genetically engineered induced pluripotent stem cells (iPSCs) with tissue engineering to elucidate the pathophysiology underlying the cardiomyopathy of Barth syndrome (BTHS), a mitochondrial disorder caused by mutation of the gene encoding tafazzin (TAZ). Using BTHS iPSC-derived cardiomyocytes (iPSC-CMs), we defined metabolic, structural and functional abnormalities associated with TAZ mutation. BTHS iPSC-CMs assembled sparse and irregular sarcomeres, and engineered BTHS 'heart-on-chip' tissues contracted weakly. Gene replacement and genome editing demonstrated that TAZ mutation is necessary and sufficient for these phenotypes. Sarcomere assembly and myocardial contraction abnormalities occurred in the context of normal whole-cell ATP levels. Excess levels of reactive oxygen species mechanistically linked TAZ mutation to impaired cardiomyocyte function. Our study provides new insights into the pathogenesis of Barth syndrome, suggests new treatment strategies and advances iPSC-based in vitro modeling of cardiomyopathy., BTHS is an X-linked cardiac and skeletal mitochondrial myopathy caused by mutation of the gene encoding tafazzin (1), an acyltransferase responsible for normal acylation of cardiolipin, the major phospholipid of [...]

The Catholic Church has a long history of conducting schools as part of its mission to evangelize. This paper will contend that in order for teachers to implement the evangelistic mission of Catholic schools, they themselves need an integral formation that puts every dimension of their human nature—body, emotions, will, and intellect—in ongoing communion with Christ and His Church. A brief examination of the impact of secularization in the United States on the Catholic school mission indicates that teachers are inadequately formed to fulfill that mission. Contemplative practice, a common faith formation practice used for Catholic school teachers, will be evaluated as insufficient for achieving its goal because it does not fully account for the way God created human beings. Contemplative practice relies heavily on the work of John Dewey, who applied inadequate anthropological principles to the task of human learning and teacher education. By contrast, faith formation efforts that account for human nature engage both the intellectus and the ratio, and in so doing engage the teacher's whole integrated person. Teacher faith formation can facilitate the teacher's encounter with God, allowing Him to form her, by providing analogical encounters with Him through the transcendentals and sacramental encounters with Him in the liturgy. [ABSTRACT FROM AUTHOR]

Purpose: This study presents an analysis of language skills in individuals with Noonan syndrome (NS), an autosomal dominant genetic disorder. We investigated whether the language impairments affecting some individuals arise from deficits specifically within the linguistic system or whether they are associated with cognitive, perceptual, and motor factors. Comparisons of language abilities among the different NS genotypes were also conducted. Method: Sixty-six children and adolescents with NS were evaluated using standardized speech, language, and literacy assessments. Additional cognitive, perceptual, and motor tasks were administered to examine the relation of these factors to language development. Genotype was noted for those who underwent genetic testing. Results: Language impairments were more frequent in NS than in the general population and were associated with higher risk for reading and spelling difficulties. Language was significantly correlated with nonverbal cognition, hearing ability, articulation, motor dexterity, and phonological memory. Genotype analyses suggest that the higher performance of SOSJ-positive than PTPNJJ-positive individuals on language tasks was largely mediated by differences in cognitive ability. Conclusions: Our results indicate that variation in language skill in NS is closely related to cognitive, perceptual, and motor factors. It does not appear that specific aspects of language are selectively affected in this syndrome. KEY WORDS: Noonan syndrome, language, articulation, literacy, developmental disorders, Noonan syndrome (NS) is a multiple congenital anomaly syndrome first described by Noonan and Ehmke (1963). The incidence is estimated to be 1:1,000 to 1:2,500 live births (Mendez, Opitz, & [...]

RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen‐activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed. [ABSTRACT FROM AUTHOR]

Several studies are conducted to determine the molecular basis, as well as the after effects of the craniofacial disorder, branchio-oculo-facial syndrome (BOFS). The analysis concludes that BOFS is normally caused by the mutations involving the TFAP2A gene.

A study was undertaken to ascertain whether genetic history played any part in the onset of cardiac hypertrophy among children. Results revealed that most of the cases of childhood hypertrophy had genetic causes and called for evaluation of family history.

The clinical and molecular characterization of people presenting symptoms of the Loeys-Dietz syndrome was undertaken to distinguish them from the similar symptoms of vascular Ehlers-Danlos syndrome. Aggressive arterial aneurysms, such as thoracic aortic aneurysms and aortic dissection, are found to be caused by mutations in the genes encoding the transforming growth factor beta (TGF-beta) I or II, a distinguishing feature of the Loeys-Dietz syndrome.

Pulmonary vein stenosis (PVS) is a rare, frequently lethal disease with heterogeneous phenotypes and an unclear etiology. Limited studies have reported associations between PVS and congenital heart disease (CHD), chronic lung disease (CLD), and/or prematurity; however, to date, there have been no studies that report detailed clinical syndromic phenotypes and the potential role of genetics in PVS. An existing registry of multivessel PVS patients seen at Boston Children's Hospital (BCH) was queried between August 2006 and January 2017 for all existing genetic testing data on these patients. PVS was defined as an intraluminal pulmonary venous obstruction in ≥2 vessels with mean pressure gradients > 4 mmHg. One-hundred-and-fifty-seven patients (46% female, with a median age at PVS diagnosis of 3 months) formed the cohort. Seventy-one (45%) patients had available genetic testing information. Of the 71 patients, a likely genetic diagnosis was found in 23 (32%) patients: 13 (57%) were diagnosed with Trisomy 21 (T21), five (22%) with Smith-Lemli-Opitz Syndrome, five (22%) had other pathologic genetic disease, and 24 (33%) had variants of unknown significance. The majority of 13 patients with T21 and PVS had common atrioventricular canal (CAVC) (10, 77%) and all had severe pulmonary hypertension (PHTN), which led to their PVS diagnosis. In our study, PVS was associated with T21, the majority of whom also had CAVC and PHTN. Therefore, complete assessment of the pulmonary veins should be considered for all T21 patients, especially those with CAVC presenting with PHTN. Furthermore, prospective standardized genetic testing with detailed clinical phenotyping may prove informative about potential genetic etiologies of PVS. [ABSTRACT FROM AUTHOR]

Introduction: Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined.Methods and Results: We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10-5; U.S. cohort, P = 2.2×10-13).Conclusion: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy. [ABSTRACT FROM AUTHOR]