Genetic Basis Research Articles

Genetic dissection of ear-related trait divergence between maize and teosinte.

Maize has undergone remarkable domestication and shows striking differences in architecture and ear morphology compared to its wild progenitor, called teosinte. However, our understanding of the genetic mechanisms underlying the ear morphology differences between teosinte and cultivated maize is still limited. In this study, we explored the genetic basis of ear-related traits at both early and mature stages by analyzing a population derived from a cross between Mo17 and a teosinte line, mexicana. We identified 31 quantitative trait loci (QTLs) associated with four IM-related and four ear-related traits, with 27 QTLs subjected to selection during the domestication process. Several key genes related to ear development were found under selection, including KN1 and RA1. Analysis of gene expression in the IM of developing ears from the population revealed the prominent roles of cis-variants in gene regulation. We also identified a large number of trans-eQTLs responsible for gene expression variation, and enrichment analysis on a trans-eQTL hotspot revealed the possible involvement of the sulfur metabolic pathway in controlling ear traits. Integrating the expression and phenotypic mapping data, we pinpointed several candidate genes potentially influencing ear development. Our findings advance the understanding of the genetic basis driving ear trait variation during maize domestication.

Investigation of growth traits in Turkish Merino lambs using multi-locus GWAS approaches: Middle Anatolian Merino

This study explored the genetic basis of growth traits in Middle Anatolian Merino lambs using multi-locus genome-wide association study (GWAS) analyses. Descriptive statistics indicated moderate heritability (h² = 0.363) for birth weight (BW) and (h² = 0.309) for weaning weight (WW), both statistically significant (p < 0.001). Strong genetic correlations were observed between WW and BW (rG = 0.922) and WW and Kleiber ratio (KR, rG = 0.896), implying that simultaneous improvements may be possible through targeted selection. Five multi-locus methods (mrMLM, FASTmrMLM, pLARmEB, FASTmrEMMA, and ISIS EM-BLASSO) were used to identify the polygenic basis of the traits. For BW and WW, 20 and 18 significant SNPs (LOD ≥ 5) were detected, respectively, with some SNPs co-detected by multiple methods. In contrast, only 10 significant SNPs were identified for KR, all exclusively by the ISIS EM-BLASSO approach. Pathway analyses within ± 100 Kb of associated SNPs revealed genes and pathways influencing these traits, which could be leveraged in future breeding programs for enhanced growth performance. The identified SNPs, particularly those associated with BW and WW traits, could facilitate genomic selection if validated in larger and more diverse populations.

Exploring the genetic diversity and population structure of an ancient hexaploid wheat species Triticum sphaerococcum using SNP markers

BackgroundUnderstanding genetic diversity and population structure is crucial for strategizing and enhancing breeding efficiency. Wheat, a globally cultivated crop, is a significant source of daily calories for humans. To overcome challenges such as extreme climatic fluctuations, stagnant yields, and diminishing genetic variation, it is essential to develop diverse germplasms with new alleles. Triticum sphaerococcum, an underutilized ancient hexaploid wheat species, shows promise for contributing beneficial alleles. However, the genetic diversity of its germplasms remains unstudied. This is the first report where we have examined the genetic diversity and population structure of 116 T. sphaerococcum accessions using a 35 K SNP Array. The objective of this study is to apply these findings to improve wheat breeding programs.ResultsAnalysis of the population’s genetic structure identified four potential subpopulations, which was supported by principal coordinate analysis. Allele neutrality tests showed an abundance of intermediate genotypes, suggesting that many beneficial alleles are maintained through balancing selection. Among the three subgenomes, subgenome B exhibited the highest genetic diversity. AMOVA (Analysis of Molecular Variance) revealed significant variation both among (35%) and within (65%) the four subpopulations. The high genetic differentiation between subpopulations was corroborated by a moderate level of haploid migrant numbers (Nm = 1.286), indicating sufficient gene flow. SP4 emerged as the most diverse subpopulation, showing the highest values for allelic pattern indices due to its larger size and higher percentage of polymorphic loci. The D subgenome displayed a faster linkage disequilibrium (LD) decay rate compared to the A and B subgenomes. Haplotype block analysis identified 260 haplotype blocks of varying sizes distributed across the genome.ConclusionsThis research demonstrates that Indian dwarf wheat accessions, sourced from three distinct gene banks and local collections, possess considerable genetic diversity. These germplasm collections offer valuable opportunities to investigate their unexplored genetic potential. They can be utilized in wheat improvement initiatives to tackle both present and future breeding challenges. Furthermore, these accessions can introduce new alleles to broaden the genetic base of modern wheat varieties, enhancing their overall diversity.

QTL analysis in the Mianmai 902×Taichang 29 RIL population reveals the genetic basis for the high-yield of wheat cultivars Mianmai 902 in terms of spike and plant architecture

Spike-related traits and plant height (PH) are greatly associated with wheat yield. Identification of stable quantitative trait loci (QTL) for these traits is crucial for understanding the genetic basis for yield and their further application in breeding. In this study, QTL analysis for spikelet number per spike (SNS), spike length (SL), spike compactness (SC) and PH was performed using a recombinant inbred line (RIL) population derived from a cross between wheat cultivars Mianmai902 (MM902) and Taichang29 (TC29). Thirteen stably expressed QTLs were identified, and the most favorable alleles were contributed by MM902. The mjaor QTL, QSNS-MT.cib-2D, QSL-MT.cib-2D, QSC-MT.cib-2D, QSC-MT.cib-6 A, QPH-MT.cib-4B and QPH-MT.cib-4D, were repeatedly detected in multiple environments and explained 5.77-47.11% of the phenotypic variations. By employing the Kompetitive Allele Specific PCR markers, the most major QTLs were successfully validated in multiple populations derived from different genetic backgrounds. Moreover, the individual and pyramiding effects of major QTLs on SNS, SL, SC, PH, grain number per spike (GNS) and thousand-grain weight (TGW) were investigated and their potential utilization value in breeding was showcased. Ppd-D1 was predicted as the candidate for QSNS/SL/SC/PH-MT.cib-2D, and MM902 carried the Ppd-D1d allele. Ppd-D1d is rare in Chinese winter wheat cultivars and may be an elite alternative allele of the Ppd-D1a allele. In summary, these QTLs revealed the genetic basis of the spike-related traits and PH of MM902, which partially contributed to the high yield of MM902 and have application potential in wheat breeding by optimizing spike morphology and PH to improve yield.

Polar localization and local translation of RHO-RELATED PROTEIN FROM PLANTS2 mRNAs promote root hair growth in Arabidopsis.

Root hairs are tip-growing cells that anchor plants in the soil and are critical for water uptake, nutrient acquisition, and plant-environment interactions. While the molecular mechanisms that maintain the polar growth of root hairs through the asymmetric distribution of proteins, such as RHO-RELATED PROTEIN FROM PLANTS 2 (ROP2), have been described, it is unclear whether and how the transcripts encoding these tip-localized proteins are polarly localized and locally translated. Here, we demonstrated that ROP2 mRNA exhibits polar localization in Arabidopsis (Arabidopsis thaliana) root hairs. We showed that region VI (250-350 bp downstream of the stop codon) of the ROP2 3' untranslated region (UTR) is necessary for proper mRNA localization. Moreover, region VI-mediated ROP2 mRNA polar localization was required for local translation of ROP2 transcripts, contributing to the proper subcellular localization of ROP2. Region III (100-200 bp downstream of the stop codon) influenced the local translation of ROP2 mRNA. Phenotypic investigations demonstrated that both regions III and VI of the ROP2 3' UTR play crucial roles in modulating root hair growth. These findings help explain the local protein biosynthesis of ROP2, advancing our understanding of the regulatory mechanism and genetic basis of mRNA localization and local translation in plants.

Genome-wide association study reveals the advantaged genes regulating japonica rice grain shape traits in northern China

Background Rice, a staple food for over half of the global population, exhibits significant diversity in grain shape characteristics, which impact not only appearance and milling quality but also grain weight and yield. Identifying genes and loci underlying these traits is crucial for improving rice breeding programs. Previous studies have identified multiple quantitative trait loci (QTLs) and genes regulating grain length, width, and length-width ratio; however, further investigation is necessary to elucidate their regulatory pathways and their practical application in crop improvement. Methods This study employed a genome-wide association study (GWAS) on 280 japonica rice varieties from northern China to decipher the genetic basis of grain shape traits. Phenotyping included measurements of 11 grain-related traits, such as grain length, width, and area, along with their brown and white rice counterparts. High-density single nucleotide polymorphism (SNP) markers (33,579) were utilized for genotyping, and GWAS was performed using a mixed linear model (MLM) incorporating principal component analysis (PCA) and kinship (K) matrix to account for population structure and relatedness. Results Our analysis detected 15 QTLs associated with the 11 grain shape traits, of which five major QTL clusters emerged as crucial. Candidate genes, including LOC_Os01g50720 (qGL1), OsMKK4 (LOC_Os02g54600, influencing qBA2, qWL2, and qWA2), GW5 (LOC_Os05g09520, controlling qGW5, qBW5, qBR5, qWW5, and qWR5), GW6a (LOC_Os06g44100, associated with qGW6, qBW6, qBR6, qWW6, and qWR6), and FZP (LOC_Os07g47330, linked to qWL7), were identified based on functional annotations and haplotype analysis. These findings offer valuable insights into the genetic mechanisms underlying rice grain shape and suggest promising targets for marker-assisted selection to enhance rice quality and yield.

A chromosome-scale reference genome of the Banna miniature inbred pig

The Banna miniature inbred pig (BN) is an intensively inbred line for biomedical research and xenotransplantation due to its low individual variation and stable genetic background. Although it is originated from the Diannan miniature pig (DN), substantial genetic changes have actually occurred. However, the lack of a BN reference genome has limited studies on the complete genomic architecture and utilization as a biomedical model. Here, we present a high-quality genome for BN using PacBio HiFi and Hi-C sequencing technologies, with a total length of 2.66 Gb, a scaffold N50 of 143.60 Mb, and 97.59% of the sequences anchored to chromosomes. Its BUSCO score is 96.30%, higher than porcine reference assembly and DN. The genome contains 48.49% of repeats, 19,756 protein-coding genes, and 7,207 non-coding RNAs according to our annotation. The OMArk score shows a proteome completeness and consistency of 99.58% and 93.62%, respectively. These findings indicate that the chromosome-scale genome of BN provides a valuable resource for studying the genetic basis of inbreeding, facilitating further research and clinical applications.

Dissecting the shared genetic architecture between nonalcoholic fatty liver disease and type 2 diabetes.

Observational studies have reported a bidirectional correlation between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D), but the shared genetic basis between the two conditions remains unclear. Using genome-wide association study (GWAS) summary data from European-ancestry populations, we examined the cross-trait genetic correlation and identified genomic overlaps and shared risk loci. We employed a latent causal variable model and Mendelian randomization (MR) analysis to infer causal relationships. Colocalization analysis and conditional/conjunctional false discovery rate (condFDR/conjFDR) were used to identify genomic overlaps and shared risk loci. Two-step MR analysis was utilized to identify potential mediators. We observed a strong positive genomic correlation between NAFLD and T2D (rg = 0.652, P = 5.67 × 10-6) and identified tissue-specific transcriptomic correlations in the pancreas, liver, skeletal muscle, subcutaneous adipose, and blood. Genetic enrichment was observed in NAFLD conditional on associations with T2D and vice versa, indicating significant polygenic overlaps. We found robust evidence for the causal effect of NAFLD on T2D, particularly insulin-related T2D, rather than vice versa. Colocalization analysis identified shared genomic regions between NAFLD and T2D, including GCKR, FTO, MAU2-TM6SF2, and PNPLA3-SAMM50. High-density lipoprotein cholesterol and insulin were partly mediated the association between NAFLD and T2D. These findings unveil a close genetic link between NAFLD and T2D, shedding light on the biological mechanisms connecting NAFLD progression to T2D.

Ancient genomes reveal a deep history of treponemal disease in the Americas.

Human treponemal infections are caused by a family of closely related Treponema pallidum that give rise to the diseases yaws, bejel, pinta and, most famously, syphilis1. Debates on both a common origin for these pathogens and the history of syphilis itself has weighed evidence for the "Columbian hypothesis"2, which argues for an American origin, against that for the "pre-Columbian hypothesis"3, which argues for presence of the disease in Eurasia in the Medieval period and possibly earlier. While molecular data has provided a genetic basis for distinction of the typed subspecies4, deep evolution of the complex has remained unresolved due to limitations in the conclusions that can be drawn from the sparse paleogenomic data currently available. Here we explore this evolutionary history through analyses of five pre- and peri-contact ancient treponemal genomes from the Americas that represent ancient relatives of the T. pallidum pallidum (syphilis), T. pallidum pertenue (yaws) and T. pallidum endemicum (bejel) lineages. Our data indicate unexplored diversity and an emergence of T. pallidum that post-dates human occupation in the Americas. Together these results support an American origin for all T. pallidum characterized at the genomic level, both modern and ancient.

The maintenance of genetic polymorphism underlying sexually antagonistic traits

Abstract Selection often favors different trait values in males and females, leading to genetic conflicts between the sexes when traits have a shared genetic basis. Such sexual antagonism has been proposed to maintain genetic polymorphism. However, this notion is based on insights from population genetic models of single loci with fixed fitness effects. It is thus unclear how readily polymorphism emerges from sex-specific selection acting on continuous traits, where fitness effects arise from the genotype-phenotype map and the fitness landscape. Here, we model the evolution of a continuous trait that has a shared genetic basis but different optima in males and females, considering a wide variety of genetic architectures and fitness landscapes. For autosomal loci, the long-term maintenance of polymorphism requires strong conflict between males and females that generates uncharacteristic sex-specific fitness patterns. Instead, more plausible sex-specific fitness landscapes typically generate stabilizing selection leading to an evolutionarily stable state that consists of a single homozygous genotype. Except for sites tightly linked to the sex-determining region, our results indicate that genetic variation due to sexual antagonism should arise only rarely and often be transient, making these signatures challenging to detect in genomic data.

The transcription factor OsNAC25 regulates potassium homeostasis in rice.

Over-application of potassium (K) fertilizer in fields has a negative impact on the environment. Developing rice varieties with high KUE will reduce fertilizer for sustainable agriculture. However, the genetic basis of KUE in a more diverse and inclusive population remains largely unexplored. Here, we show that the transcription factor OsNAC25 enhances K+ uptake and confers high KUE under low K+ supply. Disruption of OsNAC25 by CRISPR/Cas9-mediated mutagenesis led to a considerable loss of K+ uptake capacity in rice roots, coupled with reduced K+ accumulation in rice and severe plant growth defects under low- K+ conditions. However, the overexpression of OsNAC25 enhanced K+ accumulation by regulating proper K+ uptake capacity in rice roots. Further analysis displayed that OsNAC25 can bind to the promoter of OsSLAH3 to repress its transcription in response to low- K+ stress. Nucleotide diversity analyses suggested that OsNAC25 may be selected during japonica populations' adaptation of low K+ tolerance. Natural variation of OsNAC25 might cause differential expression in different haplotype varieties, thus conferring low K+ tolerance in the Hap 1 and Hap 4 -carrying varieties, and the japonica allele OsNAC25 could enhance low K+ tolerance in indica variety, conferring great potential to improve indica low K+ tolerance and grain development. Taken together, we have identified a new NAC regulator involved in rice low K+ tolerance and grain development, and provide a potential target gene for improving low K+ tolerance and grain development in rice.

Calcium Signaling and Molecular Adhesion Processes May Hold the Key to Genetic Risk for Autism: A Molecular Pathway Analysis on Two Independent Samples

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by limited interests, difficulties in social interactions, repetitive behaviors, and impairments in social communication. ASD tends to run in families, and twin studies suggest a strong genetic basis for the disorder. However, the definition of a genetic profile that indicates a risk for ASD remains unclear. Methods: This analysis includes an investigation (Autism Dataset 4 from the NIMH repository, n = 2890) and a replication (Autism Dataset 3 from the NIMH repository, n = 1233) of trio samples with GWAS data. In Phase 1, a molecular pathway analysis is conducted on the investigation sample to test for the enrichment of specific Gene Ontology (GO) terms associated with autism. In Phase 2, the identified pathways are tested for enrichment in the replication sample. Permutation tests are performed to reduce the risk of false-positive findings. Quality assessment is conducted using QQ-plots and λ values, with Plink and R utilized for the Transmission Disequilibrium Test (TDT) and permutation tests. Results: The GO term GO:0007417 was found to be enriched in both the investigation and replication samples. SNPs associated with this pathway were observed at a frequency higher than expected in the replication sample. Conclusions: The GO term GO:0007417 (development of the nervous system) was associated with autism in both trio samples. Variations in the genes TMPRSS4, TRPC4, and PCDH9 were consistently linked to autism across the two independent samples, highlighting the role of calcium signaling and cell adhesion molecules in the risk of autism-related disorders. The pathways and variations associated with autism are described in detail, which can contribute to the engineering of new pharmacological treatments for ASD.

Whole exome sequencing reveals heparan sulfate proteoglycan 2 (HSPG2) as a potential causative gene for kidney stone disease in a Thai family

Kidney stone disease (KSD) is a prevalent and complex condition, with an incidence of 85 cases per 100,000 individuals in Thailand. Notably, over 40% of cases are concentrated in the northeastern region, indicating a potential genetic influence, which is supported by genetic mutations reported in several families by our research group. Despite this, the genetic basis of KSD remains largely unknown for many Thai families. This study aimed to identify the genetic mutation responsible for KSD in a specific Thai family, the UBRS131 family, which includes four affected individuals. Whole exome sequencing was performed, and variant filtering using the VarCards2 program identified 10 potentially causative mutations across 9 genes. These mutations were subjected to segregation analysis among family members and screened in 180 control and 179 case samples using real-time PCR-HRM or PCR-RFLP techniques. Prioritization of these variants using GeneDistiller identified the p.Asp775Glu mutation in the heparan sulfate proteoglycan 2 (HSPG2) gene as the likely causative mutation for KSD in this family. The Asp775 residue is highly conserved across vertebrates, and structural analysis suggests that the Glu775 substitution may disrupt the formation of two crucial hydrogen bonds, potentially altering the mutant protein’s configuration. Immunohistochemistry confirmed the presence of perlecan (HSPG2 protein) in the proximal tubules in nephrons. These findings highlight the significant role of the HSPG2 gene in familial KSD within this study family.

Unveiling genetic insights: Array-CGH and WES discoveries in a cohort of 122 children with essential autism spectrum disorder

BackgroundAutistic Spectrum Disorder (ASD) is a neurodevelopmental disorder with a strong genetic component and high heterogeneity. Essential ASD refers to patients who do not have other comorbidities. This study aimed to investigate the genetic basis of essential ASD using whole exome sequencing (WES) and array-comparative genomic hybridization (array-CGH).ResultsIn a cohort of 122 children with essential ASD, WES detected 382 variants across 223 genes, while array-CGH identified 46 copy number variants (CNVs). The combined use of WES and array-CGH revealed pathogenic variants in four patients (3.1% detection rate) and likely pathogenic variants in 34 patients (27.8% detection rate). Only one patient had a pathogenic CNV (0.8% detection rate). Including likely pathogenic variants, the overall detection rate was 31.2%. Additionally, 33 de novo heterozygous sequence variants were identified by WES, with three classified as pathogenic and 13 as likely pathogenic. Sequence variants were found in 85 genes already associated with ASD, and 138 genes not previously included in the SFARI dataset were identified as potential new candidate genes.ConclusionsThe study enhances genetic understanding of essential ASD and identifies new candidate genes of interest. The findings suggest that using both array-CGH and WES in patients with essential ASD can improve the detection of pathogenic and likely pathogenic genetic variants, contributing to better diagnosis and potentially guiding future research and treatment strategies.

Analysis of a Chinese pedigree with female infertility due to WEE2 gene c.495del homozygous frameshifting variant induced fertilization disorder

To explore the genetic basis for a patient with repeated fertilization failure during assisted reproductive therapy, and to identify the source and mode of mutation. A couple treated at the Center for Reproductive Medicine, Gansu Provincial Maternal and Child Health Care Hospital in January 2024 for infertility with incomplete left tube obstruction was selected as the study subject. Relevant clinical data was collected. The couple was subjected to whole exome sequencing (WES), and the candidate variant was verified by Sanger sequencing of their family members and bioinformatic analysis. WES has identified a homozygous c.495del frameshifting mutation of the WEE2 gene in the female partner, whilst no relevant variant was suspected in the male partner. The elder brother of the female partner was homozygous for the above variant, while her parents, maternal and paternal aunts, uncle, grandmother, and grandmother were heterozygous for it. Based on the guidelines from the American College of Medical Genetics and Genomics, above variant was rated to be pathogenic. The homozygous c.495del frameshifting mutation of the WEE2 gene probably underlay the oocyte fertilization disorder in this couple, which has conformed to an autosomal recessive inheritance.

Linking Iris Cis-Regulatory Variants to Primary Angle-Closure Glaucoma Via Clinical Imaging and Multiomics.

To elucidate the genetic basis of primary angle-closure glaucoma (PACG) by identifying pathogenic tissue and critical tissue-specific variants. The correlations among PACG susceptibility, axial length (AL), and anterior chamber depth (ACD) were evaluated using meta-analyses. Propensity score matching was utilized on 2161 participants from the Handan Eye Study to determine the risk factors independent of ACD and AL for PACG. Subsequently, we employed the assay for transposase-accessible chromatin with sequencing (ATAC-seq) and allele-specific self-transcribing active regulatory region sequencing (STARR-seq) to screen 202 PACG genome-wide association study (GWAS) variants for chromatin accessibility and functional roles. The meta-analysis found that PACG susceptibility loci are not associated with ACD or AL. However, abnormal iris phenotypes emerged as significant independent risk factors for primary angle-closure disease (PACD), unrelated to ACD and AL. Substantial enrichment of PACG heritability was observed in the open chromatin regions of the human iris. Within the iris-relevant cellular context, 22 out of the 202 PACG GWAS variants could influence enhancer activity. Two variants in the iris open chromatin regions were implicated in the modulation of PLEKHA7 and C10orf53 expression. The downregulation of these two genes affects cytoskeletal organization. Our findings underscore the importance of the iris in the pathogenesis of PACG and identified iris-specific, enhancer-modulating variants that may influence disease risk. Our approach also provides a generalizable framework for studying ocular diseases from the perspective of enhancer-modulating variants.

Parental attitudes and experiences in pursuing genetic testing for their child's motor speech disorder.

Rare and typically severe motor speech disorders such as childhood apraxia of speech (CAS) and dysarthria affect about 1 in 1000 children. The genetic basis of these speech disorders is well-documented, with approximately 30% of children who undergo genomic testing receiving an explanatory genetic diagnosis. As more children with speech disorders are offered genetic testing, understanding parental views and experiences around genetic testing for their child is critical in providing effective pre- and post-test genetic counselling. This research explored parental attitudes, experiences, and perceived implications of pursuing genetic testing for their child with motor speech disorder. Semi-structured interviews were conducted with 20 parents of children with CAS or dysarthria who had undergone exome sequencing. Eight parents had received a genetic diagnosis for their child and 12 received uninformative genetic test results. Interviews were transcribed verbatim, co-coded, and analysed using reflexive thematic analysis. Parents were highly motivated to pursue genetic testing for their child's speech disorder due to the perceived personal, clinical, social, and financial utility in obtaining a genetic diagnosis. Regardless of testing outcome, parents experienced complex emotional responses in receiving their child's genetic test results. Parents whose child received a genetic diagnosis reported improved access to funding and clinical care; however, they also hoped for ongoing informational, clinical, and peer support in navigating the uncertainty surrounding their child's rare diagnosis. Conversely, parents who received uninformative genetic test results reported finding meaning in this test outcome, and used emotional-focused and problem-focused strategies to cope with their child's continued diagnostic odyssey.

Sex-stratified Genomic Structural Equation Models of Posttraumatic Stress Inform PTSD Etiology: L'utilisation de la modélisation génomique par équations structurelles stratifiée par sexe du stress post-traumatique pour expliquer l'étiologie du TSPT.

Posttraumatic stress disorder (PTSD) affects 3.9%-5.6% of the worldwide population, with well-documented sex-related differences. While psychosocial and hormonal factors affecting sex differences in PTSD and posttraumatic stress (PTS) symptom etiology have been explored, there has been limited focus on the genetic bases of these differences. Many symptom combinations may confer a PTSD diagnosis. We hypothesized that these symptom combinations have sex-specific patterns, the examination of which could inform etiological differences in PTSD genetics between males and females. To investigate this, we performed a sex-stratified multivariate genome-wide association study (GWAS) in unrelated UK Biobank (UKB) individuals of European ancestry. Using GWAS summary association data, genomic structural equation modelling was performed to generate sex-specific factor models using 6 indicator variables: trouble concentrating, feeling distant from others, irritability, disturbing thoughts, upset feelings, and avoidance of places/activities which remind the individual of a traumatic event. Models of male and female PTSD symptoms differed substantially (local standardized root mean square difference = 3.12) and significantly (χ2(5) = 28.03, P = 3.6 × 10-5). Independent 2-factor models best fit the data in both males and females; these factors were subjected to GWAS in each sex, revealing 3 genome-wide significant loci in females, mapping to SCAND3, WDPCP, and FAM120A. No genome-wide significant loci were identified in males. All 4 PTS factors (2 in males and 2 in females) were heritable. By assessing the relationship between sex and PTSD symptoms, this study informs correlative and putatively causal etiological differences between males and females which support further investigation of sex differences in PTSD genetics.

Novel CACNA1F pathogenic variant in pediatric incomplete X-linked CSNB: integrating portable ERG and genetic analysis.

To report a novel hemizygous nonsense variant in the CACNA1F gene associated with congenital stationary night blindness (CSNB) in a pediatric patient, emphasizing the utility of portable electroretinography (ERG) and genetic testing in diagnosing unexplained visual impairments. The patient, a 5-year-old male, underwent comprehensive clinical evaluation, including detailed anterior segment and fundus examinations, full-field electroretinogram (ffERG) using a RETeval™ portable device, and whole exome sequencing (WES) to elucidate the genetic basis of his visual impairment. Structural modeling of the mutated protein was performed using SWISS-MODEL and PYMOL. Best-corrected visual acuity was 0.4 logMAR bilaterally, with unremarkable anterior segment and fundus examinations. FFERG revealed significant abnormalities consistent with incomplete CSNB: severely reduced rod response in dark-adapted (DA) 0.01, negative waveform with b/a wave ratio < 1.0 in DA 3.0, and diminished cone response in light-adapted ERG. WES identified a novel pathogenic variant in the CACNA1F gene (c.1234G > T, p.E412*), inherited maternally. This variant introduces a premature stop codon at position 412, likely resulting in a truncated CACNA1F protein. This case highlights the importance of comprehensive clinical assessments and genetic testing in pediatric patients with unexplained visual impairments, revealing a novel CACNA1F variant that expands our understanding of CSNB. The use of a portable ERG device proved particularly valuable in assessing retinal function in this young patient. Further investigations are warranted to elucidate the clinical implications of this novel pathogenic variant.

Gain of function NOTCH3 variants cause familial partial lipodystrophy due to activation of senescence pathways.

Despite elucidation of the molecular genetic basis of several lipodystrophy syndromes, molecular defects in some ultra-rare subtypes of familial lipodystrophies remain unidentified. We analyzed whole exome sequencing (WES) data of four affected and two unaffected females from an undiagnosed autosomal dominant familial partial lipodystrophy (FPL) pedigree and identified only one novel heterozygous variant, p.Ala1603Tyr in NOTCH3 meeting the filtering criteria. Further analysis of WES data of 222 unexplained FPL patients identified two unrelated FPL patients with novel heterozygous, p.Cys1600Tyr and p.Gln1552Pro, NOTCH3 variants. All variants were clustered in the heterodimerization domain of the negative regulatory region of NOTCH3. RNA-Seq and proteomics analysis of skin fibroblasts revealed significantly higher RNA and protein expression of NOTCH3 and activation of widespread senescence pathways in the FPL patients versus controls. NOTCH3 is highly expressed in adipose tissue and plays many crucial roles in developmental patterning, cell fate decisions, regulation of cell survival and proliferation. We conclude that gain-of-function missense variants in the negative regulatory region of NOTCH3 cause a novel subtype of FPL by activation of senescence pathways. This novel variety of FPL should be considered for non-obese patients with early- or childhood-onset diabetes mellitus.