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PubMed1986

Neurovirulence and latency in inbred mice of two HSV-1 intrastrain variants of divergent pathogenicity.

The pathogenicity pattern of the HSV-1 strain ANG which is nonencephalitogenic in mice is compared with that of a selected neurovirulent variant of this strain in DBA-2 mice. After i.p. inoculation both variants replicate to high titers in the mouse peritoneum and build up a virus reservoir in the spleen. Both viruses have no effect on visceral mouse organs other than the spleen; both viruses lead to an inefficient and masked viraemia and both replicate efficiently in CNS tissue after direct intracranial injection. Only the pathogenic variant, however, spreads to the CNS and leads to lethal encephalitis upon intraperitoneal infection. The assumption that infection of the CNS would be mediated by hematogenous transport is not supported by the data obtained from transfer and cocultivation experiments with lymphocytes or experiments involving artificial viraemia. In a model to analyse the capacity of the viruses to invade nerve axons and to induce a latent infection both viruses were found to be latency positive in dorsal root ganglia. It is clear that non-neurovirulent HSV-1 strains are subjected to a postganglionic block of virus spread from the periphery to the CNS. The experiments led to the hypothesis that axonal transport even beyond the dorsal root ganglia to the CNS proceeds unrestricted, whereas lethal CNS invasion is prevented by a restriction of viral replication of HSV-1 ANG in the CNS by a virus-induced host defence mechanism.

Animals↗

PubMed2026

Inference of elevated mutation rates and variant effects using 700k exomes.

Genomic sequencing is now widely accessible for genetic diagnostics and is emerging as a component of newborn screening. This technological development generates the need to characterize incoming mutations, create comprehensive datasets of genes causing rare Mendelian disorders, and identify pathogenic variants. Large-scale exome sequencing datasets such as Genome Aggregation Database (gnomAD) have been assembled to help address these challenges. The recent release of gnomAD (v4; n = 730,947) uncovers millions of rare coding variants, many of which have arisen more than once by independent recurrent mutations in the rapidly growing recent human population. Here, we use newly developed theoretical understanding of sampling properties of rare variants to estimate key population genetics parameters of practical importance to human genetics such as demography history, mutation rate, and selection. Solely relying on population data, our method Population Inferred Estimates of Selection (PIES) identifies novel genes with loss-of-function mutational hotspots likely due to selection in spermatogonia. PIES efficiently estimates selection coefficients for heterozygous loss-of-function variants. Combining population genetics inference with variant effect predictors, PIES predicts pathogenic missense mutations and improves variant prioritization for genetic diagnostics and newborn screening.

Journal Article↗

PubMed2026

FBN1-related connective tissue disorders: unraveling cardiovascular, skeletal, and ocular complications through TGF-β signaling dysregulation and genotypic correlations.

Fibrillin-1 is an extracellular matrix glycoprotein essential for microfibril integrity, mediating cell-matrix interactions, providing structural support to tissues, and serving as a scaffold for elastogenesis. Pathogenic variants in the fibrillin 1 gene (FBN1) give rise to a spectrum of autosomal dominant connective tissue disorders collectively termed type-1 fibrillinopathies, which include Marfan syndrome, geleophysic dysplasia 2, acromicric dysplasia, Weill-Marchesani syndrome 2, marfanoid-progeroid-lipodystrophy syndrome, stiff skin syndrome, MASS syndrome, and isolated ectopia lentis 1. These disorders predominantly manifest cardiovascular, skeletal, and ocular abnormalities. Among these, aortic and valvular lesions are the principal and most life-threatening complications and therefore warrant the greatest clinical attention. Skeletal anomalies are diverse and can even be diametrically opposed across different phenotypes, while ectopia lentis represents the hallmark of ocular conditions. Notably, mutant fibrillin-1 disrupts microfibril structure and/or function, leading to dysregulated transforming growth factor-β (TGF-β) signaling, which is widely recognized as a central mechanism underlying type-1 fibrillinopathies. Although numerous pathogenic FBN1 variants have been identified, the knowledge of genotype-phenotype correlations remains limited in some specific regions. This review synthesizes the current understanding of the FBN1-related molecular mechanisms linking aberrant TGF-β signaling to distinct phenotypic outcomes and discusses how genetically engineered animal models and human induced pluripotent stem cell models advance mechanistic insights and facilitate therapy development. Additionally, clinical manifestations and genetic characteristics across all phenotypes are elaborated to facilitate diagnosis, treatment, and management of these complex disorders.

Cardiovascular complications↗

PubMed2003

Identification of neutral mutants surrounding two naturally occurring variants of Potato spindle tuber viroid.

Single point mutations in the pathogenicity domain of Potato spindle tuber viroid (PSTVd) can have a dramatic effect on disease expression, and only three substitutions are required for the spontaneous conversion of the type strain PSTVd-Intermediate to the rapidly replicating, highly pathogenic variant RG1 (Gruner et al., Virology 209, 60-69, 1995). To identify available evolutionary pathways linking these two variants, we mutagenized five positions in an infectious cDNA copy of PSTVd-Intermediate and screened the resulting mixture of 768 sequences for neutral or near-neutral mutants. Numerical simulations based on the bioassay data indicate that the 23 variants recovered represent >80 % of all such sequences. RG1 was the only naturally occurring variant recovered, and the overall pattern of sequence changes observed indicates that PSTVd-Int occupies a comparatively steep peak within the fitness landscape.

Base Sequence↗

PubMed2025

Genetic heterogeneity in patients with enlarged vestibular aqueduct and Pendred syndrome.

BACKGROUND: Pathogenic variants in the SLC26A4 gene, encoding for Cl-/HCO3- and I- anion transporter pendrin, are associated with non-syndromic hearing loss with enlarged vestibular aqueduct (NSEVA) and Pendred syndrome (PDS). In the Caucasian population, up to 75% of patients fail to identify a genetic cause through biallelic mutations in the SLC26A4 gene. The CEVA haplotype could therefore play an important role in the diagnostics of NSEVA. The aim of the study was to determine the genetic etiology of hearing loss with EVA or with fully developed PDS in 37 probands and the functional characterization of novel variants identified in the SLC26A4 gene. METHODS: To determine the genetic etiology, Sanger sequencing, WES and KASP genotyping assay were used. Functional characterization of SLC26A4 variants c.140G>A (p.R47Q), c.415G>A (p.G139R), c.441G>A (p.M147I), c.481T>A (p.F161I), c.1589A>C (p.Y530S) and c.2260del (p.D754Ifs*5) involved determination of iodide influx, total and plasma membrane pendrin expression level and subcellular localization of pendrin by confocal imaging. The nanopore sequencing of nasopharyngeal swab samples was performed to confirm the pathogenic effect of potential splice site variant c.415G>A. RESULTS: Biallelic variants in the SLC26A4 gene (M2 genotype) were identified in ten probands and a complete CEVA haplotype was confirmed in three probands harbouring SLC26A4 monoallelic variants (M1 genotype). Fifteen variants in the SLC26A4 gene were identified in total, three of which are novel. The functional characterization of the novel variants and variants which were not yet functionally characterized confirmed the pathogenic potential of five out of six tested variants (p.G139R, p.M147I, p.Y530S, p.D754Ifs*5, and p.F161I). Analysis of nasopharyngeal swab samples confirmed exon 4 skipping due to novel variant SLC26A4:c.415G>A. Probands with biallelic SLC26A4 variants had significantly larger thyroid volume per m2 of body surface area than subjects with monoallelic SLC26A4 variants and the CEVA haplotype. CONCLUSIONS: The genetic aetiology was determined in 13 out of 37 probands (35%), seven manifested with PDS and six with NSEVA. The present study highlights the importance of functional testing to confirm the pathogenicity of SLC26A4 variants and the phenotype-genotype correlation in SLC26A4-related disorders.

Humans↗

PubMed2026

Beyond in silico prediction: multi-omics to identify a pathogenic deep intronic HNRNPK variant in Au-Kline syndrome.

Pathogenic variants in HNRNPK are associated with autosomal dominant Au-Kline syndrome (AKS, Au-Kline-Okamoto syndrome, OMIM #616580). This syndrome is characterized by developmental delay and intellectual disability, hypotonia, and distinctive facial features. Despite the use of whole-genome sequencing (WGS) as a powerful diagnostic tool, we nearly dismissed a novel intronic variant (NM_031263.4(HNRNPK):c.214-55 T > A) affecting HNRNPK splicing and function. Although commonly used bioinformatic splice prediction tools, including SpliceAI and PDIVAS, yielded inconclusive results, Face2Gene analysis indicated a high phenotypic similarity to AKS. Characteristic facial features described by Choufani et al. [1] supported the clinical diagnosis of AKS. Subsequent functional studies demonstrated aberrant splicing with intron retention, and DNA methylation profiling revealed a positive HNRNPK-specific episignature. These insights and the de novo status support an evaluation as likely pathogenic. This case report supports the relevance of facial analysis and comprehensive variant validation strategies, particularly for deep intronic variants with ambiguous in silico splicing predictions.

Journal Article↗

PubMed2026

TargetQC: A targeted quality control framework for clinical genomic testing.

Reliable genetic testing depends on accurate assessment of sequencing quality in clinically relevant genomic regions that directly influence variant interpretation. We developed TargetQC, a flexible quality control framework that supports user-defined gene sets, coverage thresholds, and variant sets for evaluating sequencing performance across exome sequencing (ES) and genome sequencing (GS) platforms. TargetQC assesses exon and gene coverage, identifies regions meeting predefined coverage thresholds, evaluates variant detection accuracy, and measures sequencing quality at pathogenic variant sites. We applied TargetQC to the reference sample NA12878 and 665 clinical samples across five ES platforms and one GS platform. ES-VendorB and ES-VendorE achieved the most complete coverage of OMIM coding regions in NA12878, whereas ES-VendorD and ES-VendorE showed the highest coverage compliance in clinical samples. ES-VendorB and GS demonstrated the highest variant detection accuracy. TargetQC provides a practical framework for benchmarking sequencing performance and informing platform selection in clinical genomics.

exome sequencing↗

PubMed2002

A plasmid from a non-insect-transmissible line of a phytoplasma lacks two open reading frames that exist in the plasmid from the wild-type line.

Two novel rolling circle replication (RCR) plasmids, pOYM (3932 nt) and pOYNIM (3062 nt), were isolated from a mildly pathogenic variant line (OY-M) and a mildly pathogenic plus non-insect-transmissible line (OY-NIM), respectively, of onion yellows (OY) phytoplasma, a plant and insect endocellular mollicute. OY-M was isolated from an original wild-type line (OY-W) after regular maintenance using alternate plant/insect infections, while OY-NIM was further isolated from OY-M after maintenance by plant grafting without insect vectors. The RCR-initiator proteins (Rep) of both plasmids, which have a characteristic structure with both plasmid- and virus-like domains, were highly homologous to that of a previously described OY-W plasmid, pOYW (3933 nt), and were expressed in OY-M- and OY-NIM-infected plants, indicating that this replicon is stably maintained in the phytoplasma. Interestingly, pOYNIM lacked two ORFs that exist in both pOYW and pOYM, which encode a single-stranded DNA binding protein (SSB) and an uncharacterized putative membrane protein, indicating that these two proteins are not necessary for the phytoplasma to live in plant cells. These are the first candidates as phytoplasma proteins possibly related to host specificity.

Animals↗

PubMed2005

Simian immunodeficiency virus variants that differ in pathogenicity differ in fitness under rapid cell turnover conditions.

Simian immunodeficiency virus (SIV) has been shown to progress through a number of changes that lead to the emergence of pathogenic viral variants in macaques initially infected with a mildly cytopathic variant, SIVMneCL8. One of these late-stage isolates, SIVMne170, replicates to high levels in vivo and causes a rapid disease course when reintroduced into naïve macaques, resulting in a viral set point up to 3,000-fold higher than the set point of the parental virus, SIVMneCL8. However, in cell culture both viruses replicate with similar kinetics. One major difference between in vivo and in vitro cultures is the life span of the infected cells. Here, we manipulated the life span of infected cells in vitro, and we show that the fitness of SIVMne170 in cultures with a limited cell life span dramatically increased compared to its fitness in cultures with a nonlimited life span of cells. The increase in fitness was at least partially due to the fact that the rapid turnover system eliminates the negative influence of the cytopathic effects associated with replication of SIVMne170. Because the relative fitness of SIVMneCL8 and SIVMne170 observed in the rapid turnover system more accurately reflects their fitness in vivo, the system represents an improved approach to comparing relative fitness of viruses.

Cell Line↗

PubMed2004

The changing field of vaccine development in the genomics era.

An improved understanding of the human immune system and the genetic make-up of pathogens, together with advances in instrumentation and bioinformatics, have provided new insights into the variation of immune responses to vaccines within the human population. Pathogen variation and the diversity of the immune system components within the human population make the design of universal vaccines difficult. New subunit vaccines that target immunologically similar subgroups of the human population and representative pathogen variants are emerging from research that combines immunomics, pathogen genomics, and high-throughput instrumentation.

Genome, Human↗

PubMed2026

Expansion of the allelic and phenotypic spectrum of MED25-related developmental disorder: novel compound heterozygous variants with structural domain implications.

MED25-related developmental disorder (Basel-Vanagaite-Smirin-Yosef syndrome) is a rare autosomal recessive disorder, defined by severe neurodevelopmental delay, corpus callosum abnormalities, ocular involvement, epilepsy, and marked facial appearance. MED25 pathogenic variants interfere with the functioning of the Mediator complex, which is responsible for RNA polymerase II transcription. We report a 9-year-old girl who presents with significant global developmental delay, agenesis of the corpus callosum, congenital cataracts, epilepsy, hypotonia, musculoskeletal abnormalities, and typical craniofacial features. Trio-based whole-exome sequencing revealed compound heterozygous variants in MED25: a maternally transmitted truncating variant (c.1366 C > T; p.Gln456*) and a paternally inherited missense variant (c.430 C > T; p.Leu144Phe). The new classification of the missense variant as potentially pathogenic is supported by a systematic ACMG re-evaluation supported by segregation analysis, phenotypic specificity, computational prediction, and structural localization in the MED25 Activator Interaction Domain (ACID). Comparative phenotypic analyses show strong agreement with reported cases but add more data to fine-tune clinical spectrum. This article broadens the allelic and phenotypic spectrum of MED25-related developmental disorder and highlights the need for comprehensive evaluation across molecular, structural, and phenotypic pathways to elucidate variant signature in rare genetic disease models correctly.

Humans↗

PubMed1987

Hydrophobic adherence and phase variation in Bordetella pertussis.

The hydrophobicity of Bordetella pertussis was assayed by measuring the ability of cells in suspension to adhere to a polystyrene surface. The quantity of adhered bacteria was measured by the binding of enzyme-conjugated anti B. pertussis antibodies. Hydrophobic adherence of non-pathogenic variant strains was about 20% of that exhibited by pathogenic strains. Hydrophobicity was a stable trait as it did not change with passaging or storage. Assays of a series of characterized stable variants suggested that the Filamentous Hemagglutinin (FHA) is the cell surface moiety responsible for hydrophobic adherence in B. pertussis.

Bacterial Adhesion↗

PubMed1998

Systematic analysis of hMSH2 and hMLH1 in young colon cancer patients and controls.

Germ-line mutations in DNA mismatch-repair genes impart a markedly elevated cancer risk, often presenting as autosomal dominant hereditary nonpolyposis colorectal cancer (HNPCC). However, there are no pathognomonic features of HNPCC, not all gene carriers have a family history of the disease, and families fulfilling the Amsterdam criteria are relatively uncommon. Genetic testing of probands with early-onset colorectal cancer, irrespective of family history, is one approach that would allow predictive genetic testing of at-risk relatives. We cloned and sequenced hMSH2 and hMLH1 introns, to optimize genomic sequencing. We then systematically analyzed the entire hMSH2 and hMLH1 genes, by genomic sequencing and in vitro synthesized-protein-truncation assay (IVSP), in 50 colorectal cancer patients <30 years of age at diagnosis. To determine polymorphic variants, 26 anonymous donors also were sequenced. All subjects analyzed had at least 1 of 37 different polymorphic or pathogenic variants. IVSP complemented genomic sequencing, by detection of mutations not identified by genomic analysis. Fourteen cancer patients (28%) had pathogenic mutations, and a number of other variants also may have had a pathogenic significance that remains to be elucidated. Tumor replication-error status was useful in targeting sequencing efforts for this cohort of young patients: sensitivity was 86%, specificity 73%, and positive and negative predictive values 63% and 90%, respectively. These data indicate that an appreciable proportion of young colon cancer probands carry a germ-line mutation in a DNA mismatch-repair gene.

Adaptor Proteins, Signal Transducing↗

PubMed2025

Heterozygous loss-of-function variants in SPTAN1 cause an early childhood onset distal myopathy.

PURPOSE: Heterozygous pathogenic variants in SPTAN1 cause a diverse spectrum of neurogenetic disorders ranging from peripheral and central nervous system involvement to complex syndromic presentations. We set out to investigate the role of SPTAN1 in genetically unsolved hereditary myopathies. METHODS: Through international collaboration we identified 14 families with distal weakness and heterozygous SPTAN1 loss-of-function variants. Clinical data, electrophysiology, muscle computed tomography or magnetic resonance imaging, and muscle biopsy findings were collected and standardized. SPTAN1 protein, messenger RNA expression analysis and copy DNA sequencing was performed on muscle tissue from 2 participants. RESULTS: Five families showed autosomal dominant mode of inheritance, whereas in 9 patients the variant was shown to be de novo, including 2 pairs of monozygotic twins. In 2 families, further segregation analysis was not possible. All affected participants presented with early childhood-onset distal weakness and foot abnormalities. Muscle magnetic resonance imaging or computed tomography in 10 patients showed fatty infiltration of the distal lower limb anterior compartment and/or selective involvement of the extensor hallucis longus muscle. Muscle biopsy revealed myopathic changes in 7 patients. Finally, we provide proof for nonsense-mediated decay in muscle tissue derived from 2 patients. CONCLUSION: We present evidence linking heterozygous SPTAN1 loss-of-function variants to childhood-onset distal myopathy in 14 unrelated families.

Humans↗

PubMed2026

A novel truncating FBN1 variant in a family with Marfan syndrome.

Marfan syndrome is caused by pathogenic variants in FBN1. We identified a novel heterozygous frameshift variant in FBN1 (NM_000138.5: c.6784_6787del, NP_000129.3:p.(Gln2262TrpfsTer28)) in an adult male with severe cardiovascular manifestations. The variant was absent from population databases and fulfilled PVS1 and PM2 criteria. This finding expands the mutational and phenotypic spectrum of FBN1 and highlights the clinical utility of genetic testing in family-based clinical management of Marfan syndrome.

Journal Article↗

PubMed2026

Systematic functional evaluation of CNGA1 missense variants associated with retinitis pigmentosa.

BACKGROUND: Missense variants are frequently classified as variants of uncertain significance (VUS) according to the guidelines of the American College of Medical Genetics and Genomics and the Association of Molecular Pathology (ACMG/AMP). Consequently, disease relevance remains elusive, impeding molecular genetic diagnostics, patients` and family genetic counseling, and identification of patients eligible for clinical trials. Functional studies are critical for resolving the clinical significance of VUS. CNGA1 encodes the main subunit of the rod cyclic nucleotide-gated (CNG) channel, a vital component of the phototransduction cascade. Variants in CNGA1 are a rare cause of autosomal recessive retinitis pigmentosa and a phase I/II gene augmentation trial (NCT06291935) is currently ongoing highlighting the necessity to differentiate benign from pathogenic variants. METHODS: CNGA1 missense variants compiled from retinal disease patient cohorts, public databases and literature were functionally investigated using a medium-throughput aequorin-based assay and in vitro minigene splice assays for predicted exonic spliceogenic variants. Functional data were correlated with the in silico prediction of five variant effect predictors (VEPs) and applied to support or revise variants' ACMG/AMP classification. RESULTS: Data mining revealed 86 missense CNGA1 variants - including three novel - most of them lacking functional data; 65.1% of the variants were initially classified as VUS. The aequorin-based assay showed that 72.1% of tested variants significantly impaired CNG channel function and were classified as functionally abnormal, while 23.3% were functionally normal and 5% remained functionally uncertain. Correlation of the functional data with in silico predictions identified AlphaMissense and CPT-1 to be the most suitable tools for assessing CNGA1 missense variants. Using in vitro minigene splice assays, two putative missense variants were shown to induce missplicing. Based on the functional findings, 62.1% of the variants initially classified as VUS were re-categorized as likely pathogenic or likely benign. Furthermore, 93.3% of the variants initially classified as likely pathogenic showed an effect on CNGA1 channel function, confirming their disease relevance and supporting their reclassification as pathogenic. CONCLUSION: This study represents the first comprehensive functional assessment of disease-associated CNGA1 missense variants, thus significantly advancing the understanding of their disease relevance and improving molecular genetic diagnostics in patients.

Humans↗

PubMed2025

Somatic and germinal mosaicism of a canonical splicing variant causing limb-girdle muscular dystrophy type 1B.

Limb-girdle muscular dystrophy type 1B is one of several muscular dystrophies caused by pathogenic variants in the LMNA gene. In this study, we investigated the clinical, pathological, and genetic findings of an LGMD1B family. Genetic sequencing identified the proband and her younger brother both carried the canonical splicing c.513 + 1G > A variant in the LMNA gene. The variant was absent in the proband's mother, and a certain percentage of the LMNA variant was identified in the venous blood, urine, and semen sample of the proband's father by pyrophosphate sequencing. Further cDNA analysis demonstrated that the canonical splicing c.513 + 1G > A variant in intron 2 induced retention of the first 45 bp of intron 2, resulting in an in-frame insertion of 15 amino acids. Our study directly confirmed the presence of somatic and germinal mosaicism in the LGMD1B family and the pathogenicity of the canonical splicing variant in the LMNA gene.

Humans↗

PubMed1998

Sequence flexibility in the polytropic env gp70-derived region of the membrane glycoprotein (gp55) of Friend spleen focus-forming virus affects its biological activity.

We previously reported (N. Watanabe, M. Nishi, Y. Ikawa, and H. Amanuma, J. Virol. 65:132-137, 1991) that the mutant Friend spleen focus-forming virus (F-SFFV(MS)), which encodes a mutant gp55 membrane glycoprotein with an ecotropic env gp70 sequence, was nonpathogenic. Here we injected the F-SFFV(MS)-Friend murine leukemia virus (F-MuLV) clone 57 complex into newborn DBA/2 mice. We obtained four groups of pathogenic variant F-SFFV complexes, each showing a different degree of pathogenicity in adult mice and a different gp55 profile. Of these, group 1 variant F-SFFV was particularly interesting, because it was the most frequently obtained and because it produced doublet bands of gp55 (59 and 57 kDa), neither of which reacted with the nonecotropic gp70-specific monoclonal antibody, and because its DNA intermediate did not hybridize with the nonecotropic env-specific probe. Cloning and DNA sequence analysis of the env region of one isolate of the group 1 variant F-SFFV revealed that this virus consisted of two distinct F-SFFV genomes; one (clone 117) differed from the other (clone 118) due to the presence of a 39-bp in-frame deletion. Reconstitution to full-length F-SFFV genomes and a pathogenicity assay showed that each reconstituted F-SFFV was pathogenic, with clone 117 showing a higher degree of pathogenicity than clone 118. Both reconstituted F-SFFVs caused activation of the mouse erythropoietin receptor in the factor-independent cell proliferation assay, although much less efficiently than the wild-type polycythemia-inducing isolate F-SFFVp. Clone 118 produced a gp55 of 59 kDa, while clone 117 produced one of 57 kDa. Clone 118 had a substitution by the F-MuLV clone 57 gp70 sequence, indicating that it was derived from the F-SFFV(MS) env gene by a homologous recombination with the F-MuLV clone 57 env gene. The site of the 39-bp deletion in clone 117 corresponded to the portion of the clone 118 sequence which was unique to the ecotropic env genes. These results indicated the importance for the biological activity of gp55 of the sequences in the gp70 differential region, which are contained in both polytropic and ecotropic env genes.

3T3 Cells↗