Teaching effects of the online and offline flipped classroom model (FCM) in the post-epidemic era: Development and feasibility study.

With the rapid development of multimedia technology, the student centered flipped classroom model (FCM) and massive open online courses (MOOCs) have been increasingly introduced and implemented in higher medical education. However, comparative analyses of the offline face-to-face FCM and completely online FCM have been rarely reported. In this study, we focused specifically on a set of flipped classrooms in which prerecorded videos were provided before class. Using the Zhihuishu platform as the major online course platform, our team built a MOOC and evaluated the teaching effectiveness of the FCM in both the offline face-to-face class and the online electronic live class for medical genetics education. Questionnaires, paper-based and oral exams were used to collect data on the teaching effects of the different teaching methods. We found that student satisfaction and overall student performance in the offline FCM group was significantly higher than that in the completely online teaching group. Although online FCM allowed students to play back and review anywhere and anytime after class, students taught in offline FCM had a significantly higher degree of knowledge mastery, had a deeper understanding of theoretical knowledge, and were better at knowledge comprehensive application. The effects of their training on genetic disease clinical diagnosis and treatment skills were significantly better, and their capacity for scientific research was also significantly improved. Our research discussed the advantages of the online courses and the problems brought about by using these technologies, and it provided insight into online teaching practices in the era of internet-based medical education.

Enhancing prediction accuracy of coronary artery disease through machine learning-driven genomic variant selection.

Machine learning (ML) methods are increasingly becoming crucial in genome-wide association studies for identifying key genetic variants or SNPs that statistical methods might overlook. Statistical methods predominantly identify SNPs with notable effect sizes by conducting association tests on individual genetic variants, one at a time, to determine their relationship with the target phenotype. These genetic variants are then used to create polygenic risk scores (PRSs), estimating an individual's genetic risk for complex diseases like cancer or cardiovascular disorders. Unlike traditional methods, ML algorithms can identify groups of low-risk genetic variants that improve prediction accuracy when combined in a mathematical model. However, the application of ML strategies requires addressing the feature selection challenge to prevent overfitting. Moreover, ensuring the ML model depends on a concise set of genomic variants enhances its clinical applicability, where testing is feasible for only a limited number of SNPs. In this study, we introduce a robust pipeline that applies ML algorithms in combination with feature selection (ML-FS algorithms), aimed at identifying the most significant genomic variants associated with the coronary artery disease (CAD) phenotype. The proposed computational approach was tested on individuals from the UK Biobank, differentiating between CAD and non-CAD individuals within this extensive cohort, and benchmarked against standard PRS-based methodologies like LDpred2 and Lassosum. Our strategy incorporates cross-validation to ensure a more robust evaluation of genomic variant-based prediction models. This method is commonly applied in machine learning strategies but has often been neglected in previous studies assessing the predictive performance of polygenic risk scores. Our results demonstrate that the ML-FS algorithm can identify panels with as few as 50 genetic markers that can achieve approximately 80% accuracy when used in combination with known risk factors. The modest increase in accuracy over PRS performances is noteworthy, especially considering that PRS models incorporate a substantially larger number of genetic variants. This extensive variant selection can pose practical challenges in clinical settings. Additionally, the proposed approach revealed novel CAD-genetic variant associations.

"Why did I choose genetics?": A survey of current and recent medical genetics and genomics residents provides insight into recruitment efforts.

There is a shortage of clinical geneticists, even with concerted recruitment efforts. Previously, no data had been collected about why young career geneticists chose this specialty. To investigate this question, we carried out a survey of current and recent medical genetics and genomics residents. The goal of this survey was to understand their reasons for pursuing medical genetics and genomics as a specialty. Results demonstrate that, for most, interest in genetics begins in medical school and was largely influenced by mentorship. This suggests that placing greater focus on introducing medical genetics as a clinical specialty and fostering robust mentorship of students in preclinical years may increase recruitment into medical genetics residencies.

Genome-first evaluation with exome sequence and clinical data uncovers underdiagnosed genetic disorders in a large healthcare system.

Population-based genomic screening may help diagnose individuals with disease-risk variants. Here, we perform a genome-first evaluation for nine disorders in 29,039 participants with linked exome sequences and electronic health records (EHRs). We identify 614 individuals with 303 pathogenic/likely pathogenic or predicted loss-of-function (P/LP/LoF) variants, yielding 644 observations; 487 observations (76%) lack a corresponding clinical diagnosis in the EHR. Upon further investigation, 75 clinically undiagnosed observations (15%) have evidence of symptomatic untreated disease, including familial hypercholesterolemia (3 of 6 [50%] undiagnosed observations with disease evidence) and breast cancer (23 of 106 [22%]). These genetic findings enable targeted phenotyping that reveals new diagnoses in previously undiagnosed individuals. Disease yield is greater with variants in penetrant genes for which disease is observed in carriers in an independent cohort. The prevalence of P/LP/LoF variants exceeds that of clinical diagnoses, and some clinically undiagnosed carriers are discovered to have disease. These results highlight the potential of population-based genomic screening.

Validation of 3 Computer-Aided Facial Phenotyping Tools (DeepGestalt, GestaltMatcher, and D-Score): Comparative Diagnostic Accuracy Study.

BACKGROUND: While characteristic facial features provide important clues for finding the correct diagnosis in genetic syndromes, valid assessment can be challenging. The next-generation phenotyping algorithm DeepGestalt analyzes patient images and provides syndrome suggestions. GestaltMatcher matches patient images with similar facial features. The new D-Score provides a score for the degree of facial dysmorphism. OBJECTIVE: We aimed to test state-of-the-art facial phenotyping tools by benchmarking GestaltMatcher and D-Score and comparing them to DeepGestalt. METHODS: Using a retrospective sample of 4796 images of patients with 486 different genetic syndromes (London Medical Database, GestaltMatcher Database, and literature images) and 323 inconspicuous control images, we determined the clinical use of D-Score, GestaltMatcher, and DeepGestalt, evaluating sensitivity; specificity; accuracy; the number of supported diagnoses; and potential biases such as age, sex, and ethnicity. RESULTS: DeepGestalt suggested 340 distinct syndromes and GestaltMatcher suggested 1128 syndromes. The top-30 sensitivity was higher for DeepGestalt (88%, SD 18%) than for GestaltMatcher (76%, SD 26%). DeepGestalt generally assigned lower scores but provided higher scores for patient images than for inconspicuous control images, thus allowing the 2 cohorts to be separated with an area under the receiver operating characteristic curve (AUROC) of 0.73. GestaltMatcher could not separate the 2 classes (AUROC 0.55). Trained for this purpose, D-Score achieved the highest discriminatory power (AUROC 0.86). D-Score's levels increased with the age of the depicted individuals. Male individuals yielded higher D-scores than female individuals. Ethnicity did not appear to influence D-scores. CONCLUSIONS: If used with caution, algorithms such as D-score could help clinicians with constrained resources or limited experience in syndromology to decide whether a patient needs further genetic evaluation. Algorithms such as DeepGestalt could support diagnosing rather common genetic syndromes with facial abnormalities, whereas algorithms such as GestaltMatcher could suggest rare diagnoses that are unknown to the clinician in patients with a characteristic, dysmorphic face.

Overcoming Challenges in Hemihyperplasia Through Surgical Innovation and Genetic Diagnosis: A Case Report.

This case report sheds light on the complex management of hemihyperplasia (HHP), highlighting the difficulties associated with diagnosis and the critical importance of a multimodal approach to treatment. The story of Acharya Vinoba Bhave Rural Hospital's (AVBRH) successful resolution following a misdiagnosis at another clinic emphasizes the value of expert care. The successful outcome resulted from the fusion of surgical innovation, genetic insights, and psychosocial factors through genetic testing, liposuction, and postoperative rehabilitation. This example emphasizes the need to treat congenital illnesses holistically and the transforming power of individualized, multidisciplinary treatment to improve the functional and esthetic elements of life for patients with HHP.

Personal journeys to and in human genetics and dysmorphology.

Genetics has become a critical component of medicine over the past five to six decades. Alongside genetics, a relatively new discipline, dysmorphology, has also begun to play an important role in providing critically important diagnoses to individuals and families. Both have become indispensable to unraveling rare diseases. Almost every medical specialty relies on individuals experienced in these specialties to provide diagnoses for patients who present themselves to other doctors. Additionally, both specialties have become reliant on molecular geneticists to identify genes associated with human disorders. Many of the medical geneticists, dysmorphologists, and molecular geneticists traveled a circuitous route before arriving at the position they occupied. The purpose of collecting the memoirs contained in this article was to convey to the reader that many of the individuals who contributed to the advancement of genetics and dysmorphology since the late 1960s/early 1970s traveled along a journey based on many chances taken, replying to the necessities they faced along the way before finding full enjoyment in the practice of medical and human genetics or dysmorphology. Additionally, and of equal importance, all exhibited an ability to evolve with their field of expertise as human genetics became human genomics with the development of novel technologies.

Discovery of BMP10 as a new gene underpinning congenital heart defects.

OBJECTIVE: Aggregating evidence convincingly establishes the predominant genetic basis underlying congenital heart defects (CHD), though the heritable determinants contributing to CHD in the majority of cases remain elusive. In the current investigation, BMP10 was selected as a prime candidate gene for human CHD mainly due to cardiovascular developmental abnormalities in Bmp10-knockout animals. The objective of this retrospective study was to identify a new BMP10 mutation responsible for CHD and characterize the functional effect of the identified CHD-causing BMP10 mutation. METHODS: Sequencing assay of BMP10 was fulfilled in a cohort of 276 probands with various CHD and a total of 288 non-CHD volunteers. The available family members from the proband harboring an identified BMP10 mutation were also BMP10-genotyped. The effect of the identified CHD-causative BMP10 mutation on the transactivation of TBX20 and NKX2.5 by BMP10 was quantitatively analyzed in maintained HeLa cells utilizing a dual-luciferase reporter assay system. RESULTS: A novel heterozygous BMP10 mutation, NM_014482.3:c.247G>T;p.(Glu83*), was identified in one proband with patent ductus arteriosus (PDA), which was confirmed to co-segregate with the PDA phenotype in the mutation carrier's family. The nonsense mutation was not observed in 288 non-CHD volunteers. Functional analysis unveiled that Glu83*-mutant BMP10 had no transactivation on its two representative target genes TBX20 and NKX2.5, which were both reported to cause CHD. CONCLUSION: These findings provide strong evidence indicating that genetically compromised BMP10 predisposes human beings to CHD, which sheds light on the new molecular mechanism that underlies CHD and allows for antenatal genetic counseling and individualized precise management of CHD.

Acute Lymphoblastic Leukemia in a Pediatric Patient With Turnpenny-Fry Syndrome.

Turnpenny-Fry Syndrome (TPFS) is a rare genetic disorder characterized by a severe developmental delay and a distinctive facial gestalt. It is caused by mutations in the Polycomb Group Ring Finger Protein 2 (PCGF2) gene, which is also known to play a role in numerous tumor types. Up to date, there have been no published case reports of patients with TPFS and concomitant malignancies. The present case describes the clinical evaluation and follow-up of a male infant with severe global developmental delay (GDD) and a distinctive phenotype. At 4 years of age, clinical exome sequencing confirmed the diagnosis of TPFS. Posteriorly, at 5 years of age, the patient was also diagnosed with T-cell acute lymphoblastic leukemia (ALL). Given the scarce literature regarding this syndrome, the authors expect that this case report will provide valuable information that could improve the follow-up of patients with TPFS. Furthermore, this case highlights the necessity for the appropriate diagnosis of developmental disorders, to ensure adequate care, surveillance of comorbidities and proper genetic counselling.

Investigation on the construction of teaching case base in medical genetics.

Medical genetics is a basic medical course that discusses the diagnosis, prevention and treatment of diseases in relation with genetic factors. This course requires students who have abilities of strong logical thinking, independent thinking, problem analyzing and solving. Single "cramming" teaching is difficult to mobilize students' autonomous learning, and hardly achieves teaching effect of medical genetics. Teaching of case-based discussion breaks passive teaching mode in traditional class. The teacher throws out typically clinical cases. The students prepare materials around relevant problems of cases, and carry out class discussion. Then, key and difficult points of the course are integrated in teaching and learning interaction, which reaches a remarkable effect of teaching. Since 2013, the teaching and research group has carried out teaching of case-based discussion in undergraduates majoring in clinical medicine. In this paper, we screen and sort clinical cases on the basis of course teaching plan and case-based discussion in the teaching of medical genetics. The cases are summarized into 8 chapters in teaching case base, which basically cover the teaching of disease genetics and clinical genetics.The construction of teaching case base in medical genetics has realized the deep integration of clinical cases and teaching. Students can understand and master important and difficult points of teaching in a more intuitive way, which is helpful to stimulate students' innovative thinking, improve students' learning interest and class participation.

Two New Families and a Literature Review of ELOVL4-Associated Spinocerebellar Ataxia Type 34.

Autosomal dominant variants in ELOVL4 cause spinocerebellar ataxia type 34 (SCA34; ATX-ELOVL4), classically associated with a skin condition known as erythrokeratoderma. Here, we report a large Italian-Maltese-Australian family with spinocerebellar ataxia. Notably, while there were dermatological manifestations (eczema), erythrokeratoderma was not present. Using a next-generation sequencing panel, we identified a previously reported ELOVL4 variant, NM_022726.4: c.698C > T p.(Thr233Met). The variant was initially classified as a variant of uncertain significance; however, through segregation studies, we reclassified the variant as likely pathogenic. We next identified an individual from another family (Algerian-Maltese-Australian) with the same ELOVL4 variant with spinocerebellar ataxia but without dermatological manifestations. We subsequently performed the first dedicated literature review of ELOVL4-associated ataxia to gain further insights into genotype-phenotype relationships. We identified a total of 60 reported cases of SCA34 to date. The majority had gait ataxia (88.3%), limb ataxia (76.7%), dysarthria (63.3%), and nystagmus (58.3%). Of note, skin lesions related to erythrokeratoderma were seen in a minority of cases (33.3%). Other extracerebellar manifestations included pyramidal tract signs, autonomic disturbances, retinitis pigmentosa, and cognitive impairment. For brain MRI data, cerebellar atrophy was seen in all cases (100%), whereas the hot cross bun sign (typically associated with multiple system atrophy type C) was seen in 32.4% of cases. Our family study and literature review highlight the variable phenotypic spectrum of SCA34. Importantly, it shows that erythrokeratoderma is not found in most cases and that, while a dermatological assessment may be helpful in these patients, SCA34 diagnosis should be considered irrespective of dermatological manifestations.

Functional and phenotypic consequences of an unusual inversion in MSH2.

Lynch syndrome is an autosomal dominant disorder that usually results from a pathogenic germline variant in one of four genes (MSH2, MSH6, MLH1, PMS2) involved in DNA mismatch repair. Carriers of such variants are at risk of developing numerous cancers during adulthood. Here we report on a family suspected of having Lynch syndrome due to a history of endometrial adenocarcinoma, ovarian clear cell carcinoma, and adenocarcinoma of the duodenum in whom we identified a germline 29 nucleotide in-frame inversion in exon 3 of MSH2. We further show that this variant is almost completely absent at the protein level, and that the associated cancers have complete loss of MSH2 and MSH6 expression by immunohistochemistry. Functional investigation of this inversion in a laboratory setting revealed a resultant abnormal protein function. Thus, we have identified an unusual, small germline inversion in a mismatch repair gene that does not lead to a premature stop codon yet appears likely to be causal for the observed cancers.

Aprendizagem baseada em casos clínicos no ensino de genética para medicina / Learning based on clinical cases in the teaching of genetics for medicine

Resumo Introdução: A necessidade premente de formar médicos autônomos e proativos implica novas abordagens didáticas e formas de mediar o conteúdo. Nesse contexto, a utilização de métodos ativos de ensino e aprendizagem pode incrementar o perfil do novo profissional. A Aprendizagem Baseada em Casos (ABC) é uma estratégia fundamentada na capacidade de o estudante relacionar teoria e prática com autonomia e tomada de decisão. A disciplina de genética aborda conteúdos que podem parecer distantes do cotidiano e da prática profissional futura, e, por isso, a necessidade de utilizar estratégias de ensino que facilitem a compreensão da aplicação desse conhecimento na prática médica. Objetivo: O presente trabalho teve por objetivo avaliar a ABC como abordagem pedagógica no processo de ensino-aprendizagem de genética para o curso de Medicina de uma instituição pública. Método: Aplicou-se um protocolo de método ativo composto por nove casos clínicos a 46 estudantes de Medicina da Universidade de Brasília que, posteriormente, foram divididos em nove grupos. Por meio de questionários, avaliaram-se o desempenho e as percepções em relação ao método. Os resultados quantitativos foram analisados por meio do teste t de Student. Resultado: O rendimento do trabalho em grupo foi estatisticamente maior em oito dos nove casos em comparação ao trabalho individual. A atividade foi considerada boa ou muito boa por 76% dos estudantes, e 90% mencionaram que houve aumento da motivação. Além disso, 71,4% destes demonstraram interesse em estudar mais sobre o assunto após a aula, 20% se consideraram capazes de ensinar o assunto a outras pessoas, e 42% avaliaram que acertariam todas ou a maioria das questões caso fossem submetidos a uma nova avaliação. Com relação ao trabalho em equipe, 38% relataram se sentir mais motivados. Por fim, 86% consideraram relevante ou muito relevante a discussão de casos clínicos para a formação profissional. Conclusão: Os resultados demostraram sucesso no uso do método ABC na abordagem de genética, porém apontaram que há dificuldades na utilização de métodos de ensino alternativos à aula expositiva. Apesar disso, fica explícito que a estratégia adotada pode levar à mobilização de conhecimentos prévios em situações da prática profissional.

Abstract Introduction: The pressing need to train autonomous and proactive professionals demands new ways of mediating content. In this context, the use of active teaching and learning methods can improve the profile of the new professional. Case-Based Learning (CBL) is a strategy based on the student's ability to relate theory and practice, with autonomy and decision-making. The discipline of Genetics addresses contents that may seem distant from everyday life and future professional practice, so it is necessary to use teaching strategies that facilitate the understanding of the application of this knowledge in medical practice. Objective: This study aimed to evaluate the CBL as a pedagogical approach in the teaching-learning process of Genetics for Medicine courses in a public institution. Methods: An active methodology protocol that consisted of nine clinical cases was applied to 46 medical students from Universidade de Brasília, who were later divided into nine groups. The performance and perceptions regarding the methodology were evaluated by questionnaires. Quantitative results were analyzed using Student's t test. Results: The performance of group work was statistically higher in 8 of 9 cases compared to individual work. Most students considered the activity good or very good (76%), but approximately half reported no increase in motivation. Moreover, 71.4% felt motivated to learn more about the subject after class and 20% considered they were able to teach the subject to others and 42% assessed they would get all or most of the questions correct if they were submitted to a new assessment. Regarding teamwork, 38% reported feeling more motivated. Finally, 86% considered the discussion of clinical cases relevant or very relevant for professional training. Final considerations: The results show, in general, success in the use of CBL on the study of genetic diseases but point out that there are difficulties in the use of alternative teaching methods to the lecture. Despite this, it is clear that learning based on clinical cases can lead to the mobilization of previous knowledge in situations of professional practice.

Mapping the value for money of precision medicine: a systematic literature review and meta-analysis.

Objective: This study aimed to quantify heterogeneity in the value for money of precision medicine (PM) by application types across contexts and conditions and to quantify sources of heterogeneity to areas of particular promises or concerns as the field of PM moves forward. Methods: A systemic search was performed in Embase, Medline, EconLit, and CRD databases for studies published between 2011 and 2021 on cost-effectiveness analysis (CEA) of PM interventions. Based on a willingness-to-pay threshold of one-time GDP per capita of each study country, the net monetary benefit (NMB) of PM was pooled using random-effects meta-analyses. Sources of heterogeneity and study biases were examined using random-effects meta-regressions, jackknife sensitivity analysis, and the biases in economic studies checklist. Results: Among the 275 unique CEAs of PM, publicly sponsored studies found neither genetic testing nor gene therapy cost-effective in general, which was contradictory to studies funded by commercial entities and early stage evaluations. Evidence of PM being cost-effective was concentrated in a genetic test for screening, diagnosis, or as companion diagnostics (pooled NMBs, $48,152, $8,869, $5,693, p < 0.001), in the form of multigene panel testing (pooled NMBs = $31,026, p < 0.001), which only applied to a few disease areas such as cancer and high-income countries. Incremental effectiveness was an essential value driver for varied genetic tests but not gene therapy. Conclusion: Precision medicine's value for money across application types and contexts was difficult to conclude from published studies, which might be subject to systematic bias. The conducting and reporting of CEA of PM should be locally based and standardized for meaningful comparisons.

Aprendizaje creativo en estudiantes de Medicina desde la Genética Médica

Fundamento: En la carrera de Medicina es necesario formar profesionales con pensamiento creativo que permita la solución de problemas vinculados con el ejercicio de su profesión. La Genética Médica aporta la posibilidad de reflexionar y crear soluciones creativas. Objetivo: Proponer actividades que posibiliten el aprendizaje creativo en estudiantes de Medicina desde la Genética Médica. Metodología: Se emplearon métodos teóricos, empíricos y matemático-estadístico, con una muestra de 34 estudiantes y 3 profesores que imparten la asignatura. Resultados: Los docentes reconocen que, a pesar de hacer intentos para alcanzar el aprendizaje creativo, desconocen algunas vías y manifiestan no contar con el tiempo suficiente para su logro. El accionar didáctico no favorece el conocimiento, aplicación y disposición de estudiantes para un aprendizaje creativo. Se propusieron actividades sustentadas en procederes en Genética Médica, como parte de la estrategia didáctica de los docentes, asimismo contribuir al perfeccionamiento del aprendizaje creativo en los estudiantes. Las mismas centradas en métodos problémicos y el uso de recursos tecnológicos. Conclusiones: La formación de los médicos necesita expresar un aprendizaje creativo vinculado a un desempeño eficiente en la solución de problemas de la comunidad, lo cual se puede facilitar mediante la utilización de actividades en la asignatura Genética Médica.

Background: In the Medicine career it is necessary to form professionals with creative thoughts that allow the solution of problems linked to their professional practice. Medical Genetics provides the possibility to reflect and create creative solutions. Objective: To propose activities that allow creative learning in Medical students from the Medical Genetics perspective. Methodology: Theoretical, empirical and mathematical-statistical methods were applied, with a sample of 34 students and 3 teachers who teach the subject. Results: Teachers recognize that, despite making attempts to achieve creative learning, they are unaware of some ways and declare that they do not have enough time to achieve it. The didactic action does not favor the knowledge, application and disposition of students for creative learning. Activities supported by procedures in Medical Genetics were proposed as part of the didactic strategy of the teachers, likewise contribute to the improvement of creative learning in students. The same ones are focused on problem-solving methods and the use of technological resources. Conclusions: Physician education needs to express creative learning coupled with efficient performance in solving community problems, which may be facilitated through the use of activities in Medical Genetics Medical subject.

Ocular manifestations in a cohort of 43 patients with KBG syndrome.

Ophthalmological conditions are underreported in patients with KBG syndrome, which is classically described as presenting with dental, developmental, intellectual, skeletal, and craniofacial abnormalities. This study analyzed the prevalence of four ophthalmological conditions (strabismus, astigmatism, myopia, hyperopia) in 43 patients with KBG syndrome carrying variants in ANKRD11 or deletions in 16q24.3 and compared it to the literature. Forty-three patients were recruited via self-referral or a private Facebook group hosted by the KBG Foundation, with 40 of them having pathogenic or likely pathogenic variants. Virtual interviews were conducted to collect a comprehensive medical history verified by medical records. From these records, data analysis was performed to calculate the prevalence of ophthalmological conditions. Out of the 40 participants with pathogenic or likely pathogenic variants, strabismus was reported in 9 (22.5%) participants, while astigmatism, myopia, and hyperopia were reported in 11 (27.5%), 6 (15.0%), and 8 (20.0%) participants, respectively. Other reported conditions include anisometropia, amblyopia, and nystagmus. When compared to the literature, the prevalence of strabismus and refractive errors is higher than other studies. However, more research is needed to determine if variants in ANKRD11 play a role in abnormal development of the visual system. In patients with established KBG syndrome, screening for misalignment or refractive errors should be done, as interventions in patients with these conditions can improve functioning and quality of life.

Genes and environment: An old pair in a new era.

What is the relationship between our genes and the environment we live in with regard to health? Like the debate about nature or nurture in the determination of our personality and behavior, the issue of genes and environment has been discussed intensely in the last two centuries. Is it Darwin or Lamarck who is right about the basic determinants of our health, especially as we age in a rapidly changing environment? Evolutionary biology as proposed by Darwin with natural selection at its core may not be able to explain almost instant adjustments of phenotypic traits to the pressures of the environment. Epigenesis, a concept that dates from Aristotle, provides a mechanism for the environment to affect variation in genetic traits that may become heritable. Indeed, Lamarck first described the inheritance of acquired characteristics. Thus, it appears that in contemporary genetics, both Darwin and Lamarck are right: environmental pressures may affect our genes through epigenetics, in ways that allow for inheritance of the changes, a Lamarckian concept; however, evolution through natural selection is the basis for incorporation (or rejection) of new traits and their sustained inheritance, a Darwinian concept. In this review, we present the synthesis of Darwin's and Lamarck's theories, the only way to understand how our health, and that of our progeny, responds to challenging and fast-changing environmental cues. In addition, we present other examples of environment-driven changes in disease frequency or expression.

Discovery of TBX20 as a Novel Gene Underlying Atrial Fibrillation.

Atrial fibrillation (AF), the most prevalent type of sustained cardiac dysrhythmia globally, confers strikingly enhanced risks for cognitive dysfunction, stroke, chronic cardiac failure, and sudden cardiovascular demise. Aggregating studies underscore the crucial roles of inherited determinants in the occurrence and perpetuation of AF. However, due to conspicuous genetic heterogeneity, the inherited defects accounting for AF remain largely indefinite. Here, via whole-genome genotyping with genetic markers and a linkage assay in a family suffering from AF, a new AF-causative locus was located at human chromosome 7p14.2-p14.3, a ~4.89 cM (~4.43-Mb) interval between the markers D7S526 and D7S2250. An exome-wide sequencing assay unveiled that, at the defined locus, the mutation in the TBX20 gene, NM_001077653.2: c.695A>G; p.(His232Arg), was solely co-segregated with AF in the family. Additionally, a Sanger sequencing assay of TBX20 in another family suffering from AF uncovered a novel mutation, NM_001077653.2: c.862G>C; p.(Asp288His). Neither of the two mutations were observed in 600 unrelated control individuals. Functional investigations demonstrated that the two mutations both significantly reduced the transactivation of the target gene KCNH2 (a well-established AF-causing gene) and the ability to bind the promoter of KCNH2, while they had no effect on the nuclear distribution of TBX20. Conclusively, these findings reveal a new AF-causative locus at human chromosome 7p14.2-p14.3 and strongly indicate TBX20 as a novel AF-predisposing gene, shedding light on the mechanism underlying AF and suggesting clinical significance for the allele-specific treatment of AF patients.

Resolving complex structural variants via nanopore sequencing.

The recent development of high-throughput sequencing platforms provided impressive insights into the field of human genetics and contributed to considering structural variants (SVs) as the hallmark of genome instability, leading to the establishment of several pathologic conditions, including neoplasia and neurodegenerative and cognitive disorders. While SV detection is addressed by next-generation sequencing (NGS) technologies, the introduction of more recent long-read sequencing technologies have already been proven to be invaluable in overcoming the inaccuracy and limitations of NGS technologies when applied to resolve wide and structurally complex SVs due to the short length (100-500 bp) of the sequencing read utilized. Among the long-read sequencing technologies, Oxford Nanopore Technologies developed a sequencing platform based on a protein nanopore that allows the sequencing of "native" long DNA molecules of virtually unlimited length (typical range 1-100 Kb). In this review, we focus on the bioinformatics methods that improve the identification and genotyping of known and novel SVs to investigate human pathological conditions, discussing the possibility of introducing nanopore sequencing technology into routine diagnostics.