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PubMed1986

Cloning of open reading frames and promoters from the Saccharomyces cerevisiae genome: construction of genomic libraries of random small fragments.

We have developed a novel efficient method, carrier-facilitated insertion, to insert small (150-600 bp) DNA fragments into plasmid vectors. This method employs a carrier segment of vector DNA to circumvent the difficulties in ligating two fragments together to generate a recombinant circle efficiently. We have used carrier-facilitated insertion to construct three genomic libraries of random (DNase I-generated) fragments from the Saccharomyces cerevisiae genome. One of these was an expression library, and the other two were promoter-cloning libraries. 87-90% of the Escherichia coli colonies in each library contained recombinant plasmids, and less than 3% of the recombinants contained more than one insert. Detection of open reading frames among the inserts in the expression library was accomplished by testing for beta-galactosidase activity. This methodology, unencumbered by the intrinsic disproportionality of cDNA libraries, can be used to identify and clone DNA that codes for a specific antigenic determinant. When used in combination with a method to detect and isolate random constitutive, repressible and inducible yeast promoters, these libraries should permit a comprehensive analysis of the yeast genome and its expression.

Cloning, Molecular↗
PubMed1990

Left atrial dimensions in growth and development: normal limits for two-dimensional echocardiography.

Reference values for normal left atrial dimensions have been based primarily on blind M-mode measurements, with no reports based on two-dimensional echocardiography to provide a comprehensive analysis of the two-dimensional measurements from infancy to old age. This report analyzes the left atrial dimensions from two-dimensional echocardiographic studies in 268 normal healthy subjects to determine normal limits and relations among linear, area and volume measurements of the left atrium. The group mean values change with body size, fitting well to the exponential growth model (r = 0.78 to 0.92). The variance about the mean (which determines normal limits) is represented effectively by a quadratic function of body surface area (r = 0.84 to 0.99). The variables determined by this modeling simplify evaluation of normal limits for any body size at any desired level of confidence, and the data are useful reference standards for interpretation of two-dimensional echocardiograms.

Adult↗
PubMed1992

Chemotherapy of advanced epithelial cancer--a critical review.

This article is a short version of a report which presents a comprehensive analysis of clinical trials and publications examining the value of cytotoxic chemotherapy in the treatment of advanced epithelial cancer. As a result of the analysis and the comments received from hundreds of oncologists in reply to a request for information, the following facts can be noted. Apart from lung cancer, in particular small-cell lung cancer, there is no direct evidence that chemotherapy prolongs survival in patients with advanced carcinoma. Except for ovarian cancer, available indirect evidence rather supports the absence of a positive effect. In treatment of lung cancer and ovarian cancer, the therapeutical benefit is at best rather small, and a less aggressive treatment seems to be at least as effective as the usual one. It is possible that certain sub-groups of patients benefit from the treatment, yet so far the available results do not allow a sufficiently precise definition of these groups. Many oncologists take it for granted that response to therapy prolongs survival, an opinion which is based on a fallacy and which is not supported by clinical studies. To date, it is unclear whether the treated patients, as a whole, benefit from chemotherapy as to their quality of life. For most cancer sites, urgently required types of studies such as randomized de-escalations of dose or comparisons of immediate versus deferred chemotherapy are still lacking. With few exceptions, there is no good scientific basis for the application of chemotherapy in symptom-free patients with advanced epithelial malignancy.

Bias↗
PubMed1992

Relationships between quantitative histological measurements and noninvasive assessments of bone mass.

We performed a comprehensive analysis of the relationships between histologic indices in the iliac crest (cancellous bone volume, trabecular structural indices, cortical width, and core width) and bone density in the spine, hip, and wrist in 81 patients with various metabolic bone diseases including osteoporosis, osteomalacia, hyperparathyroidism, and Paget's disease. In the whole group, all of the histologic indices correlated significantly with bone mineral density (BMD) of the spine and the three regions of the hip (r = 0.28-0.73), with the exception of cortical width which correlated with the hip but not the spine (r = 0.21). There was no relationship between the histologic variables and either the distal or proximal radius. When the osteoporotic subgroup was considered separately, the relationships between BMD and both cancellous bone volume and the structural indices (trabecular number, separation, and thickness) were lost. In contrast, cortical width correlated more strongly with both spine and hip BMD. The relationship between core width and the spine was lost but persisted in the hip region. In female osteoporotic patients alone, only cortical width remained significantly correlated with spine or hip BMD. We conclude that the relationships between bone densities in the axial and peripheral regions and histomorphometric variables in iliac crest are not constant. In addition, cancellous bone volume and the trabecular structural indices relate well to noninvasive axial BMD measurements only in a heterogenous group with a large variance in both parameters. In the more homogeneous group with osteoporosis, cortical width appears to be a more powerful predictor of BMD at the important sites of osteoporotic fracture.

Bone Density↗
PubMed2026

Antibody-drug conjugates against multidrug-resistant cancers: Biomarker-guided patient selection, payload engineering, linker chemistry, and bystander effects.

Antibody-drug conjugates (ADCs) are one of the most significant advancements in modern cancer therapeutics. Combining the target selectivity of monoclonal antibodies with the cytotoxic potential of payloads, ADCs effectively kill cancer cells and offer hope to patients with even refractory cancer types. Beyond simply increasing the number of therapeutic options available for cancer patients, ADCs have become a powerful frontline agent in overcoming multidrug resistance (MDR). As one of the most challenging obstacles to effective cancer care, MDR is mediated by ATP-binding cassette (ABC) transporter-mediated drug efflux, target-based mutations, and dysregulated apoptosis. The clinical success of ADCs specifically engineered to overcome MDR, including in heterogeneous tumors and cancer cells that exhibit bypass signaling, is well established. This is especially evident with trastuzumab deruxtecan (T-DXd) in HER2-low, HER2-positive, and HER2-mutant cancers; sacituzumab govitecan (SG) in TROP2-expressing triple-negative breast cancer (TNBC) and urothelial carcinoma; and enfortumab vedotin in Nectin-4-positive bladder cancer. By overcoming MDR, ADCs have enabled more effective treatment algorithms across multiple malignancies. Most importantly, the clinical application of ADCs has become inextricably linked to cancer genomics. HER2 testing has evolved from a two-tiered system to a continuous spectrum including HER2-ultralow, HER2-low, HER2-positive, and ERBB2-mutant categories. Each of these categories exhibits different eligibility guidelines for ADC patient selection. As cancer cells continue to evolve and develop resistance to even ADCs through mutations and variants, researchers and clinicians have used pharmacogenomics to predict ADC response and resistance. To define the genomic architecture of ADC-resistant tumor subpopulations, single-cell transcriptomic studies and liquid biopsy approaches are being used to enable real-time examination of the tumor genome during ADC therapy, thereby optimizing treatment and circumventing resistance driven by emerging mutations and variants. This review provides a comprehensive analysis of the molecular structure of ADCs, the pharmacological principles underlying their potent cytotoxic activity against MDR cancer cells, the genomic and transcriptomic biomarkers that guide ADC patient selection, and the emerging resistance mechanisms that will shape the next generation of promising ADC development.

Humans↗
PubMed2025

One thousand SARS-CoV-2 antibody structures reveal convergent binding and near-universal immune escape.

Understanding antibody recognition and adaptation to viral evolution is central to vaccine and therapeutic development. Over 1,100 SARS-CoV-2 antibody structures have been resolved, marking the largest structural biology effort for a single pathogen. We present a comprehensive analysis of this landmark dataset to investigate the principles of antibody recognition and immune escape. Human immunoglobulins and camelid single-chain antibodies dominate, collectively mapping 99% of the receptor-binding domain. Despite remarkable sequence and conformational diversity, antibodies exhibit convergence in their paratope structures, revealing evolutionary constraints in epitope selection. Analyses reveal near-universal immune escape of antibodies, including all clinical monoclonals, by advanced variants such as KP3.1.1. On average, over one-third of antibody epitope residues are mutated. These findings support pervasive immune escape, underscoring the need to effectively leverage multi-epitope-targeting strategies to achieve durable immunity. To support community accessibility, we developed an interactive web server for visualization and analysis of antibody-antigen complexes and mutational data.

SARS-CoV-2↗
PubMed2026

Comprehensive identification of carboxylic acids by using bromine isotope-based chemical isotope labelling and structure-guided molecular network.

Carboxylic acids (CAs) are important contributors to the flavor quality of sauce-flavor Chinese Baijiu, yet their comprehensive analysis remains challenging due to poor ionization efficiency, weak chromatographic retention, and limited annotation capability. Herein, we developed a workflow for the high-coverage discovery and annotation of CAs in Baijiu by coupling chemical isotope labeling-liquid chromatography-mass spectrometry with a structure-guided molecular network strategy (SGMNS). A bromine-containing derivatization reagent, 1-(3-aminopropyl)-3-bromoquinolin-1-ium bromide (APBQ), was designed and synthesized to exploit the natural isotope distribution of bromine and characteristic MS/MS fragmentation behavior. Following APBQ derivatization, the target CAs showed superior chromatographic retention and favorable analytical performance. Based on isotopic peak pairing in MS1 and diagnostic fragment validation in MS2, 372 potential CA derivatives were discovered from pooled Baijiu samples and 355 of them were validated by diagnostic fragments in MS2 spectra. To address the scarcity of derivatized spectral libraries, SGMNS was employed for annotation using a background network constructed from APBQ-labeled candidates derived from the Expanded Chinese Baijiu Compound Database. The developed method was further applied to profile Baijiu samples, revealing pronounced differences in CA composition across the seven fermentation rounds. Notably, rounds 3 to 5 exhibited the largest numbers of differential CAs. This study provided an effective analytical strategy for large-scale CA profiling, offering new insight into the chemical basis of flavor formation during multi-round fermentation of sauce-flavor Baijiu.

Isotope Labeling↗
PubMed2026

Clinical and endocrine correlates of genetic etiologies in severe hypospadias: Study from 34 patients.

OBJECTIVE: Hypospadias is a prevalent congenital anomaly (0.3%-1.0%); however, severe hypospadias (defined as proximal cases with the meatus at the penoscrotal junction, scrotum, or perineum) is a rare and clinically challenging entity with a multifactorial etiology. This study aimed to characterize the interrelationships among the clinical, endocrine, and genetic profiles in children with severe hypospadias. MATERIALS AND METHODS: We conducted a comprehensive analysis of 34 male patients with severe hypospadias. Preoperative hormone levels were measured using two methods: chemiluminescent immunoassay for luteinizing hormone and follicle-stimulating hormone, and liquid chromatography-tandem mass spectrometry for testosterone (T), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), 17α-hydroxyprogesterone (17α-OHP), and other steroids. Genetic analysis was conducted via whole exome sequencing. RESULTS: The diagnostic yield of clinically relevant genetic variants (including pathogenic and likely pathogenic, and variants of uncertain significance) in our cohort was 41.2% (14/34) of patients. Patients carrying these variants exhibited a more complex phenotypic profile compared to non-carriers, including a significantly higher rate of patients with ≥3 associated malformations and a greater prevalence of cryptorchidism. Furthermore, the group with clinically relevant variants showed selective elevations in adrenal-derived precursors, specifically 17α-OHP and DHEA. Correlation analysis revealed significant positive associations of both 17α-OHP levels and the T/DHT ratio with the number of associated malformations. CONCLUSION: This study reveals significant genetic heterogeneity in patients with severe hypospadias. Those carrying genetic variants was associated with more severe clinical phenotypes, while certain endocrine variations, including the elevation of adrenal-derived hormones, were also observed in this cohort.

Humans↗
PubMed2024

Identification of a Proteomic Signature for Predicting Immunotherapy Response in Patients With Metastatic Non-Small Cell Lung Cancer.

Immunotherapy has improved survival rates in patients with cancer, but identifying those who will respond to treatment remains a challenge. Advances in proteomic technologies have enabled the identification and quantification of nearly all expressed proteins in a single experiment. Integrating mass spectrometry with high-throughput technologies has facilitated comprehensive analysis of the plasma proteome in cancer, facilitating early diagnosis and personalized treatment. In this context, our study aimed to investigate the predictive and prognostic value of plasma proteome analysis using the SWATH-MS (Sequential Window Acquisition of All Theoretical Mass Spectra) strategy in newly diagnosed patients with non-small cell lung cancer (NSCLC) receiving pembrolizumab therapy. We enrolled 64 newly diagnosed patients with advanced NSCLC treated with pembrolizumab. Blood samples were collected from all patients before and during therapy. A total of 171 blood samples were analyzed using the SWATH-MS strategy. Plasma protein expression in metastatic NSCLC patients prior to receiving pembrolizumab was analyzed. A first cohort (discovery cohort) was employed to identify a proteomic signature predicting immunotherapy response. Thus, 324 differentially expressed proteins between responder and non-responder patients were identified. In addition, we developed a predictive model and found a combination of seven proteins, including ATG9A, DCDC2, HPS5, FIL1L, LZTL1, PGTA, and SPTN2, with stronger predictive value than PD-L1 expression alone. Additionally, survival analyses showed an association between the levels of ATG9A, DCDC2, SPTN2 and HPS5 with progression-free survival (PFS) and/or overall survival (OS). Our findings highlight the potential of proteomic technologies to detect predictive biomarkers in blood samples from NSCLC patients, emphasizing the correlation between immunotherapy response and the idenfied protein set.

Humans↗
PubMed2025

Structural diversity and evolutionary constraints of oxidative phosphorylation.

The oxidative phosphorylation (OxPhos) system is central to metabolism. The more than 90 structural subunits are encoded by different chromosome categories (autosomal, X, and mtDNA). The system is envisioned as an invariant structure between cells and individuals. However, a comprehensive analysis of the 1,000 Genomes Project data reveals unexpected genetic intra-individual variability resulting from the heterozygosity of diploid autosomal genes, while diversity at the population level is generated by variability in mtDNA. We characterized the different levels of structural constriction at evolutionary and population levels for all OxPhos protein residues. To support this analysis, we developed ConScore, a conservation-based predictor of variant impact within OxPhos proteins (area under the receiver operating characteristic curve [ROC-AUC] = 0.97; area under the precision-recall curve [PR-AUC] = 0.94). Notably, for the nuclear-encoded subunits, we found mechanisms limiting individual variability as allelic imbalance or homozygosity bias. Integrating structural, functional, and genetic data, we highlight the significance of each OxPhos protein position, expanding insights into its role in speciation and disease.

Oxidative Phosphorylation↗
PubMed1990

Using FACS vs. communication scores to measure spontaneous facial expression of emotion in brain-damaged patients: a reply to Mammucari et al. (1988).

Buck and Duffy (1980) and Borod et al. (1985) found evidence of deficits in spontaneous expressiveness in right brain-damaged (RBD) patients relative to LBD patients and controls. Using FACS, Mammucari et al. (1988) failed to replicate this result and questioned our methods and findings. This paper replies (a) that Mammucari et al. (1988)'s review of our work is selective and misleading; (b) that there are aspects of their study that can account for their null results, including the insufficient sensitivity of FACS for the measurement of spontaneous expressiveness; and (c) that the results of Mammucari et al. (1988) regarding "aversive eye movements" to a negative film in LBD and control, but not RBD, patients are in fact compatible with our findings. This paper also suggests a general strategy for the objective and comprehensive analysis of spontaneous emotional expressiveness.

Brain Damage, Chronic↗
PubMed1989

Interplay of hydrophobic and electrostatic interactions in biopolymer chromatography. Effect of salts on the retention of proteins.

The effect of salt on the retention behavior of proteins in electrostatic and hydrophobic interaction chromatography is described by a three-parameter equation, log k' = A - B log ms + Cms, where k' is the retention factor and ms is the molality of the salt in the eluent. Parameter B, termed the electrostatic interaction parameter, depends on the characteristic charge of the protein and the salt counterion and governs the change of retention with the salt concentration in ion-exchange chromatography. According to the model the magnitude of the hydrophobic interaction parameter C is determined by the hydrophobic contact area upon protein binding at the stationary phase surface and the properties of the salt as measured by its molal surface tension increment. Retention data measured at different salt concentrations in the eluent on a variety of ion exchangers can be fitted to the above equation which yields U-shaped plots of log k' against log ms. The limiting slopes of the appropriate plots at sufficiently low and high salt concentrations can be used to evaluate the electrostatic and hydrophobic interaction parameters, respectively. The approach, which is based on a combination of established treatments of electrostatic and hydrophobic interactions offers a convenient framework for analyzing retention data in biopolymer high-performance liquid chromatography and for the characterization of stationary phases. Furthermore, it may facilitate some characterization of protein molecules on the basis of their retention behavior as a function of the concentration and nature of the salt in the eluent. In the treatment of electrostatic interactions use is made of the counterion condensation theory that is believed to make possible a more comprehensive analysis than the traditional stoichiometric ion-exchange model which assumes binding of the proteins by coulombic interactions at discrete sites. The treatment of hydrophobic interactions is based on an adaptation of the solvophobic theory which predicts that the hydrophobic portion of the free energy of binding is proportional to the hydrophobic contact area and the microthermodynamic surface tension of the aqueous salt solution. Despite its simplicity the theory was successful in explaining the observed effect of the nature and concentration of salt in the eluent, the pH and the effect of the density of fixed charges at the surface of the stationary phase in the absence of specific salt effects.

Biopolymers↗
PubMed1989

Patellofemoral instability in total knee arthroplasty.

Patellofemoral instability following total knee arthroplasty remains one of the major complications requiring operative intervention. In spite of recent advances in technique and instrumentation, the rate of this complication remains disturbingly high. A comprehensive analysis of cause reveals malalignment of any of the components to be potentially responsible, particularly valgus or internal rotation malalignment of either femoral or tibial component, as well as lateral displacement of the patellar component. Underresection of the patella or oversizing the femoral component may also contribute to excessive lateral retinacular tightness. When confronted with patellofemoral instability, the surgeon must first look for and correct the cause. Component malalignment requires component revision. Extensor mechanism imbalance requires either proximal or distal realignment. Lateral release alone invites recurrence of the problem.

Arthroplasty↗
PubMed1989

How does gender influence age at first hospitalization for schizophrenia? A transnational case register study.

Numerous studies have reported a lower mean age at first hospitalization for schizophrenia in males than in females. For this finding not only a gender difference in age at first onset of schizophrenia, but also other factors can be responsible. With the aim of providing a comprehensive analysis of gender differences in onset, symptomatology and course of schizophrenia, we started by testing the hypothesis postulating a gender difference in mean age at first hospitalization. By using the Danish and the Mannheim psychiatric case registers we analysed all hospital admissions for schizophrenia and related diagnoses and all previous admissions for other diagnoses of the Danish population in 1976 and those of the inhabitants of the German city of Mannheim in the period of 1978-80. Artefacts were controlled for systematically. The impact of intervening variables such as selection factors as well as the influence of gender on the ascription of a diagnosis of schizophrenia for the first time were assessed. We found a mean difference of 5 to 6 years in age at first hospitalization between males and females in both countries when a broad definition of the diagnosis was used and of 4 to 5 years when a restrictive definition was applied. The higher mean age at first hospitalization among females is not attributable to artefacts, diagnostic procedures or to any essential extent to gender differences in help-seeking behaviour or occupational status. When a distinction was made between 'single' and 'married', the significant difference in age at first hospitalization between the sexes disappeared in singles. With case register data and without knowing the chronological order of marriage and onset of the disease, it remains an open question whether this finding can be explained by purely correlative associations between sex, marital status and age of onset or by causal effects.

Adolescent↗
PubMed1990

C-erbB2 mRNA expression in human breast tumours: comparison with c-erbB2 DNA amplification and correlation with prognosis.

In this study, we have investigated the expression of the proto-oncogene c-erbB2 in a total of 70 human primary breast tumours. In agreement with other workers, we observed c-erbB2 gene amplification in 17.5% of the tumours studied. In addition, we carried out a comprehensive analysis of c-erbB2 mRNA expression in the tumours using RNase mapping and in situ hybridisation techniques. Our results indicated a more frequent (30%) overexpression of c-erbB2 mRNA, which was associated only with breast carcinomas of a ductal origin. Furthermore, analysis of the c-erbB2 mRNA gene locus in the same tumours demonstrated that enhanced c-erbB2 expression could occur in the presence or absence of gene amplification, suggesting that additional molecular mechanisms may result in overexpression of c-erbB2 mRNA in human mammary tumours. In situ hybridisation showed that elevated levels of c-erbB2 mRNA were specific to malignant cells within the breast tumour. Analysis of the association between c-erbB2 mRNA overexpression and clinicopathological factors revealed a significant correlation with poor tumour grade, but not with steroid receptor status or patient menopausal status. No significant correlation was observed between overexpression of c-erbB2 mRNA and early disease recurrence in our group of patients, although there was a definite trend towards poorer prognosis.

Adult↗
PubMed2025

The histone modifier KAT2A presents a selective target in a subset of well-differentiated microsatellite-stable colorectal cancers.

Lysine acetyltransferase 2 A (KAT2A) plays a pivotal role in epigenetic gene regulation across various types of cancer. In colorectal cancer (CRC), increased KAT2A expression is associated with a more aggressive phenotype. Our study aims to elucidate the molecular underpinnings of KAT2A dependency in CRC and assess the consequences of KAT2A depletion. We conducted a comprehensive analysis by integrating CRISPR-Cas9 screening data with genomics, transcriptomics, and global acetylation patterns in CRC cell lines to pinpoint molecular markers indicative of KAT2A dependency. Additionally, we characterized the phenotypic effect of a CRISPR-interference-mediated KAT2A knockdown in CRC cell lines and patient-derived 3D spheroid cultures. Moreover, we assessed the effect of KAT2A depletion within a patient-derived xenograft mouse model in vivo. Our findings reveal that KAT2A dependency is closely associated with microsatellite stability, lower mutational burden, and increased molecular differentiation signatures in CRC, independent of the KAT2A expression levels. KAT2A-dependent CRC cells display higher gene expression levels and enriched H3K27ac marks at gene loci linked to enterocytic differentiation. Furthermore, loss of KAT2A leads to decreased cell growth and viability in vitro and in vivo, downregulation of proliferation- and stem cell-associated genes, and induction of differentiation markers. Altogether, our data show that a specific subset of CRCs with a more differentiated phenotype relies on KAT2A. For these CRC cases, KAT2A might represent a promising novel therapeutic target.

Humans↗
PubMed2026

Concealed cardiomyopathy in sudden childhood death: translation from molecular autopsy to family assessment.

One of the ongoing challenges in childhood remains the unexplained sudden death. Autopsies identify a subset of cases that harbor rare variants in genes associated with cardiomyopathy in structurally normal hearts, suggesting a concealed cardiomyopathy. Our goal is to interpret all available data in each case to provide answers to unexplained deaths, while also implementing preventative measures for at-risk family members. Our retrospective study included 68 childhood cases of sudden death, classified as inconclusive at autopsy. Molecular autopsy analyzed all genes currently associated with inherited arrhythmogenic syndromes. Variants were reinterpreted according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. Seventeen autopsy-inconclusive childhood cases (70.59% males) carried at least one rare variant in any of the cardiomyopathy-susceptibility genes. A definite deleterious variant was identified in seven cases (10.3%), whereas ten (14.7%) carried only variants of uncertain significance. Slight non-diagnostic myocardial alterations were identified in five cases (7.35%), and three of them carried a deleterious variant. Clinical and genetic analyses of all families identified a carrier of deleterious variants with a diagnosis of cardiomyopathy in six of them (8.82%). Our data support the inclusion of a comprehensive analysis of all genes associated with inherited cardiomyopathies in childhood cases of unexpected death. A personalized multidisciplinary interpretation of post-mortem and genetic data, including family assessment, helps to clarify the role of rare variants and determine the most plausible cause of the unexpected death in one-tenth of the childhood individuals.

Journal Article↗
PubMed2025

Complex de novo structural variants are an underestimated cause of rare disorders.

Complex de novo structural variants (dnSVs) are crucial genetic factors in rare disorders, yet their prevalence and characteristics in rare disorders remain poorly understood. Here, we conduct a comprehensive analysis of whole-genome sequencing data of 12,568 families, including 13,698 offspring with rare diseases, obtained as part of the UK 100,000 Genomes Project. We identify 1,870 dnSVs, constituting the largest dnSV dataset reported to date. Complex dnSVs (n = 158; 8.4%) emerge as the third most common type of SV, following simple deletions and duplications. We classify 65% of these complex dnSVs into 11 subtypes. Among probands with dnSVs (n = 1,696), 9% exhibit exon-disrupting pathogenic dnSVs associated with the probands' phenotype. Notably, 12% of exon-disrupting pathogenic dnSVs and 22% of de novo deletions or duplications previously identified by array-based or whole-exome sequencing methods are found to be complex dnSVs. We also find distinct genomic properties of de novo deletions depending on the parent of origin. This study highlights the importance of complex dnSVs in the cause of rare disorders and demonstrates the necessity of specific genomic analysis to avoid overlooking these variants.

Humans↗