Novel heterozygous mutation of CACNA2D1 gene in a Chinese family with arrhythmia.

BACKGROUND: Primary electrical disorders (PEDs) are a group of cardiac rhythm abnormalities that occur in the absence of detectable structural heart disease and are a significant cause of sudden cardiac death (SCD). The initiation of cardiac muscle contraction and relaxation is orchestrated by the action potential (AP), generated through ionic changes across the membrane. Mutations in the AP-related gene CACNA2D1 have been identified as a causative factor for PED. METHODS: We recruited a Chinese family with a history of arrhythmia. The proband has experienced palpitations and chest tightness for over 40 years, with symptoms worsening over the past year. Whole exome sequencing (WES) was used to determine the genetic etiologies in this family. RESULTS: A novel heterozygous missense mutation (NM_000722.3: c.1685G > C;p.G562A) of CACNA2D1 gene was detected. Genotyping of the proband's parents indicated that the arrhythmia phenotype in the proband was caused by a de novo mutation. CONCLUSIONS: WES was utilized to explore the genetic etiology in a family with arrhythmia, leading to the identification of a novel mutation in the CACNA2D1 gene. This study not only expands the mutation spectrum of the CACNA2D1 gene but also contributes to genetic counseling and clinical diagnosis for this family.

Recapitulation, Heredity, and Freud's View of Human Nature.

There's something strange about Freud's Civilization and its Discontents (1930). Biologically, Freud was a Neo-Lamarckian, who believed in both the modification of organisms through need and the inheritance of acquired characteristics. However, in Civilization, Freud argued that because human nature is immutable, society has dim odds of improving substantially. Lamarckians, of course, rejected that any species-nature is immutable, as species can always be transformed via the inheritance of acquired characteristics. In fact, many of Freud's Viennese contemporaries-such as Wilhelm Reich, Julius Tandler, and Paul Kammerer-took their Lamarckism to license precisely the sorts of radical social projects Freud deemed impossible. Thus the Freud of Civilization helped himself to a rigid view of human nature which, given his associated biological views, he seemingly ought to have rejected. In this paper, I explain this apparent inconsistency, and suggest Freud resolved it in the following way: Freud was not merely a Lamarckian, but also a strong and peculiar kind of recapitulationist, who believed stages of psychological development both recapitulate phylogeny, and "remain with us" throughout both individual lives and future species-history. I suggest Freud's recapitulationism supposed a certain inertia: what occurred in phylogenetic history cannot un-occur, and therefore there are aspects of our nature which we cannot un-acquire. In this way, Freud reached a rigid conception of human nature despite his Lamarckism.

Positive genetic effect of hypertension family history on stroke: A cross Mendelian randomization study.

BACKGROUND: Clinical observational study demonstrated that hypertension is an independent risk factor for stroke. Furthermore, both hypertension and stroke exhibit genetic predispositions. However, the genetic relationship between hypertension and stroke in first-degree relatives remains unclear. METHOD: The Genetic effects were validated using an across-Mendelian randomization (MR) approach. The Genome-Wide Association Study summary data used in this study were obtained from a publicly available platform. The primary MR effect employed was inverse-variance weighted (IVW), and the other analysis methods included MR-Egger, weighted median, simple mode, and weighted mode. Prior to MR analysis, tests for MR_PRESSO, pleiotropy, and heterogeneity were conducted. RESULT: The presence of family history of hypertension significantly contributed to the genetic predisposition to various types of stroke, including ischemic stroke, subarachnoid hemorrhage, lacunar stroke, cardioembolic ischemic stroke, small vessel ischemic stroke, and large artery atherosclerosis-related ischemic stroke. CONCLUSION: Briefly, hypertension in first-degree relatives has a genetic impact on the risk of stroke development. Shared genetic factors may exist between hypertension and stroke.

Combination of FLNC and JUP variants causing arrhythmogenic cardiomyopathy in an Iranian family with different clinical features.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) characterized by progressive myocardial loss and replacement with fibro-fatty tissue is a major cause of sudden cardiac death (SCD). In particular, ACM with predominantly left ventricular involvement, known as arrhythmogenic left ventricular cardiomyopathy (ALVC), has a poor prognosis. METHODS: The proband underwent whole-exome sequencing (WES) to determine the etiology of ALVC. Family members were then analyzed using PCR and Sanger sequencing. Clinical evaluations including 12-lead ECG, transthoracic echocardiography, and cardiac MRI were performed for all available first-degree relatives. RESULTS: WES identified two variants in the FLNC (c.G3694A) and JUP (c.G1372A) genes, the combination of which results in ALVC and SCD. CONCLUSION: The present study comprehensively investigates the involvement of two discovered variants of FLNC and JUP in the pathogenesis of ALVC. More study is necessary to elucidate the genetic factors involved in the etiology of ALVC.

Stem cell models of inherited arrhythmias.

Inherited arrhythmias are a heterogeneous group of conditions that confer risk of sudden death. Many inherited arrhythmias have been linked to pathogenic genetic variants that result in ion channel dysfunction, although current genetic testing panels fail to identify variants in many patients, potentially secondary to their underlying substrates being oligogenic or polygenic. Here we review the current state of knowledge surrounding the cellular mechanisms of inherited arrhythmias generated from stem cell models with a focus on integrating genetic and mechanistic data. The utility and limitations of human induced pluripotent stem cell models in disease modeling and drug development are also explored with a particular focus on examples of pharmacogenetics and precision medicine. We submit that progress in understanding inherited arrhythmias is likely to be made by using human induced pluripotent stem cells to model probable polygenic cases as well as to interrogate the diverse and potentially complex molecular networks implicated by genome-wide association studies.

Genetic Polymorphisms in Cardiovascular Disease: Effects Across Three Generations Exposed to Radiation from the Semipalatinsk Nuclear Test Site.

The population in the areas neighboring the Semipalatinsk Nuclear Test Site (SNTS) in the eastern region of Kazakhstan faces increased cardiovascular disease (CVD) risk. Previous research has not explored gene polymorphisms related to CVD in this population. Therefore, the present study examines the prevalence of six CVD-associated genotypes in three generations exposed to SNTS radiation. The genotyping of ApoE Leu28 → Pro, AGT Met174 → Thr, AGT Met235 → Thr, eNOS T786 → C, PON1 Gln192 → Arg, and EDN 1 Lys198 → Asn was performed using real-time polymerase chain reaction. The present study encompassed a cohort of 218 participants with a familial history of arterial hypertension and/or carotid artery disease spanning at least three generations. The analysis unveiled significant disparities in the prevalence of ApoE Leu28 → Pro, eNOS T786 → C, and PON1 Gln192 → Arg genotypes across different generations. Furthermore, a substantial variation in the distribution of the eNOS T786 → C genotype was observed between individuals of Kazakh and Russian ethnicities. Nevertheless, no significant discrepancies were detected in the frequencies of the investigated genotypes between genders. Further research in this area is warranted to enhance the understanding of the genetic factors contributing to CVD in the population exposed to radiation from the SNTS. Specifically, future studies should broaden the scope of genetic polymorphisms investigated and include representatives of healthy individuals who have not been exposed to radiation as controls.

"Re-evaluation of variants of uncertain significance in patients with hereditary arrhythmogenic disorders".

BACKGROUND: Genetic diagnostics support the diagnosis of hereditary arrhythmogenic diseases, but variants of uncertain significance (VUS) complicate matters, emphasising the need for regular reassessment. Our study aims to reanalyse rare variants in different genes in order to decrease VUS diagnoses and thus improve risk stratification and personalized treatment for patients with arrhythmogenic disorders. METHODS: Genomic DNA was analysed using Sanger sequencing and next-generation sequencing (NGS). The Data was evaluated using various databases and in silico prediction tools and classified according to current ACMG standards by two independent experts. RESULTS: We identified 53 VUS in 30 genes, of which 17 variants (32%) were reclassified. 13% each were downgraded to likely benign (LB) and benign (B) and 6% were upgraded to likely pathogenic (LP). Reclassifications mainly occurred among variants initially classified in 2017-2019, with rates ranging from 50 to 60%. CONCLUSION: The results support the assumption that regular reclassification of VUS is important, as it provides new insights for genetic diagnostics, that benefit patients and guide therapeutic approach.

Sheep litter size heredity basis using genome-wide selective analysis.

Sheep are important herbivorous domestic animal globally, and the Chinese indigenous sheep breed has a multitude of economically significant variations due to the diverse geographical and ecological conditions. In particular, certain native breeds exhibit a visible high litter size phenotype due to the selection pressure of natural and artificial for thousands of years, offering an ideal animal model for investigating sheep's fecundity. In this study, selective signal analysis was performed on public whole-genome sequencing data from 60 sheep across eight breeds to identify candidate genes related to litter size. Results revealed that a total of 34,065,017 single-nucleotide polymorphisms (SNPs) were identified from all sheep, and 65 candidate genes (CDGs) were pinpointed from the top 1% of interacted windows and SNPs between the pairwise fixation index (FST, >0.149543) and cross-population extended haplotype homozygosity (XP-EHH, >0.701551). A total of 41 CDGs (e.g. VRTN, EYA2 and MCPH1) were annotated to 576 GO terms, of which seven terms were directly linked to follicular and embryonic development (e.g. TBXT, BMPR1B, and BMP2). In addition, 73 KEGG pathways were enriched by 21 CDGs (e.g. ENTPD5, ABCD4 and RXFP2), mainly related to Hippo (TCF4, BMPR1B and BMP2), TGF-ß (BMPR1B and BMP2), PI3K-Akt (ITGB4, IL4R and PPP2R5A) and Jak-STAT signalling pathways (IL20RA and IL4R). Notably, a series of CDGs was under strong selection in sheep with high litter size traits. These findings result could improve the comprehension of the genetic underpinnings of sheep litter size. Furthermore, it provides valuable CDGS for future molecular breeding.

Genetic analysis and family screening for dilated cardiomyopathy: a retrospective analysis of the stepwise pedigree approach.

AIMS: This study aimed to assess the practicality of using a stepwise pedigree-based approach to differentiate between familial and sporadic Dilated Cardiomyopathy (DCM), while also considering timing of the genetic analysis. The analysis includes an examination of the extent to which complete family investigations were conducted in real-world scenarios as well as the length of the investigation. METHODS: The stepwise pedigree approach involved conducting a comprehensive family history spanning 3 to 4 generations, reviewing medical records of relatives, and conducting clinical screening using echocardiography and electrocardiogram on first-degree relatives. Familial DCM was diagnosed when at least 2 family members were found to have DCM, and genetic analysis was considered as an option. This study involved a manual review of all DCM investigations conducted at the Centre of Cardiovascular Genetics at Umeå University Hospital, where the stepwise pedigree approach has been employed since 2007. RESULTS: The investigation process had a mean duration of 643 days (95% CI 560.5-724.9). Of the investigations preformed, 94 (68%) were complete, 12 (9%) were ongoing, and 33 (24%) were prematurely terminated and thus incomplete. At the conclusion of the investigations, 55 cases (43%) were classified as familial DCM, 50 (39%) as sporadic DCM, and 22 (18%) remained unassessed due to incomplete pedigrees. Among the familial cases, genetic verification was achieved in 40%. CONCLUSION: The stepwise pedigree approach is time consuming, and the investigations are often incomplete which may suggest that a more direct approach to genetic analysis, may be warranted.

[The hereditary vessel disease CADASIL].

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary small vessel disease of the brain characterized by progressive white matter lesions, subcortical infarcts, and cognitive decline. This autosomal dominant disorder is caused by mutations in the NOTCH3 gene located on chromosome 19, resulting in the accumulation of granular osmiophilic material within the walls of small arteries and arterioles. Clinically, CADASIL typically manifests in mid-adulthood with recurrent ischemic events, migraine with aura, mood disturbances, and cognitive impairment. Neuroimaging plays a crucial role in the diagnosis of CADASIL, with characteristic findings including white matter hyperintensities particularly in the anterior temporal lobe and external capsule.

Clarifying Mendelian vs non-Mendelian inheritance.

Gregor Mendel developed the principles of segregation and independent assortment in the mid-1800s based on his detailed analysis of several traits in pea plants. Those principles, now called Mendel's laws, in fact, explain the behavior of genes and alleles during meiosis and are now understood to underlie "Mendelian inheritance" of a wide range of traits and diseases across organisms. When asked to give examples of inheritance that do NOT follow Mendel's laws, in other words, examples of non-Mendelian inheritance, students sometimes list incomplete dominance, codominance, multiple alleles, sex-linked traits, and multigene traits and cite as their sources the Khan Academy, Wikipedia, and other online sites. Against this background, the goals of this Perspective are to (1) explain to students, healthcare workers, and other stakeholders why the examples above, in fact, display Mendelian inheritance, as they obey Mendel's laws of segregation and independent assortment, even though they do not produce classic Mendelian phenotypic ratios and (2) urge individuals with an intimate knowledge of genetic principles to monitor the accuracy of learning resources and work with us and those resources to correct information that is misleading.

Whole-exome sequencing revealed a likely pathogenic variant in NF1 causing neurofibromatosis type I and Arrhythmogenic Cardiomyopathy.

BACKGROUND: Neurofibromatosis type I (NF1) is a genetic disorder characterized by the tumor's development in nerve tissue. Complications of NF1 can include pigmented lesions, skin neurofibromas, and heart problems such as cardiomyopathy. In this study, we performed whole-exome sequencing (WES) on an Iranian patient with NF1 to identify the genetic cause of the disease. METHODS: Following clinical assessment, WES was used to identify genetic variants in a family with a son suffering from NF1. No symptomatic manifestations were observed in other family members. In the studied family, in silico and segregation analysis were applied to survey candidate variants. RESULTS: Clinical manifestations were consistent with arrhythmogenic cardiomyopathy (ACM). WES detected a likely pathogenic heterozygous missense variant, c.3277G > A:p.Val1093Met, in the NF1 gene, confirmed by PCR and Sanger sequencing. The patient's parents and brother had a normal sequence at this locus. CONCLUSIONS: Although there is no cure for NF1, genetic tests, such as WES, can detect at-risk asymptomatic family members. Furthermore, cardiac evaluation could also help these patients before heart disease development.

A novel heterozygous variant of the SALL1 gene with atypical Townes-Brocks syndrome phenotypes in Chinese family.

Townes-Brocks syndrome (TBS) is an autosomal dominant disorder characterised by the triad of anorectal, thumb, and ear malformations. It may also be accompanied by defects in kidney, heart, eyes, hearing, and feet. TBS has been demonstrated to result from heterozygous variants in the SALL1 gene, which encodes zinc finger protein believed to function as a transcriptional repressor. The clinical characteristics of an atypical TBS phenotype patient from a Chinese family are described, with predominant manifestations including external ear dysplasia, unilateral renal hypoplasia with mild renal dysfunction, and hearing impairment. A novel heterozygous variant c.3060T>A (p.Tyr1020*) in exon 2 of the SALL1 gene was identified in this proband. Pyrosequencing of the complementary DNA of the proband revealed that the variant transcript accounted for 48% of the total transcripts in peripheral leukocytes, indicating that this variant transcript has not undergone nonsense-mediated mRNA decay. This variant c.3060T > A is located at the terminal end of exon 2, proximal to the 3' end of the SALL1 gene, and exerts a relatively minor impact on protein function. We suggest that the atypical TBS phenotype observed in the proband may be attributed to the truncated protein retaining partial SALL1 function.

Genetic correlations between liver fat content, metabolic health, and adiposity distribution in the Fels Longitudinal Study.

BACKGROUND AND AIMS: Hepatic steatosis is known to be heritable, but its genetic basis is mostly uncharacterized. Steatosis is associated with metabolic and adiposity features; recent studies hypothesize that shared genetic effects between these traits could account for some of the unexplained heritability. This study aimed to quantify these genetic associations in a family-based sample of non-Hispanic white adults. METHODS AND RESULTS: 704 participants (18-95 years, 55.8% female) from the Fels Longitudinal Study with an MRI assessment of liver fat were included. Quantitative genetic analyses estimated the age- and sex-adjusted heritability of individual traits and the genetic correlations within trait pairs. Mean liver fat was 5.95% (SE = 0.23) and steatosis (liver fat >5.56%) was present in 29.8% of participants. Heritability (h2± SE) of steatosis was 0.72 ± 0.17 (p = 6.80e-6). All other traits including liver enzymes, fasting glucose, HOMA-IR, visceral and subcutaneous adipose tissue (VAT, SAT), body mass index, body fat percent, waist circumference, lipids and blood pressure were also heritable. Significant genetic correlations were found between liver fat and all traits except aspartate aminotransferase (AST), and among most trait pairs. Highest genetic correlations were between liver fat and HOMA-IR (0.85 ± 0.08, p = 1.73e-8), fasting glucose and ALT (0.89 ± 0.26, p = 6.68e-5), and HOMA-IR with: waist circumference (0.81 ± 0.12, p = 3.76e-6), body fat percent (0.78 ± 0.12 p = 2.42e-5) and VAT (0.73 ± 0.07, p = 6.37e-8). CONCLUSIONS: Common genes may exist between liver fat accumulation, metabolic features and adiposity phenotypes.

"At a Glance:" The Role of Diagrammatic Representations in Eugenics Appropriations of the "Infamous Juke Family".

The case of the Juke family is one of the most notable episodes of the history of eugenics in the USA. The Jukes were initially brought to the fore in the 1870s by a famous investigation that aimed at estimating the interplay of heredity and environment in determining the problems of poverty and crime. This inquiry triggered a harsh confrontation between two polar interpretations of the study, an "environmentalist" one and a "hereditarian" one. It was with the later reassessment of the case made by the Eugenics American Office (ERO) in the 1910s that the controversy was considered closed with the victory of the eugenicists' hereditarian stance. As a result, the family was made a living proof of the alleged hereditary nature of crime and pauperism and a case study in support of the eugenicists' plea for the sterilization of people deemed the bearers of hereditary defectiveness. In this article, I explore the role played by pedigrees and other diagrammatic representations in the eugenicists' appropriation of the meaning of the case of the Juke family and the role played by this appropriation in asserting the superiority of the ERO's method of work over rival approaches.

A Novel Mutation (Lys31Arg) in the DMD Gene Impacts on Neuromuscular Dysfunctions Found by Whole Exome Sequencing and In Silico Analyses in an Iranian Family.

BACKGROUND: Duchene Muscular Disorder (DMD) is a severe X-linked recessive neuromuscular disease. Previous reports predicted that one-third of cases with a fatal X-linked recessive disease will be caused by a novel mutation, and the mutation rate for DMD seems to be higher in males. OBJECTIVE: A novel mutation in the DMD gene DMD (NM_004006.3):c.92A>G (p.Lys31Arg) is suggested for males because of their heterozygous mothers carrying the mutant alleles. METHOD: Whole Exome Sequencing (WES) was done for a 25-year-old female followed by the screening of the novel mutation in her parents and her brother by the Sanger sequencing technique. Some in silico analyses were run to find the putative alterations in wild-type and mutant structures by PolyPhen-2 and Mupro. Notably, SWISS-MODEL was performed to build a reliable model for the mutant allele based on the PDB ID: 1DXX structure. Also, superimposition was done by PyMol. RESULTS: WES analysis revealed three novel mutations including DLD (exon13:c.G1382A:p. G461E), ABCA3 (exon12:c.G1404C:p.W468C), and DMD (exon2:c.A92G:p.K31R) in the case. Focusing on DMD mutation, Sanger sequencing of the patient's parents and brother indicated no mutant allele in her mother and brother but a mutant allele in her father as a hemizygous pattern. In silico analyses showed no considerable change regarding pathogenic impact. CONCLUSION: In conclusion, our findings revealed no pathogenic effect of the new mutation (K31R) of the DMD gene in an Iranian 25-year-old woman. Because of the DMD importance in preclinical diagnosis, these data may shed a light on the diagnosis of this mutation in future pregnancies.

William Boven's 1915 thesis "Similarity and Mendelism in the heredity of dementia praecox and manic-depressive insanity".

Boven published, in 1915, his MD thesis at the University of Lausanne in which he examined 60 3- to 4-generation pedigrees ascertained from admitted patients with dementia praecox (DP) and manic-depressive insanity (MDI). He asked three questions: (i) were DP and MDI hereditary? (ii) were they the same or distinct conditions? and (iii) were they Mendelian disorders? Based on the rarity of environmental precipitants severe enough to cause disorder onset and the pattern of disorders in relatives, Boven concluded that both disorders were inherited. He found that MDI largely ran in families through direct transmission across generations while DP was only common in collateral relatives. Both pedigrees contained a substantial number of "psychopathic" (personality disordered) relatives in which DP and MDI pedigrees typically had, respectively, paranoid, and dysthymic/cyclothymic features. Boven concludes that their inheritance is largely distinct but not exclusive, as some pedigrees contained cases of both disorders. With assistance from Wilhelm Weinberg, Boven applied algebraic models with proband correction to rates of DP and MDI in sibships and found the results inconsistent with Mendelian transmission. His study represents among the first examinations, using "modern" methods, of the familial relationship between DP and MDI and the first published in French.