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PubMed2026

Likelihood-based optimization enables accurate copy number estimation for paralogous genes using exome data.

MOTIVATION: Exome sequencing is widely used for genetic studies; however, accurate detection of copy number variants (CNV) in paralogous genes is challenging due to short-read mapping ambiguity and extensive copy-number variation. The human genome contains several hundred paralogous genes, many of which are known to harbor disease-associated CNVs. Existing exome CNV callers are primarily designed for rare CNV detection in uniquely mappable regions and are not well-suited for paralogous genes. METHODS: We describe a computational method (EdgeCopy) for copy number profiling of paralogous genes using whole-exome sequence data. EdgeCopy aggregates reads mapped to all copies of paralogous genes and relates observed read depth to copy number for multiple exome samples using an approximate composite likelihood function. The likelihood function is optimized using numerical optimization to obtain gene-level fractional copy number estimates that are discretized and refined using a Hidden Markov Model to obtain exon-level copy number estimates. RESULTS: Benchmarking of Edgecopy using experimental copy number data showed high concordance (mean = 0.973) for six disease-associated paralogous genes. We evaluated performance using whole-exome data from approximately 2400 samples across five continental populations from the 1000 Genomes Project. EdgeCopy shows robust concordance with whole-genome sequencing based estimates (0.974-0.982) across populations and 130 paralogous genes spanning a wide range of copy-number variation. In comparison, copy number analysis using a state-of-the-art exome CNV caller failed to estimate copy number for paralogous genes with very high mapping ambiguity and showed much lower concordance (0.565) for CNV events compared to EdgeCopy (0.908). AVAILABILITY: EdgeCopy is freely available at https://github.com/vibansal-lab/edgecopy.

Humans↗

PubMed2021

1q21.1 distal copy number variants are associated with cerebral and cognitive alterations in humans.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Brain↗

PubMed2024

Genetic analysis of partial duplication of the long arm of chromosome 16.

BACKGROUND: Pure partial trisomy 16q12.1q22.1 is a rare chromosome copy number variant (CNV). The primary clinical phenotypes associated with this syndrome include abnormal facial morphology, global developmental delay (GDD), short stature, and reported predisposing factors for atypical behavior, autism, the development of learning disabilities, and neuropsychiatric disorders. The dosage-sensitive genes associated with partial trisomy are not disclosed preventing to establish a genotype-phenotype correlation. METHODS: We report a case of a Chinese patient diagnosed with GDD and an abnormal facial shape, who was found to have partial trisomy 16 through karyotyping and high-throughput sequencing analysis. Karyotype and CNV tracing analyses were also conducted on the biological parents of the patient to assess for any chromosomal structural abnormalities. Additionally, we included 29 patients with pure partial trisomy 16q, reported in the DECIPHER database and the literature. We and performed a genotype-phenotype correlation analysis. RESULTS: The proband, a 2-year-old female, was found to have a de novo 21.96 Mb duplication located between 16q12.1q22.1, with no other deletions observed on other chromosomes, indicating a pure partial trisomy of 16q. Through genotype and phenotype analysis of 29 individuals, we found that patients with the duplicated region located at the distal region of 16q may exhibit more severe symptoms than those with duplication at the proximal region; however, no relationship was identified between phenotype and the size of the duplicated segment. CONCLUSION: We report, for the first time, a patient with partial trisomy 16q validated by multiple genetic tests, including CNV-seq, whole exome sequencing (WES), and karyotyping. It is speculated that partial trisomy of 16q may be associated with continuous gene duplication. However, functional studies are necessary to identify the causative gene or critical region linked to duplication syndrome of chromosome 16q.

Child, Preschool↗

PubMed2024

Copy number variant scan in more than four thousand Holstein cows bred in Lombardy, Italy.

Copy Number Variants (CNV) are modifications affecting the genome sequence of DNA, for instance, they can be duplications or deletions of a considerable number of base pairs (i.e., greater than 1000 bp and up to millions of bp). Their impact on the variation of the phenotypic traits has been widely demonstrated. In addition, CNVs are a class of markers useful to identify the genetic biodiversity among populations related to adaptation to the environment. The aim of this study was to detect CNVs in more than four thousand Holstein cows, using information derived by a genotyping done with the GGP (GeneSeek Genomic Profiler) bovine 100K SNP chip. To detect CNV the SVS 8.9 software was used, then CNV regions (CNVRs) were detected. A total of 123,814 CNVs (4,150 non redundant) were called and aggregated into 1,397 CNVRs. The PCA results obtained using the CNVs information, showed that there is some variability among animals. For many genes annotated within the CNVRs, the role in immune response is well known, as well as their association with important and economic traits object of selection in Holstein, such as milk production and quality, udder conformation and body morphology. Comparison with reference revealed unique CNVRs of the Holstein breed, and others in common with Jersey and Brown. The information regarding CNVs represents a valuable resource to understand how this class of markers may improve the accuracy in prediction of genomic value, nowadays solely based on SNPs markers.

Cattle↗

PubMed2026

Excitation/inhibition balance subtypes in autism and their genetic, neural, and clinical profiles.

Excitation (E)/inhibition (I) imbalance is considered a key mechanism in Autism Spectrum Disorder (ASD). However, E/I imbalance can have different etiologies with increased E relative to I (E > I) and increased I relative to E (E < I). Both neural profiles can be associated with altered clinical phenotype, suggesting "bell"-shape brain-behavior relationships. We derived E/I balance measures from resting-state EEG in a large sex-balanced sample of youths with and without autism (N = 310; 164 youths with ASD and 146 typically developing (TD) youths) to address group discriminative power of neural markers, their relation to social skills, and the potential to define different neural subtypes within the autistic group. We also conducted genome-wide copy number variant (CNV) and gene expression analyses to provide additional insight into distinct neural subtypes in autism. A high-density 128-channel electroencephalography (EEG) was used to register neural activity of participants, blood samples were collected from the ASD youths to obtain genomic DNA, and rich behavioral phenotyping was provided for each participant. The results revealed three subgroups within the autistic cohort with the presence of "typical" E/I, E > I, and E < I neural profiles. The two subgroups with E/I imbalance had altered clinical phenotypes. In addition, these subgroups had different genetic profiles, showing that genes within identified CNVs had distinct expression patterns with the evidence of more prenatal (E < I) vs. postnatal (E > I) gene expression. The study suggests that the proposed clustering approach has relevance for the identification of clinically meaningful neural and genetic subtypes within a heterogeneous autistic cohort.

Autism spectrum disorder↗

PubMed2026

Persistent tic disorders are associated with 17q12 duplications.

Tourette Syndrome (TS) and Persistent Tic Disorder (PTD) are childhood-onset neuropsychiatric conditions with high heritability. Due to current sample size limitations, identifying TS/PTD risk genes has been challenging. This study addressed this issue by conducting a meta-analysis of microarray copy number variant (CNV) studies from three TS/PTD genomics consortia, supplemented with new data from 3291 cases. This approach more than doubled the sample size of previous TS/PTD CNV studies, with CNV calls generated from 5725 TS/PTD cases and 10,982 matched controls. The results confirmed that TS/PTD cases 1) have a higher burden of ultra-rare deletions overlapping loss-of-function intolerant genes (OR = 1.68, P = 9.3×10-5) and 2) are more likely to carry established neurodevelopmental CNVs (OR = 1.42, P = 3.9×10-2) compared to controls. Additionally, a novel, genome-wide significant CNV locus for TS/PTD was discovered, involving duplications at 17q12 (hg19 chr17:34.8 - 36.2 Mb). This locus is associated with a known duplication syndrome associated with variable neuropsychiatric traits, but has not been previously linked to tic disorders. Eight cases and one control carried the canonical ~1.4 Mb duplication at chr17:34.8-36.2 Mb, while one additional case had a smaller 110 kb duplication within this known CNV that included only one gene, ACACA (acetyl-CoA carboxylase, OR = 26.7, P = 5.69×10-7). Overall, this study provides further evidence that rare, genic CNVs play a substantial role in the genetic architecture of TS/PTD and identifies a new genome-wide significant association with this neurodevelopmental disorder.

Journal Article↗

PubMed2026

Integrating rare and common variation in epilepsy genetics: from genetic architecture to penetrance and clinical expressivity.

Epilepsy genetics has often been interpreted through a useful but simplified dichotomous framework in which severe epilepsies, particularly developmental and epileptic encephalopathies, are attributed mainly to rare, high-effect variants, whereas more common epilepsies are viewed as arising largely from the cumulative effects of common, small-effect variation. Although this framework has been instrumental for gene discovery, molecular diagnosis, and mechanism-based treatment, it does not fully explain incomplete penetrance, intrafamilial phenotypic heterogeneity, or marked differences in severity among individuals sharing the same molecular diagnosis. Evidence from exome sequencing, copy number variant (CNV) studies, and genome-wide association studies increasingly suggests that rare SNVs/indels, CNVs, and common variant should not be interpreted as entirely independent risk sources, but may partially converge on shared genes, pathways, cell types, and neurobiological processes relevant to neuronal excitability, network stability, and seizure susceptibility. Here, we review evidence across epilepsy subtypes, focusing on convergence and divergence across the allelic spectrum, and discuss how polygenic background and other modifiers may influence penetrance and clinical expressivity among carriers of rare pathogenic variants and CNVs. We also consider implications for variant interpretation, genetic counseling, risk stratification, and precision medicine, while emphasizing that most rare-common integrated models remain insufficiently validated for routine clinical decision-making.

common variants↗

PubMed2024

Common genetic variants associated with urinary phthalate levels in children: A genome-wide study.

INTRODUCTION: Phthalates, or dieters of phthalic acid, are a ubiquitous type of plasticizer used in a variety of common consumer and industrial products. They act as endocrine disruptors and are associated with increased risk for several diseases. Once in the body, phthalates are metabolized through partially known mechanisms, involving phase I and phase II enzymes. OBJECTIVE: In this study we aimed to identify common single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) associated with the metabolism of phthalate compounds in children through genome-wide association studies (GWAS). METHODS: The study used data from 1,044 children with European ancestry from the Human Early Life Exposome (HELIX) cohort. Ten phthalate metabolites were assessed in a two-void pooled urine collected at the mean age of 8 years. Six ratios between secondary and primary phthalate metabolites were calculated. Genome-wide genotyping was done with the Infinium Global Screening Array (GSA) and imputation with the Haplotype Reference Consortium (HRC) panel. PennCNV was used to estimate copy number variants (CNVs) and CNVRanger to identify consensus regions. GWAS of SNPs and CNVs were conducted using PLINK and SNPassoc, respectively. Subsequently, functional annotation of suggestive SNPs (p-value < 1E-05) was done with the FUMA web-tool. RESULTS: We identified four genome-wide significant (p-value < 5E-08) loci at chromosome (chr) 3 (FECHP1 for oxo-MiNP_oh-MiNP ratio), chr6 (SLC17A1 for MECPP_MEHHP ratio), chr9 (RAPGEF1 for MBzP), and chr10 (CYP2C9 for MECPP_MEHHP ratio). Moreover, 115 additional loci were found at suggestive significance (p-value < 1E-05). Two CNVs located at chr11 (MRGPRX1 for oh-MiNP and SLC35F2 for MEP) were also identified. Functional annotation pointed to genes involved in phase I and phase II detoxification, molecular transfer across membranes, and renal excretion. CONCLUSION: Through genome-wide screenings we identified known and novel loci implicated in phthalate metabolism in children. Genes annotated to these loci participate in detoxification, transmembrane transfer, and renal excretion.

Humans↗

PubMed2025

Effective detection of 148 cases chromosomal mosaicism by karyotyping, chromosomal microarray analysis and QF-PCR in 32,967 prenatal diagnoses.

BACKGROUND: Detection of mosaicism has always been difficult in prenatal diagnosis, which is to assess the value of karyotyping combined with three different molecular genetic tests for prenatal diagnosis. Retrospective review of chromosomal mosaicism (CM) was conducted in 32,967 pregnant women from January 2015 to December 2022. METHODS: A total of 148 fetuses diagnosed with chromosomal mosaicism by karyotyping with copy number variant sequencing (CNV-seq)/ chromosomal microarray analysis (CMA) and quantitative fluorescent polymerase chain reaction (QF-PCR) were selected, and the results from three the methods were compared and further analyzed. The χ2 test for multiple group rates was for the 5 clinical prenatal diagnostic indication groups was used to do multiple comparison tests for statistical analysis. Inconsistent results between methods were identified and further analyzed. RESULTS: A total of 148 CM cases was detected (0.45%, 148/32967), of which karyotyping was detected in combination with CMA in 73 cases (73/85), with CNV-seq in 5 cases (5/11), and with QF-PCR in 35 cases (35/52) and the mosaic conformity rates of the three methods compared with karyotyping were 85.9% (CMA), 67.3% (QF-PCR), and 45.5% (CNV-seq), respectively. There were 49 cases of autosomal mosaicism (49/148, 33.1%) and 99 cases of sex CM (99/148, 66.9%). There were 9 cases of small supernumerary marker chromosome (sSMC)with CMA detection clarified the origin of chromosome fragments. The non-invasive prenatal testing (NIPT) group and the ultrasound abnormality group had the highest detection rates, accounting for 35.1% and 22.3%. CONCLUSIONS: In chromosomal mosaicism, there are inconsistent results between different detection methods. Therefore, karyotyping combined with CMA/CNV-seq and FISH methods significantly improves the detection rate of chromosomal mosaicism and also confirms experimental data in the literature, which is of great value for prenatal diagnosis.

Humans↗

PubMed2026

Identification of novel HUWE1 variants in Turner-type X-linked intellectual disability.

OBJECTIVE: To characterize the clinical phenotypes and identify the genetic etiology in four unrelated families affected by Turner-type X-linked intellectual disability (XLID). METHODS: Peripheral blood samples were collected from four probands and their parents. Genomic DNA was extracted, and a comprehensive genetic analysis was performed using trio-based Whole Exome Sequencing (WES) combined with low-pass Copy Number Variation sequencing (CNV-seq). Candidate variants were subsequently validated via Sanger sequencing. RESULTS: Genetic analysis identified distinct variants in the HUWE1 across the four families. Specifically, four distinct HUWE1 variants were identified across the families: a hemizygous c.10034 > T (p.Lys3345Met) in Family 1; a heterozygous c.9209G > A (p.Arg3070His) in Family 2; a heterozygous c.12688T > C (p.Phe4230Leu) in Family 3; and a hemizygous c.9070G > A (p.Ala3024Thr) in Family 4. In accordance with ACMG guidelines, the novel variants in Families 1, 3, and 4 were classified as "Likely Pathogenic" (PS2 + PM2_Supporting + PP2 + PP3). In contrast, the previously reported variant in Family 2 was categorized as "Pathogenic" based on the criteria PS2 + PM2_Supporting + PM5 + PP2 + PP3_Moderate. All probands were clinically diagnosed with Turner-type XLID. CONCLUSIONS: This study expands the pathogenic variant spectrum of HUWE1 and provides novel molecular evidence for the clinical diagnosis of Turner-type XLID. These findings are of significant value for genetic counseling, carrier screening, and prenatal diagnosis for the affected families.

Humans↗

PubMed2025

CNV-Finder: Streamlining Copy Number Variation Discovery.

Copy Number Variations (CNVs) play pivotal roles in the etiology of complex diseases and are variable across diverse populations. Understanding the association between CNVs and disease susceptibility is significant in disease genetics research and often requires analysis of large sample sizes. One of the most cost-effective and scalable methods for detecting CNVs is based on normalized signal intensity values, such as Log R Ratio (LRR) and B Allele Frequency (BAF), from Illumina genotyping arrays. In this study, we present CNV-Finder, a novel pipeline integrating deep learning techniques on array data, specifically a Long Short-Term Memory (LSTM) network, to expedite the large-scale identification of CNVs within predefined genomic regions. This facilitates efficient prioritization of samples for time-consuming or costly subsequent analyses such as Multiplex Ligation-dependent Probe Amplification (MLPA), short-read, and long-read whole genome sequencing. We incorporate four genes to establish our methods-Parkin (PRKN), Leucine Rich Repeat And Ig Domain Containing 2 (LINGO2), Microtubule Associated Protein Tau (MAPT), and alpha-Synuclein (SNCA)-which may be relevant to neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Progressive Supranuclear Palsy (PSP), or related disorders such as essential tremor (ET). By training our models on expert-annotated samples and validating them across diverse cohorts, including those from the Global Parkinson's Genetics Program (GP2) and additional dementia-specific databases, we demonstrate the efficacy of CNV-Finder in accurately detecting deletions and duplications. Our pipeline outputs app-compatible files for visualization within CNV-Finder's interactive web application. This interface enables researchers to review predictions and filter displayed samples by model prediction values, LRR range, and variant count in order to explore or confirm results. Our pipeline integrates this human feedback to enhance model performance and reduce false positive rates. Through a series of comprehensive analyses and validations using visual inspection, MLPA, short-read, and long-read sequencing data, we demonstrate the robustness and adaptability of CNV-Finder in identifying CNVs with regions of varied size, probe density, and noise. Our findings highlight the significance of contextual understanding and human expertise in enhancing the precision of CNV identification, particularly in complex genomic regions like 17q21.31. The CNV-Finder pipeline is a scalable, publicly available resource for the scientific community, available on GitHub (https://github.com/GP2code/CNV-Finder; DOI 10.5281/zenodo.14182563). CNV-Finder not only expedites accurate candidate identification but also significantly reduces the manual workload for researchers, enabling future targeted validation and downstream analyses in regions or phenotypes of interest.

Copy Number Variation (CNV)↗

PubMed2026

Comparative genomics reveals lineage-associated structural variation and diversification in a barley fungal pathogen.

Leaf rust, caused by Puccinia hordei, is a major barley disease worldwide. Despite repeated shifts in virulence, contrasting reproductive histories, and emerging fungicide insensitivity, the genomic basis of its diversification and adaptation remains poorly understood. In this study, we generated haplotype-resolved, chromosome-level genome assemblies for two isolates with contrasting virulence and analyzed 41 Australian isolates collected over 54 yr (1966-2020), integrating comparative and population genomics, mating-type gene phylogenies, chromosome-specific k-mer profiling, genome-wide copy-number variation (CNV) analysis, and gene-expression analysis. We identified a structurally dynamic chromosome characterized by repeat-associated rearrangements, structural variation, and lineage-associated CNV, representing the first evidence in a rust fungus of chromosome-scale structural diversification of this extent. Population analyses distinguished clonally expanded lineages from recombination-associated lineages, with mating-type gene phylogenies providing further support for lineage differentiation. More recently collected isolates showed increased duplication-associated variation, and CNV boundaries were associated with structural-variant breakpoints. We also identified lineage-associated amplification of Cyp51, with increased copy number associated with higher transcript abundance, supporting a potential role in fungicide adaptation. Overall, our findings highlight structural variation, contrasting reproductive histories, and lineage-associated CNV as important contributors to diversification in P. hordei, providing insights for future rust pathogen surveillance and management strategies.

Cyp51 gene↗

PubMed2026

A Novel Splice Variant in the COL1A1 Gene Leads to Exon 46 Skipping and Osteogenesis Imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is a clinical and genetic disorder characterised by bone fragility, growth deficiency and skeletal deformity. Ninety per cent of OI cases are attributable to autosomal dominant variants in the COL1A1 and COL1A2 genes. METHODS: Candidate variants were identified and verified through trio whole-exome sequencing (trio-WES), copy number variation sequencing (CNV-seq) and Sanger sequencing. Minigene splicing assays were performed in HeLa and HEK293T cells with pcDNA3.1 and pcMINI-C vectors to investigate the function of the candidate variants. A systematic review of COL1A1 splicing variants and the corresponding genotype-phenotype spectrum was performed. RESULTS: Trio-WES revealed a novel heterozygous variant in the C-terminal region of the COL1A1 gene: NM_000088.4:c.3423+5G>A. Sanger sequencing confirmed the variant in both the proband (II-2) and her foetus (III-1) who were clinically suspected of having OI. The c.3423+5G>A variant causes complete skipping of Exon 46, as demonstrated by a minigene splicing assay. We retrieved 419 COL1A1 splicing variants from PubMed, excluded 15 without phenotypic data and 2 linked to Ehlers-Danlos syndrome and stratified the remaining 402 variants into three types on the basis of splice site location: (1) Variants at canonical splicing sites (77.8%, 313/402) mostly cause mild phenotypes, whereas a minority may be severe. (2) Intron variants in other locations, such as splice region variants (17.9%, 72/402), usually cause mild clinical phenotypes, and deep intronic splice variants (0.4%, 2/402) that may result in severe phenotypes. (3) Other variants (3.7%, 15/402), such as exon variants or fragment loss, are extremely rare. We also preliminarily discuss the mechanisms underlying phenotypic variability and the characteristics of C-terminal variants. CONCLUSIONS: This intron variant in COL1A1 was classified as likely pathogenic and was confirmed to disrupt COL1A1 expression. The summary analysis results also revealed a correlation among splicing variants, C-terminal region variants and disease, suggesting that variant location provides a useful framework for prognosis prediction.

Female↗

PubMed2026

Contribution of copy number variants to schizophrenia in East Asian populations.

Studies on schizophrenia-associated rare copy number variants (CNVs) have predominantly focused on people of European (EUR) ancestry. Here we present a rare CNV study of schizophrenia in East Asian (EAS) populations, comprising 20,903 cases and 23,258 controls. We observed a significantly elevated genome-wide rare CNV burden in EAS cases compared with controls. Cross-population comparisons showed largely consistent rare CNV effects on schizophrenia risk. In the EAS sample, we identified nine genome-wide-significant schizophrenia-associated rare CNV loci. Meta-analysis with EUR data yielded 14 significant loci, including 8 that reached genome-wide significance for the first time. Genes within these 14 loci were significantly less tolerant to loss-of-function variants than genes in other CNV loci. The new rare CNVs associated with schizophrenia in EAS populations showed higher carrier frequencies in EAS than in EUR populations (0.38% versus 0.0017%). Overall, this study underscores the importance of increasing population diversity to fully capture the genetic underpinnings of schizophrenia.

Journal Article↗

PubMed2026

Prenatal diagnosis and genetic counseling of a de novo 10q11.22q11.23 duplication associated with a normal development at 12 months of age.

BACKGROUND: Copy number variants are an important source of genomic variations, ranging from pathogenic to benign. The 10q11.22q11.23 region contains complex low-copy repeats that predispose to recurrent deletions and duplications via nonallelic homologous recombination. While some reports associate duplications of this region with developmental delay, intellectual disability, and autism spectrum disorders, emerging evidence suggests that such duplications may also be observed in phenotypically normal individuals, indicating incomplete penetrance and variable expressivity. CASE PRESENTATION: A 35-year-old pregnant woman with an unremarkable obstetric history underwent amniocentesis at 20 weeks of gestation. Conventional karyotyping and copy number variation sequencing (CNV-seq) were performed. CNV-seq revealed a de novo 4.56 Mb duplication at 10q11.22q11.23. The duplication was classified as a variant of uncertain significance. After extensive genetic counseling, the parents elected to continue the pregnancy. At 40 weeks of gestation, a female infant was delivered by cesarean section with normal birth parameters. A comprehensive physical examination at birth revealed no abnormalities. At the 12-month follow-up, the infant demonstrated normal growth parameters and age-appropriate neurodevelopmental milestones, with no evidence of dysmorphic features, developmental delay, or other clinical concerns. CONCLUSION: This report describes a prenatal case of a de novo 10q11.22q11.23 duplication with a normal development at 12 months of age. Our findings contribute to the growing body of literature suggesting that duplications in this pericentromeric region may exhibit incomplete penetrance and variable expressivity, and in some cases, may represent benign familial or de novo variants without apparent clinical consequences.

10q11.22q11.23 duplication↗

PubMed2025

Novel genetic determinants contribute to hearing loss in a central European cohort with enlarged vestibular aqueduct.

BACKGROUND: The enlarged vestibular aqueduct (EVA) is the most commonly detected inner ear malformation. Biallelic pathogenic variants in the SLC26A4 gene, coding for the anion exchanger pendrin, are frequently involved in determining Pendred syndrome and nonsyndromic autosomal recessive hearing loss DFNB4 in EVA patients. In Caucasian cohorts, the genetic determinants of EVA remain unknown in approximately 50% of cases. We have recruited a cohort of 32 Austrian patients with hearing loss and EVA to define the prevalence and type of pathogenic sequence alterations in SLC26A4 and discover novel EVA-associated genes. METHODS: Sanger sequencing, single nucleotide polymorphism (SNP) assays, copy number variation (CNV) testing, and Exome Sequencing (ES) were employed for gene analysis. Cell-based functional and molecular assays were used to discriminate between gene variants with and without impact on protein function. RESULTS: SLC26A4 biallelic variants were detected in 5/32 patients (16%) and monoallelic variants in 5/32 patients (16%). The pathogenicity of the uncharacterized SLC26A4 protein variants was assigned or excluded based on their ion transport function and cellular abundance. The monoallelic or biallelic Caucasian EVA haplotype was detected in 7/32 (22%) patients, but its pathogenicity could not be confirmed. X-linked pathogenic variants in POU3F4 (2/32, 6%) and biallelic pathogenic variants in GJB2 (2/32, 6%) were also found. No CNV of SLC26A4 and STRC genes was detected. ES of eleven undiagnosed patients with bilateral EVA detected rare sequence variants in six EVA-unrelated genes (monoallelic variants in SCD5, REST, EDNRB, TJP2, TMC1, and two variants in CDH23) in five patients (5/11, 45%). Cell-based assays showed that the TJP2 variant leads to a mislocalized protein product forming dimers with the wild-type, supporting autosomal dominant pathogenicity. The genetic causes of hearing loss and EVA remained unidentified in (14/32) 44% of patients. CONCLUSIONS: The present investigation confirms the role of SLC26A4 in determining hearing loss with EVA, identifies novel genes in this pathophysiological context, highlights the importance of functional testing to exclude or assign pathogenicity of a given gene variant, proposes a possible diagnostic workflow, suggests a novel pathomechanism of disease for TJP2, and highlights voids of knowledge that deserve further investigation.

Humans↗

PubMed2025

CLINICAL AND COGNITIVE PHENOTYPING OF COPY NUMBER VARIANTS ASSOCIATED WITH NEURODEVELOPMENTAL DISORDERS FROM A MULTI-ANCESTRY BIOBANK.

Clinical biobanks with electronic health records (EHRs) linked to genotype data continue to expand yielding an opportunity to further characterize disease-relevant genomic risk factors, yet few recall-by-genotype studies from biobanks have been published to date. For example, copy number variants (CNVs) that significantly increase risk for multiple neurodevelopmental disorders (NDDs) and negatively affect neurocognition, may present in up to 2% of population cohorts, with public health implications for ascertaining NDD CNV carriers. From BioMe, a multi-ancestry biobank derived from the Mount Sinai healthcare system (New York, NY), 892 adult participants were recontacted for deep phenotyping, including 335 NDD CNV carriers as well as comparators, 217 individuals with schizophrenia and 340 controls. Clinical and cognitive assessments were administered to each participant. There was no disclosure of genetic information. Eight percent of recontacted biobank participants completed the study (30 NDD CNV carriers across 15 unique loci, 20 schizophrenia and 23 controls). The study sample had a mean age of 48.8 (10.2) years, was 66% female and of diverse ancestry, 36% African, 34% Hispanic, and 26% European. Overall, 70% of 30 NDD-CNV carriers harbored at least one neuropsychiatric or developmental phenotype, including 40% with mood or anxiety disorders. Further, 22 NDD CNV carriers were significantly impaired compared to controls on digit span backwards (Beta=-1.76, FDR=0.04) and digit span sequencing (Beta=-2.01, FDR=0.04), but higher performing than schizophrenia on verbal learning (Beta=4.5, FDR=0.05). Thirty NDD CNV carriers were successfully recruited from a multi-ancestry biobank, as well as healthy controls and low-functioning individuals with schizophrenia. Deep phenotyping corroborated past reports, while also identifying discordance with EHRs. Future recall-by-genotype studies may further benchmark the study design and elucidate feasibility.

Biobank↗

PubMed2026

Recall-by-genotype of neurodevelopmental disorder copy number variants in a multi-ancestry, healthcare-system biobank.

Clinical biobanks linking electronic health records (EHRs) with genotype data enable the study of genomic risk factors in real-world populations. However, recall-by-genotype (RbG) of psychiatric risk variants in diverse healthcare-system biobanks remains scarce. Leveraging BioMe, a multi-ancestry biobank within the Mount Sinai Health System, we recalled carriers of rare copy number variants (CNVs) that confer increased risk for neurodevelopmental disorders (NDDs) to establish empirical benchmarks for RbG implementation. We recontacted 892 participants: 335 NDD CNV carriers, 217 individuals with schizophrenia without NDD CNVs, and 340 neurotypical controls without NDD CNVs. Participants completed clinical and cognitive assessments. Overall, 18% of recontacted participants responded to recruitment, and 8% completed the study: 30 NDD CNV carriers, 20 individuals with schizophrenia, and 23 controls. The mean age was 48.8 years, 66% were female, and self-reported ancestry was 37% African, 34% Hispanic, and 26% European. Seventy percent of NDD CNV carriers had at least one neuropsychiatric or developmental condition, including mood or anxiety disorders (40%). Among 22 NDD CNV carriers at loci implicated in impaired cognition, performance was lower than controls on Digit Span Backward (β = -1.76, FDR = 0.04) and Digit Span Sequencing (β = -2.01, FDR = 0.04). NDD CNV carriers also outperformed the schizophrenia group on verbal learning (β = 4.5, FDR = 0.05). Recall of individuals-including those with psychiatric illness-yielded phenotypes not captured in EHRs and provides empirical benchmarks relevant to RbG implementation and precision psychiatry in diverse healthcare systems.

Journal Article↗