Heritable human genome editing: Research progress, ethical considerations, and hurdles to clinical practice.

Our genome at conception determines much of our health as an adult. Most human diseases have a heritable component and thus may be preventable through heritable genome editing. Preventing disease from the beginning of life before irreversible damage has occurred is an admirable goal, but the path to fruition remains unclear. Here, we review the significant scientific contributions to the field of human heritable genome editing, the unique ethical challenges that cannot be overlooked, and the hurdles that must be overcome prior to translating these technologies into clinical practice.

18S rRNA methyltransferases DIMT1 and BUD23 drive intergenerational hormesis.

Heritable non-genetic information can regulate a variety of complex phenotypes. However, what specific non-genetic cues are transmitted from parents to their descendants are poorly understood. Here, we perform metabolic methyl-labeling experiments to track the heritable transmission of methylation from ancestors to their descendants in the nematode Caenorhabditis elegans (C. elegans). We find heritable methylation in DNA, RNA, proteins, and lipids. We find that parental starvation elicits reduced fertility, increased heat stress resistance, and extended longevity in fed, naïve progeny. This intergenerational hormesis is accompanied by a heritable increase in N6'-dimethyl adenosine (m6,2A) on the 18S ribosomal RNA at adenosines 1735 and 1736. We identified DIMT-1/DIMT1 as the m6,2A and BUD-23/BUD23 as the m7G methyltransferases in C. elegans that are both required for intergenerational hormesis, while other rRNA methyltransferases are dispensable. This study labels and tracks heritable non-genetic material across generations and demonstrates the importance of rRNA methylation for regulating epigenetic inheritance.

Callus-specific CRISPR/Cas9 system to increase heritable gene mutations in maize.

MAIN CONCLUSION: A callus-specific CRISPR/Cas9 (CSC) system with Cas9 gene driven by the promoters of ZmCTA1 and ZmPLTP reduces somatic mutations and improves the production of heritable mutations in maize. The CRISPR/Cas9 system, due to its editing accuracy, provides an excellent tool for crop genetic breeding. Nevertheless, the traditional design utilizing CRISPR/Cas9 with ubiquitous expression leads to an abundance of somatic mutations, thereby complicating the detection of heritable mutations. We constructed a callus-specific CRISPR/Cas9 (CSC) system using callus-specific promoters of maize Chitinase A1 and Phospholipid transferase protein (pZmCTA1 and pZmPLTP) to drive Cas9 expression, and the target gene chosen for this study was the bZIP transcription factor Opaque2 (O2). The CRISPR/Cas9 system driven by the maize Ubiquitin promoter (pZmUbi) was employed as a comparative control. Editing efficiency analysis based on high-throughput tracking of mutations (Hi-TOM) showed that the CSC systems generated more target gene mutations than the ubiquitously expressed CRISPR/Cas9 (UC) system in calli. Transgenic plants were generated for the CSC and UC systems. We found that the CSC systems generated fewer target gene mutations than the UC system in the T0 seedlings but reduced the influence of somatic mutations. Nearly 100% of mutations in the T1 generation generated by the CSC systems were derived from the T0 plants. Only 6.3-16.7% of T1 mutations generated by the UC system were from the T0 generation. Our results demonstrated that the CSC system consistently produced more stable, heritable mutants in the subsequent generation, suggesting its potential application across various crops to facilitate the genetic breeding of desired mutations.

National registry insights on genetic aortopathies and thoracic endovascular aortic interventions.

OBJECTIVE: Thoracic endovascular aortic repair (TEVAR) in patients with genetic aortopathies (GA) is controversial, given concerns of durability. We describe characteristics and outcomes after TEVAR in patients with GA. METHODS: All patients undergoing TEVAR between 2010 and 2023 in the Vascular Quality Iniatitive were identified and categorized as having a GA or not. Demographics, baseline, and procedural characteristics were compared among groups. Multivariable logistic regression was used to evaluate the independent association of GA with postoperative outcomes. Kaplan-Meier methods and multivariable Cox regression analyses were used to evaluate 5-year survival and 2-year reinterventions. RESULTS: Of 19,340 patients, 304 (1.6%) had GA (87% Marfan syndrome, 9% Loeys-Dietz syndrome, and 4% vascular Ehlers-Danlos syndrome). Compared with patients without GA, patients with GA were younger (50 years [interquartile range, 37-72 years] vs 70 years [interquartile range, 61-77 years]), more often presented with acute dissection (28% vs 18%), postdissection aneurysm (48% vs 17%), had a symptomatic presentation (50% vs 39%), and were less likely to have degenerative aneurysms (18% vs 47%) or penetrating aortic ulcer (and intramural hematoma) (3% vs 13%) (all P < .001). Patients with GA were more likely to have prior repair of the ascending aorta/arch (open, 56% vs 11% [P < .001]; endovascular, 5.6% vs 2.1% [P = .017]) or the descending thoracic aorta (open, 12% vs 2% [P = .007]; endovascular, 8.2% vs 3.6% [P = .011]). No significant differences were found in prior abdominal suprarenal repairs; however, patients with GA had more prior open infrarenal repairs (5.3% vs 3.2%), but fewer prior endovascular infrarenal repairs (3.3% vs 5.5%) (all P < .05). After adjusting for demographics, comorbidities, and disease characteristics, patients with GA had similar odds of perioperative mortality (4.6% vs 7.0%; adjusted odds ratio [aOR], 1.1; 95% confidence interval [CI], 0.57-1.9; P = .75), any in-hospital complication (26% vs 23%; aOR, 1.24; 95% CI, 0.92-1.6; P = .14), or in-hospital reintervention (13% vs 8.3%; aOR, 1.25; 95% CI, 0.84-1.80; P = .25) compared with patients without GA. However, patients with GA had a higher likelihood of postoperative vasopressors (33% vs 27%; aOR, 1.44; 95% CI, 1.1-1.9; P = .006) and transfusion (25% vs 23%; aOR, 1.39; 95% CI, 1.03-1.9; P = .006). The 2-year reintervention rates were higher in patients with GA (25% vs 13%; adjusted hazard ratio, 1.99; 95% CI, 1.4-2.9; P < .001), but 5-year survival was similar (81% vs 74%; adjusted hazard ratio, 1.02; 95% CI, 0.70-1.50; P = .1). CONCLUSIONS: TEVAR for patients with GA seemed to be safe initially, with similar odds for in-hospital complications, in-hospital reinterventions, and perioperative mortality, as well as similar hazards for 5-year mortality compared with patients without GA. However, patients with GA had higher 2-year reintervention rates. Future studies should assess long-term durability after TEVAR compared with the recommended open repair to appropriately weigh the risks and benefits of endovascular treatment in patients with GA.

Impact of valve-sparing aortic root replacement on aortic fluid dynamics and biomechanics in patients with syndromic heritable thoracic aortic disease.

OBJECTIVES: Patients with syndromic heritable thoracic aortic diseases (sHTAD) who underwent prophylactic aortic root replacement are at high risk of distal aortic events, but the underlying mechanisms are poorly understood. This prospective, longitudinal study aims to assess the impact of valve-sparing aortic root replacement (VSARR) on aortic fluid dynamics and biomechanics in these patients, and to examine whether they present altered haemodynamics or biomechanics prior to surgery compared to sHTAD patients with no indication for surgery (sHTAD-NSx) and healthy volunteers (HV). METHODS: Sixteen patients with Marfan or Loeys-Dietz syndrome underwent two 4D flow CMR studies before (sHTAD-preSx) and after VSARR (sHTAD-postSx). Two age, sex and BSA matched cohorts of 40 HV and 16 sHTAD-NSx patients with available 4D flow CMR, were selected for comparison. In-plane rotational flow (IRF), systolic flow reversal ratio (SFRR), wall shear stress (WSS), pulse wave velocity (PWV) and aortic strain were analysed in the ascending (AscAo) and descending aorta (DescAo). RESULTS: All patients with sHTAD presented altered haemodynamics and increased aortic stiffness (p<0.05) compared to HV, both in the AscAo (median PWV 7.4 in sHTAD-NSx; 6.8 in sHTAD-preSx; 4.9m/s in HV) and DescAo (median PWV 9.1 in sHTAD-NSx; 8.1 in sHTAD-preSx; 6.3m/s in HV). Patients awaiting VSARR had markedly reduced in-plane (median IRF -2.2 vs 10.4 cm2/s in HV, p=0.001), but increased through-plane flow rotation (median SFRR 7.8 vs 3.8% in HV, p=0.002), and decreased WSS (0.36 vs 0.47N/m2 in HV, p=0.004) in the proximal DescAo. After VSARR, proximal DescAo in-plane rotational flow (p=0.010) and circumferential WSS increased (p=0.011), no longer differing from HV, but through-plane rotational flow, axial WSS and stiffness remained altered. Patients in which aortic tortuosity was reduced after surgery showed greater post-surgical increase in IRF compared to those in which tortuosity increased (median IRF increase 18.1 vs 3.3cm²/s, p=0.047). Most AscAo flow alterations were restored to physiological values after VSARR. CONCLUSIONS: In patients with sHTAD, VSARR partially restores downstream fluid dynamics to physiological levels. However, some flow disturbances and increased stiffness persist in the proximal DescAo. Further longitudinal studies are needed to evaluate whether persistent alterations contribute to post-surgical risk.

The RNA-DNA world and the emergence of DNA-encoded heritable traits.

The RNA world hypothesis confers a central role to RNA molecules in information encoding and catalysis. Even though evidence in support of this hypothesis has accumulated from both experiments and computational modelling, the transition from an RNA world to a world where heritable genetic information is encoded in DNA remains an open question. Recent experiments show that both RNA and DNA templates can extend complementary primers using free RNA/DNA nucleotides, either non-enzymatically or in the presence of a replicase ribozyme. Guided by these experiments, we analyse protocellular evolution with an expanded set of reaction pathways made possible through the presence of DNA nucleotides. By encapsulating these reactions inside three different types of protocellular compartments, each subject to distinct modes of selection, we show how protocells containing DNA-encoded replicases in low copy numbers and replicases in high copy numbers can dominate the population. This is facilitated by a reaction that leads to auto-catalytic synthesis of replicase ribozymes from DNA templates encoding the replicase after the chance emergence of a replicase through non-enzymatic reactions. Our work unveils a pathway for the transition from an RNA world to a mixed RNA-DNA world characterized by Darwinian evolution, where DNA sequences encode heritable phenotypes.

Parent-offspring similarity in hunger and thirst sensations.

The internal (i.e., interoceptive) sensations that characterise hunger vary between people, and this may also be the case for thirst, although it has not been so well explored. There are probably both heritable and learning-based causes for this interoceptive variability. Consequently, it would seem plausible that parents and their offspring would have more similar patterns of hunger and thirst than pairs of strangers. We tested this idea, in addition to exploring its potential moderating variables, by studying the similarity of self-reported hunger and thirst sensations in 170 students and their primary caregivers from childhood. Both students and caregivers completed the same online-survey, covering hunger and thirst sensations, beliefs about the causes of hunger and thirst, the Three Factor Eating Questionnaire (revised) and demographic data. We find evidence of robust student-caregiver similarity in interoceptive hunger and thirst sensations (medium effect sizes), with these being moderated by caregiver beliefs about the homeostatic nature of each state (medium effect sizes). This suggests a potential role for caregivers in the development of their offspring's interoceptive cues for hunger and for thirst. In addition, thirst, like hunger, appears to be multidimensional, and varies between people. The implications of these findings are discussed.

Computed tomographic findings in TBX4 mutation: a common cause of severe pulmonary artery hypertension in children.

BACKGROUND: Mutations in the T-Box 4 (TBX4) gene are a lesser-known cause of heritable pulmonary arterial hypertension (PAH). Patients with heritable PAH typically have worse outcomes when compared with patients with idiopathic PAH, yet little is known about the phenotypical presentation of this mutation. OBJECTIVE: This article reviews the pattern of chest CT findings in pediatric patients with PAH and TBX4 mutations and compares their radiographic presentation with those of age-matched patients with PAH but without TBX4 mutations. MATERIALS AND METHODS: A retrospective chart review of the pulmonary arterial hypertension database was performed. Pediatric patients with PAH-confirmed TBX4 mutations and an available high CT were included. Fifteen (9 females) patients met the inclusion criteria. Fourteen (8 females) age-matched controls with diagnosed PAH but without TBX4 mutations were also evaluated. The median age at diagnosis was 7.4 years (range: 0.1-16.4 years). Demographic information and clinical outcomes were collected. CTs of the chest were reviewed for multiple airway, parenchymal, and structural abnormalities (16 imaging findings in total). Chi-square tests were used to compare the prevalence of each imaging finding in the TBX4 cohort compared to the control group. RESULTS: Patients with TBX-4 mutations had increased presence of peripheral or subpleural irregularity (73% vs 0%, P < 0.01), cystic lucencies (67% vs 7%, P < 0.01), and linear or reticular opacity (53% vs 0%, P < 0.01) compared to the control group. Ground glass opacities, bronchiectasis, and centrilobular nodules were not significantly different between the two patient groups (P > 0.05). CONCLUSION: TBX4 mutations have distinct imaging phenotypes in pediatric patients with PAH. Compared to patients without this mutation, patients with TBX-4 genes typically present with peripheral or subpleural irregularity, cystic lucencies, and linear or reticular opacity.

MFAP5 variant-induced multiple giant thoracic aortic aneurysm.

Heritable thoracic aortic aneurysms are complex conditions characterised by the dilation or rupture of the thoracic aorta, often occurring as an autosomal-dominant disorder associated with life-threatening complications. In this case report, we present a de novo variant, MFAP5 c.236_237insA (p.N79Kfs9), which is implicated in the development of inherited thoracic aortic aneurysm. The proband, a 15-year-old male, presented with recurrent cough, dull chest pain, chest distress, vomiting, and reduced activity tolerance, leading to the diagnosis of heritable thoracic aortic aneurysms. Whole-exome sequencing identified a novel heterozygous variant in MFAP5 (NM_003480, c.236_237insA, and p.N79Kfs9). MutationTester and PolyPhen-s predicted this variant to be damaging and disease-causing (probability = 1), while the SFIT score indicated protein damage (0.001). Structural analysis using the AlphaFold Protein structure database revealed that this mutation disrupted the N-linked glycosylation site, resulting in a frameshift, amino acid sequence alteration, and truncation of an essential protein site. To our knowledge, this is the first case report describing a young patient with heritable thoracic aortic aneurysm carrying the novel MFAP5 c.236_237insA (p.N79Kfs*9) variant. This variant represents the third identified mutation site associated with heritable thoracic aortic aneurysm. Given the high mortality and morbidity rates associated with thoracic aortic aneurysms, the prevention of severe and fatal complications is crucial in the clinical management of this condition. Our case highlights the importance of whole-exome sequencing and genetic screening in identifying potential pathogenic or likely pathogenic variants, particularly in early-onset patients with aortic dilation, to inform appropriate management strategies.

Hemodynamic and Clinical Profiles of Pulmonary Arterial Hypertension Patients with GDF2 and BMPR2 Variants.

Asians have a higher carrier rate of pulmonary arterial hypertension (PAH)-related genetic variants than Caucasians do. This study aimed to identify PAH-related genetic variants using whole exome sequencing (WES) in Asian idiopathic and heritable PAH cohorts. A WES library was constructed, and candidate variants were further validated by polymerase chain reaction and Sanger sequencing in the PAH cohort. In a total of 69 patients, the highest incidence of variants was found in the BMPR2, ATP13A3, and GDF2 genes. Regarding the BMPR2 gene variants, there were two nonsense variants (c.994C>T, p. Arg332*; c.1750C>T, p. Arg584*), one missense variant (c.1478C>T, p. Thr493Ile), and one novel in-frame deletion variant (c.877_888del, p. Leu293_Ser296del). Regarding the GDF2 variants, there was one likely pathogenic nonsense variant (c.259C>T, p. Gln87*) and two missense variants (c.1207G>A, p. Val403Ile; c.38T>C, p. Leu13Pro). The BMPR2 and GDF2 variant subgroups had worse hemodynamics. Moreover, the GDF2 variant patients were younger and had a significantly lower GDF2 value (135.6 ± 36.2 pg/mL, p = 0.002) in comparison to the value in the non-BMPR2/non-GDF2 mutant group (267.8 ± 185.8 pg/mL). The BMPR2 variant carriers had worse hemodynamics compared to the patients with the non-BMPR2/non-GDF2 mutant group. Moreover, there was a significantly lower GDF2 value in the GDF2 variant carriers compared to the control group. GDF2 may be a protective or corrected modifier in certain genetic backgrounds.

Coding and Non-Coding Transcriptomic Landscape of Aortic Complications in Marfan Syndrome.

Marfan syndrome (MFS) is a rare congenital disorder of the connective tissue, leading to thoracic aortic aneurysms (TAA) and dissection, among other complications. Currently, the most efficient strategy to prevent life-threatening dissection is preventive surgery. Periodic imaging applying complex techniques is required to monitor TAA progression and to guide the timing of surgical intervention. Thus, there is an acute demand for non-invasive biomarkers for diagnosis and prognosis, as well as for innovative therapeutic targets of MFS. Unraveling the intricate pathomolecular mechanisms underlying the syndrome is vital to address these needs. High-throughput platforms are particularly well-suited for this purpose, as they enable the integration of different datasets, such as transcriptomic and epigenetic profiles. In this narrative review, we summarize relevant studies investigating changes in both the coding and non-coding transcriptome and epigenome in MFS-induced TAA. The collective findings highlight the implicated pathways, such as TGF-ß signaling, extracellular matrix structure, inflammation, and mitochondrial dysfunction. Potential candidates as biomarkers, such as miR-200c, as well as therapeutic targets emerged, like Tfam, associated with mitochondrial respiration, or miR-632, stimulating endothelial-to-mesenchymal transition. While these discoveries are promising, rigorous and extensive validation in large patient cohorts is indispensable to confirm their clinical relevance and therapeutic potential.

Wolbachia of phylogenetic supergroup K identified in oribatid mite Nothrus anauniensis (Acari: Oribatida: Nothridae).

Heritable endosymbionts widely occur in arthropod and nematode hosts. Among these endosymbionts, Wolbachia has been extensively detected in many arthropods, such as insects and crustaceans. Maternal inheritance is the most basic and dominant mode of transmission of Wolbachia, and it might regulate the reproductive system of the host in four ways: feminization, parthenogenesis, male killing, and cytoplasmic incompatibility. There is a relatively high percentage (10%) of thelytokous species in Oribatida, a suborder under the subclass Acari of arthropods, but the study of the endosymbionts in oribatid mites is almost negligible. In this paper, we detected endosymbiotic bacteria in two parthenogenetic oribatid species, Nothrus anauniensis Canestrini and Fanzago, 1877, which has never been tested for endosymbionts, and Oppiella nova, in which Wolbachia and Cardinium have been reported before. The results showed that Wolbachia was first found in N. anauniensis with an infection rate of 100% across three populations. Phylogenetic analysis showed that Wolbachia in N. anauniensis belonged to the supergroup K, marking the second supergroup of Wolbachia found in oribatid mites. Unlike previous studies, our study did not detect Wolbachia in O. nova, leading to the exclusion of Wolbachia's role in mediating thelytoky in this species.

Analysis of acute extremity compartment syndrome using a genealogic population database.

INTRODUCTION: Acute extremity compartment syndrome ("CS") is an under-researched, highly morbid condition affecting trauma populations. The purpose of this study was to analyze incidence rates and risk factors for extremity compartment syndrome using a high-quality population database. Additionally, we evaluated heritable risk for CS using available genealogic data. We hypothesized that diagnosis of extremity compartment syndrome would demonstrate heritability. MATERIALS AND METHODS: Adult patients with fractures of the tibia, femur, and upper extremity were retrospectively identified by ICD-9, ICD-10, and CPT codes from 1996 to 2020 in a statewide hospital database. Exposed and unexposed cohorts were created based on a diagnosis of CS. Available demographic data were analyzed to determine risk factors for compartment syndrome using logistic regression. Mortality risk at the final follow-up was evaluated using Cox proportional hazard modeling. Patients with a diagnosis of CS were matched with those without a diagnosis for heritability analysis. RESULTS: Of 158,624 fractures, 931 patients were diagnosed with CS. Incidence of CS was 0.59% (tibia 0.83%, femur 0.31%, upper extremity 0.27%). Male sex (78.1% vs. 46.4%; p < 0.001; RR = 3.24), younger age at fracture (38.8 vs. 48.0 years; p < 0.001; RR = 0.74), Medicaid enrollment (13.2% vs. 9.3%; p < 0.001; RR = 1.58), and smoking (41.1% vs. 31.1%; p < 0.001; RR 1.67) were significant risk factors for CS. CS was associated with mortality (RR 1.61, p < 0.001) at mean follow-up 8.9 years in the CS cohort. No significant heritable risk was found for diagnosis of CS. CONCLUSIONS: Without isolating high-risk fractures, rates of CS are lower than previously reported in the literature. Male sex, younger age, smoking, and Medicaid enrollment were independent risk factors for CS. CS increased mortality risk at long-term follow-up. No heritable risk was found for CS. LEVEL OF EVIDENCE: III.

Association Between Cardiac Size, Systolic Function, and Complications in Vascular Ehlers-Danlos Syndrome.

Purpose: Vascular Ehlers-Danlos syndrome (vEDS) is a rare and aggressive heritable aortic disease caused by pathogenic variants in COL3A1 gene, characterized by spontaneous arterial dissection and organ rupture. The purpose of this study is to evaluate ventricular size and function and to explore their associations with complications in vEDS. Methods: Adults with genetically confirmed vEDS who underwent clinical cardiac MRI were retrospectively compared with controls matched for age and sex. Cardiac MRI analysis included assessment of ventricular volumetry and arterial vasculature. vEDS-related complications were evaluated including dissection, aneurysm, and pneumothorax. Multivariable logistic regression was performed. Results: We studied 26 individuals with vEDS (38.6 ± 15.6 years, 50.0% female) and 26 healthy controls. Median clinical follow-up was 2.4 (1.1-3.6) years. Left and right ventricular ejection fractions were lower in vEDS compared with controls (LVEF 58 ± 6% vs 61 ± 4%, P = .03; RVEF 54 ± 5% vs 58 ± 4%, P = .03). After controlling for age, sex, and antihypertensive medication, LV end-diastolic volume indexed to body surface area (LVEDVi) predicted dissections (OR 1.1, 95% CI 1.01-1.2, P = .04) and aneurysms (OR 1.1, 95% CI 1.01-1.3, P = .03). Indexed LV end systolic volume (LVESVi) also predicted aneurysms (OR 1.2, 95% CI 1.03-1.5, P = .02). LVEF predicted the presence of any complication (OR 0.71, 95% CI 0.52-0.99, P = .04). Pneumothorax occurred exclusively in vEDS group among those with LVEF <58% (below the mean), 50.0% versus 0.0%, P = .02. Those with LVEF <58% had more frequent dissection and/or aneurysm (75.0% vs 12.5%, P = .04). Conclusion: Lower LVEF and larger cardiac size are associated with complications in vEDS.

An analysis of different concepts of "identity" in the heritable genome editing debate.

Human heritable genome editing (HHGE) involves editing the genes of human gametes and/or early human embryos. Whilst 'identity' is a key concept underpinning the current HHGE debate, there is a lack of inclusive analysis on different concepts of 'identity' which renders the overall debate confusing at times. This paper first contributes to reviewing the existing literature by consolidating how 'identity' has been discussed in the HHGE debate. Essentially, the discussion will reveal an ontological and empirical understanding of identity when different types of identity are involved. Here, I discuss genetic, numerical, qualitative and narrative and how each of them is relevant in the HHGE context. Secondly, given the different types of identity, the paper explores how we could navigate these different interpretations of identity in a way that promotes an inclusive and informed discussion between primary stakeholders and the general public in the HHGE debate. Here, I argue for and refine a multi-faceted concept of identity as a suitable framework for discussing the ethical and societal implications of HHGE because it not only could integrate different understandings of identity but also highlight the interconnectedness between these different understandings.

Genotype-Phenotype Insights of Inherited Cardiomyopathies-A Review.

Background: Cardiomyopathies (CMs) represent a heterogeneous group of primary myocardial diseases characterized by structural and functional abnormalities. They represent one of the leading causes of cardiac transplantations and cardiac death in young individuals. Clinically they vary from asymptomatic to symptomatic heart failure, with a high risk of sudden cardiac death due to malignant arrhythmias. With the increasing availability of genetic testing, a significant number of affected people are found to have an underlying genetic etiology. However, the awareness of the benefits of incorporating genetic test results into the care of these patients is relatively low. Aim: The focus of this review is to summarize the current basis of genetic CMs, including the most encountered genes associated with the main types of cardiomyopathies: hypertrophic, dilated, restrictive arrhythmogenic, and non-compaction. Materials and Methods: For this narrative review, we performed a search of multiple electronic databases, to select and evaluate relevant manuscripts. Results: Advances in genetic diagnosis led to better diagnosis precision and prognosis prediction, especially with regard to the risk of developing arrhythmias in certain subtypes of cardiomyopathies. Conclusions: Implementing the genomic information to benefit future patient care, better risk stratification and management, promises a better future for genotype-based treatment.

Early risk for child externalising symptoms: Examining genetic, prenatal, temperamental and parental influences.

This study utilized the Early Growth and Development Study (N = 561 adoptive children; 57.2% male, 55.3% White), a study of children adopted at birth, to examine heritable (birth parent psychopathology) and prenatal risk (prenatal maternal distress and smoking during pregnancy), infant negative affectivity, adoptive parent over-reactivity and warmth as independent predictors of childhood externalizing symptoms. The current study evaluated if: (1) infant negative affectivity and over-reactive parenting are candidate mediators for the effects of heritable and prenatal risk on externalizing symptoms and (2) parental warmth weakens the influence of heritable risk, prenatal risk, negative affectivity, and over-reactive parenting on externalizing symptoms. There were main effects of heritable risk, infant negative affectivity, and over-reactive parenting on child externalizing symptoms. The study found no support for the hypothesized mediation and moderation effects, suggesting that targeting parental over-reactivity rather than warmth would be more effective in reducing risk for childhood externalizing symptoms.

Heritable human genome editing: correction, selection and treatment.

Heritable human genome editing (HHGE) to correct a nuclear gene sequence that would result in a serious genetic condition in a future child is presented as 'treatment' in various ethics and policy materials, and as morally preferable to the 'selection' practice of preimplantation genetic testing (PGT), which is subject to the disability critique. However, whether HHGE is 'treatment' for a future child, or another form of 'selection', or whether HHGE instead 'treats' prospective parents, are now central questions in the debate regarding its possible legalisation. This article argues that the idea of 'treatment' for a future child is largely a proxy for 'seriousness of purpose', intended to distinguish HHGE to avoid serious genetic conditions from less obviously justifiable uses; that HHGE is best understood, and morally justified, as a form of 'treatment' for prospective parents who strongly desire an unaffected genetically related child and who have no, or poor, options to achieve this; that HHGE would be morally permissible if consistent with that child's welfare; that legalisation is supportable with reference to the right to respect for private and family life under Article 8 of the European Convention on Human Rights; and that HHGE is morally distinguishable from PGT.

2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.

AIM: The "2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease" provides recommendations to guide clinicians in the diagnosis, genetic evaluation and family screening, medical therapy, endovascular and surgical treatment, and long-term surveillance of patients with aortic disease across its multiple clinical presentation subsets (ie, asymptomatic, stable symptomatic, and acute aortic syndromes). METHODS: A comprehensive literature search was conducted from January 2021 to April 2021, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through June 2022 during the guideline writing process, were also considered by the writing committee, where appropriate. Structure: Recommendations from previously published AHA/ACC guidelines on thoracic aortic disease, peripheral artery disease, and bicuspid aortic valve disease have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with aortic disease have been developed. There is added emphasis on the role of shared decision making, especially in the management of patients with aortic disease both before and during pregnancy. The is also an increased emphasis on the importance of institutional interventional volume and multidisciplinary aortic team expertise in the care of patients with aortic disease.

Therapeutic Germline Editing: Sense and Sensibility.

Safe and effective heritable editing of the human genome is years away from the clinic because of formidable technical, statutory, regulatory, and societal challenges. In particular, we note the fledgling state of the science, the imperatives of editing efficiency, specificity, and uniformity, and the extant legal roadblock.