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PubMed2025

Evaluating the return of additional findings from the 100,000 Genomes Project: A mixed-methods study exploring participant experiences of receiving secondary findings from genomic sequencing.

PURPOSE: The 100,000 Genomes Project participants could consent to receive additional findings (AFs) for variants associated with susceptibility to cancer and familial hypercholesterolemia. Here, we evaluate stakeholder experiences to inform clinical practice. METHODS: Mixed-methods study conducted at 18 sites across England that comprised a cross-sectional survey and interviews with participants who received a positive AF (PAF) and interviews with participants who had no AFs (NAF). RESULTS: There were 146 surveys followed by 35 interviews with PAF participants and 29 interviews with NAF participants. Surveys found that PAF results were seen as useful and would influence health management (82%). Most (90%) had shared their result with family members. Experiences differed by PAF type; cancer PAF participants were often initially shocked and anxious and found telling family members challenging compared with participants with a familial hypercholesterolemia PAF. Although most experiences of NAF results were positive, some misunderstandings were identified. Participants supported returning AFs when offering genome sequencing. CONCLUSION: Patient experiences of receiving AFs were primarily positive, and there is support for offering AFs routinely. Considerations for offering AFs in clinical practice include adapting approaches tailored to individual conditions and greater support for people with a NAF result.

Humans↗
PubMed2025

Whole-genome sequencing of 490,640 UK Biobank participants.

Whole-genome sequencing provides an unbiased and complete view of the human genome and enables the discovery of genetic variation without the technical limitations of other genotyping technologies. Here we report on whole-genome sequencing of 490,640 UK Biobank participants, building on previous genotyping effort1. This advance deepens our understanding of how genetics associates with disease biology and further enhances the value of this open resource for the study of human biology and health. Coupling this dataset with rich phenotypic data, we surveyed within- and cross-ancestry genomic associations and identified novel genetic and clinical insights. Although most associations with disease traits were primarily observed in individuals of European ancestries, strong or novel signals were also identified in individuals of African and Asian ancestries. With the improved ability to accurately genotype structural variants and exonic variation in both coding and UTR sequences, we strengthened and revealed novel insights relative to whole-exome sequencing2,3 analyses. This dataset, representing a large collection of whole-genome sequencing data that is available to the UK Biobank research community, will enable advances of our understanding of the human genome, facilitate the discovery of diagnostics and therapeutics with higher efficacy and improved safety profile, and enable precision medicine strategies with the potential to improve global health.

Humans↗
PubMed2026

Conference report: the third Bacterial Genome Sequencing Pan-European Network conference.

The third Bacterial Genome Sequencing Pan-European Network conference, held in Engelberg, Switzerland (12-15 January 2026), brought together experts from six European countries to discuss the implementation of bacterial genome sequencing in clinical microbiology and public health. Key themes included regulatory frameworks (In Vitro Diagnostic Regulation, General Data Protection Regulation), standardization, quality control, data sharing, economic evaluation, and the integration of artificial intelligence and long-read sequencing into diagnostic workflows. Across presentations, panel discussions, and workshops, participants emphasized that successful implementation of genome sequencing requires more than technical capacity: it depends on robust validation, sustainable funding, interoperable data standards, ethical governance, and interdisciplinary collaboration. The meeting highlighted that sequencing should remain question-driven and clinically meaningful, balancing cost, turnaround time, and public health impact. Overall, the conference reinforced the need for coordinated European efforts to advance responsible, standardized, and sustainable genomic surveillance and diagnostics.

bacterial genome sequencing↗
PubMed2025

Delivering effective genome sequencing in pediatric care: From research in the 100,000 Genomes Project to routine clinical practice.

PURPOSE: Genome sequencing (GS) is increasingly used to investigate rare conditions, primarily in children. The 100,000 Genomes Project (100KG) evaluated GS ahead of implementation in the English National Health Service. In 2020, the National Health Service Genomic Medicine Service (GMS) became the first public health care system to offer GS in routine clinical care. We investigate how learning from 100KG informed GMS service delivery. METHODS: We compare GS outcomes in children tested at a large pediatric hospital via GMS (n = 501) and 100KG research (n = 1759). RESULTS: GMS diagnostic yield (29%) was higher than that in 100KG (22%) (P < .0016). Median age at testing was 8 years in 100KG and 6 in the GMS (P < .05). In 100KG, the diagnostic yield was <10% for 15 indications, none of which are included in GMS testing. 100KG data showed little benefit to application of >3 panels. Use of fewer but larger GMS panels resulted in a significantly higher number of genes tested per patient: median 2801 vs 1373 in 100KG (P < .001). In 100KG, diagnostic yield was not significantly increased by testing more than 3 family members (n = 34/142, 24%). CONCLUSION: Learning from 100KG has informed GS clinical service delivery, resulting in higher diagnostic yields and earlier age at testing. Lessons are broadly applicable to all services providing GS, enabling earlier access to tailored management with fewer investigations.

Humans↗
PubMed2026

Proteomics identify disease-associated variants in patients with rare diseases undiagnosed after genome sequencing.

Despite the introduction of genome sequencing (GS) for rare disease diagnostics, a genetic cause is not identified in most patients. Here, we explored the potential of proteomics to improve the diagnostic yield in 424 patients with rare diseases from the 100,000 Genomes Project (100kGP) without a genetic diagnosis. Serum proteomic profiling was performed using the Olink Explore 1536 assay (N&#xa0;=&#xa0;1463 proteins). For 13 patients without genetic diagnoses, detection of lower serum protein "outliers" (z-score&#xa0;<&#xa0;-2) led to confirmed genetic diagnoses by resolving variants of uncertain significance or prioritizing genes for targeted GS reanalysis. For 23 additional patients without genetic diagnoses (64% of findings), we identified candidate gene-disease links and variants through convergent evidence from lower protein outliers and variants ranked through the variant prioritization tool Exomiser. For example, we identified a candidate heterozygous missense variant [Genome Aggregation Database (gnomAD) minor allele frequency&#xa0;=&#xa0;0.006%] in tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains 1 (TIE1) that was only present in a patient with lower TIE1 serum abundance (z-score&#xa0;=&#xa0;-5.12) and their father, both of whom were affected by the same monogenic cardiac disorder, but in no other individuals from the 100kGP. Missense (52.5%) and splice region (27.5%) variants accounted for most diagnostic or candidate variants prioritized. This proof-of-principle study demonstrated that serum proteomics can support rare disease diagnosis and identify disease-causing genes in patients undiagnosed after GS, although successful implementation will likely depend on tissue specificity of protein expression, detectability in blood, proteomic platform coverage, and sensitivity.

Humans↗
PubMed2025

Whole genome sequencing and phylogenetic classification accelerate the implementation of respiratory syncytial virus genomic surveillance in Canada: a pilot study.

UNLABELLED: Whole genome sequencing (WGS) has emerged as a powerful tool to facilitate the study of existing and emerging infectious diseases. WGS-based genomic surveillance provides information on the genetic diversity and tracks the evolution of important viral pathogens, including respiratory syncytial virus (RSV). Multiplex tiling polymerase chain reaction (PCR) assays have been used to facilitate sequencing of a variety of pathogens in support of genomics-based surveillance initiatives. We developed, optimized, and implemented multiplex tiling PCR assays for RSVA and RSVB capable of generating near-complete genomes in the majority of contemporaneous specimens tested. A pilot data set comprising 52 RSVA and 37 RSVB genomes derived from Canadian clinical specimens during the 2022-2023 respiratory virus season was used to perform phylogenetic analyses using both near-complete genome and glycoprotein (G) sequences. Overall, the RSV phylogenetic tree built with whole genomes showed identical lineage clusters as compared to the G gene but was more discriminatory. Moreover, the availability of complete genomes enables the identification of a broader range of mutations. For instance, mutations identified in the fusion protein among Canadian isolates tested here, including S377N, K272M, S276N, S211N, S206I, and S209Q, could affect the efficacy of current vaccines or antiviral-based therapeutics. In conclusion, our work reinforces other recent studies demonstrating the utility of multiplex tiling PCR assays to facilitate high-throughput WGS of RSV, which is capable of supporting enhanced genomic surveillance initiatives, as well as the more comprehensive genomic analyses required to inform public health strategies for the development and usage of vaccines and antiviral drugs. IMPORTANCE: We present assays to efficiently sequence genomes of RSVA and RSVB. This enables researchers and public health agencies to acquire high-quality genomic data using rapid and cost-effective approaches. Genomic data-based comparative analysis can be used to conduct surveillance and monitor circulating isolates for efficacy of vaccines and antiviral therapeutics.

Humans↗
PubMed2026

Molecular residual disease assessment in colorectal and bladder cancer by somatic structural variant analysis of cell-free DNA whole-genome sequencing data.

BACKGROUND: Whole-genome sequencing (WGS)-based methods for circulating tumor DNA (ctDNA) detection typically rely on tumor-informed identification of somatic single nucleotide variants (SNVs). Somatic structural variants (SVs) are another type of cancer-specific genomic alteration, which owing to their larger genomic footprint and unique breakpoint junctions, are easier to distinguish from sequencing noise than SNVs. They are, however, rarely used for ctDNA detection because of (1) artifacts from WGS procedures that SV callers may falsely interpret as genuine SVs. This makes it difficult to establish high-confidence SV catalogos from short-read tumor WGS and can cause false-positive ctDNA detections. (2) Lack of robust strategies to quantify SV-supporting reads in plasma WGS. To address these barriers and enable integration of SV biomarkers into WGS-based ctDNA detection, we present a bioinformatic framework for algorithmic curation of somatic SV calls from fresh-frozen and formalin-fixed paraffin-embedded (FFPE) tumors, coupled with a novel approach for sensitive, accurate mapping and quantification of SV breakpoint-supporting reads in plasma WGS. METHODS: Tumor, normal and plasma WGS data from 144 patients with stage III colorectal cancer was used to establish the bioinformatic framework. This included ~30x WGS data from 1564 serially collected plasma samples. The framework was validated using tumor/normal/plasma WGS data from 32 patients with muscle-invasive bladder cancer. SV-based ctDNA detection was benchmarked against previously published SNV-based ctDNA results for the same samples. RESULTS: After curation of SV calls and quantification in plasma WGS, our SV-based approach enabled robust ctDNA detection with overall specificity exceeding 99% in plasma samples. Furthermore, we observed strong concordance (Pearson&#x2019;s r&#x2009;>&#x2009;0.93, p&#x2009;<&#x2009;2.2&#x2009;&#xd7;&#x2009;10&#x2212; 16) between ctDNA-positive samples identified by our SV-based method and previous SNV-based analyses, validating the reliability of our approach. Finally, we demonstrated application of the method in an independent bladder cancer cohort, highlighting its generalizability and potential clinical use. CONCLUSIONS: We provide a bioinformatic framework that establishes somatic SVs as ultra-specific biomarkers for WGS-based, tumor-informed ctDNA detection. The approach delivers specific detection even when the SV catalogos are established from FFPE samples. The SV framework can stand alone or enhance SNV-based analysis pipelines.

Humans↗
PubMed2026

Whole-Genome Sequencing Reveals Population Structure, Genetic Diversity, and Selection Signatures in Kazakh Dromedary and Bactrian Camels.

Understanding the genomic basis of environmental adaptation is essential for the conservation and genetic improvement of domestic camels. In this study, we investigated the population structure, genetic diversity, and genomic variation potentially associated with environmental adaptation of Kazakh dromedary and Bactrian camels using whole-genome sequencing. Whole-genome sequencing data were generated for Kazakh camels (15 dromedaries and 16 Bactrian camels) and integrated with 131 publicly available genomes representing camel populations from the Arabian Peninsula, Iran, Xinjiang, Inner Mongolia, and Mongolian wild camels. Population structure, genetic diversity, and genome-wide selection were evaluated using principal component analysis, ADMIXTURE, nucleotide diversity, linkage disequilibrium, runs of homozygosity, genomic inbreeding (FROH), and selection scans based on FST, &#x3b8;&#x3c0; ratio, and XP-EHH. Population genomic analyses revealed clear differentiation between dromedary and Bactrian camels, whereas Kazakh camel populations exhibited higher nucleotide diversity (&#x3b8;&#x3c0; = 1.307-1.551 &#xd7; 10-3), and lower genomic inbreeding (median FROH: 0.037-0.056) than Arabian populations. Genome-wide selection analyses identified MC4R as the prominent candidate gene in Kazakh dromedaries and RYR1 as a prominent candidate gene in Kazakh Bactrian camels. Functional enrichment analyses highlighted pathways related to energy metabolism, thermogenesis, calcium signaling, skeletal muscle function, mitochondrial activity, and oxidative stress response. These findings provide new insights into genomic variation potentially associated with environmental adaptation in Kazakh camels and offer valuable genomic resources for future conservation, breeding, and evolutionary studies.

MC4R↗
PubMed2026

Evaluation of one-step amplicon-based targeted enrichment for SARS-CoV-2 whole-genome sequencing using the Midnight amplicon scheme.

Genomic surveillance proved invaluable during the COVID-19 pandemic for tracking SARS-CoV-2 variants and guiding outbreak responses, underscoring the ongoing need to reduce whole-genome sequencing (WGS) costs and improve workflow efficiency to ensure accessibility in resource limited settings. Here, we evaluated a one-step reverse transcription polymerase chain reaction (RT-PCR) approach using the Midnight V2 primer scheme for targeted amplification of the SARS-CoV-2 genome, assessed its compatibility with Illumina sequencing, and compared its performance to a well-established two-step method. Initially, we determined optimal RT-PCR reaction conditions using the Midnight V2 primer panel for the one-step RT-PCR kit and scaled reaction volumes for both RT-PCR and library preparation. Clinical specimens (n&#x202f;=&#x202f;53) that had undergone routine WGS for surveillance purposes using the established two-step RT-PCR method were compared using the one-step RT-PCR assay. For samples with genome completeness greater than 70%, both methods gave comparable results with similar sequence coverage and 100% concordance for lineage assignment. Further investigation revealed a higher percentage of reads aligning to the SARS-CoV-2 genome with a greater depth of coverage using the one-step method compared to the two-step method. Finally, analysis of scaled one-step and library reaction volumes revealed significant cost savings for samples undergoing WGS. Overall, the results presented here verify the accuracy and reproducibility of one-step targeted amplification and offer an efficient and cost-effective workflow for routine SARS-CoV-2 genomic surveillance.

Humans↗
PubMed2025

Streamlining large-scale genomic data management: Insights from the UK Biobank whole-genome sequencing data.

Biobank-scale whole-genome sequencing (WGS) studies are increasingly pivotal in unraveling the genetic bases of diverse health outcomes. However, managing and analyzing these datasets' sheer volume and complexity presents significant challenges. We highlight the annotated genomic data structure (aGDS) format, substantially reducing the WGS data file size while enabling seamless integration of genomic and functional information for comprehensive WGS analyses. The aGDS format yielded 23 chromosome-specific files for the UK Biobank 500k WGS dataset, occupying only 1.10 tebibytes of storage. We develop the vcf2agds toolkit that streamlines the conversion of WGS data from VCF to aGDS format. Additionally, the STAARpipeline equipped with the aGDS files enabled scalable, comprehensive, and functionally informed WGS analysis, facilitating the detection of common and rare coding and noncoding phenotype-genotype associations. Overall, the vcf2agds toolkit and STAARpipeline provide a streamlined solution that facilitates efficient data management and analysis of biobank-scale WGS data across hundreds of thousands of samples.

Humans↗
PubMed2001

Of mice and genome sequence.

Availability of the mouse genome sequence will have a major impact on the study of vertebrate evolution, mammalian biology, and animal models of human disease. Resources to explore genome biology in mice will maximize the effect of this watershed event.

Animals↗
PubMed2026

Equity in genome sequencing for rare disease diagnosis: a cross-sectional analysis of data from the UK 100,000 Genomes Project.

BACKGROUND: Genome sequencing has improved rare disease diagnosis and is now part of routine clinical care in the National Health Service in England. Automated prioritisation pipelines narrow millions of variants per patient to a small subset for clinical review, a process that relies on allele frequency resources that do not fully represent human genetic diversity. We assessed ancestry-related differences in variant prioritisation and diagnostic outcomes in patients from the UK 100,000 Genomes Project. METHODS: We analysed 29,405 rare disease probands with genome sequencing and linked clinical outcomes data. We used multivariable regression to assess ancestry-related differences in the number of variants prioritised for clinical review, the proportion of prioritised variants that were recorded as diagnostic, and diagnostic yield. We also evaluated the use of ancestry-stratified allele frequency filters derived from an independent, diverse UK cohort (n = 33,724). FINDINGS: Compared with the European ancestry group, the East African group had nearly three times more variants prioritised for clinical review (IRR 2.77, 95% CI 2.33-3.29). Other non-European groups also had significantly higher counts. Diagnostic yield was similar across ancestry groups after adjustment (LRT p = 0.1650). Prioritised variants were less likely to be recorded as diagnostic in East African (OR 0.32, 95% CI 0.22-0.46), West African (0.47, 0.39-0.57), South Asian (0.65, 0.58-0.73), and Middle Eastern (0.68, 0.54-0.86) groups. Applying ancestry-stratified allele-frequency filters removed 3.1% of prioritised variants overall-24.3% in the East African group-without loss of diagnostic sensitivity, including 29.5% of recorded VUS in this group. INTERPRETATION: Differences in the likelihood of prioritised variants being recorded as diagnostic partly reflect limitations of current allele frequency resources, which use broad population groupings that mask within-group diversity. Increased representation of diverse ancestries in reference databases and better estimation of ancestry-appropriate allele frequencies will help reduce inefficiencies and improve equity in variant prioritisation for rare disease diagnosis. FUNDING: The UK Department of Health and Social Care and the EU's Horizon 2020 Research and Innovation Programme.

Humans↗
PubMed2025

Whole genome sequence analysis of low-density lipoprotein cholesterol across 246&#xa0;K individuals.

BACKGROUND: Rare genetic variation provided by whole genome sequence datasets has been relatively less explored for its contributions to human traits. Meta-analysis of sequencing data offers advantages by integrating larger sample sizes from diverse cohorts, thereby increasing the likelihood of discovering novel insights into complex traits. Furthermore, emerging methods in genome-wide rare variant association testing further improve power and interpretability. RESULTS: Here, we conduct the largest meta-analysis of whole genome sequencing for low-density lipoprotein cholesterol (LDL-C), a therapeutic target for coronary artery disease, analyzing data from 246&#xa0;K participants and integrating 1.23B variants from the UK Biobank and the Trans-Omics for Precision Medicine (TOPMed) program. We identify numerous rare coding and non-coding gene associations related to LDL-C, with replication across 86&#xa0;K participants in All of Us. Our findings are based on single-variant analyses, rare coding and non-coding variant aggregation tests, and sliding window approaches. Through this comprehensive analysis, we identify 704 novel single-variant associations, 25 novel rare coding variant aggregates, 28 novel rare non-coding variant aggregates, and one novel sliding window aggregate. CONCLUSIONS: This study provides a meta-analysis framework for large-scale whole genome sequence association analyses from diverse population groups, yielding novel rare non-coding variant associations.

Humans↗
PubMed2025

Genome sequencing reveals the impact of pseudoexons in rare genetic disease.

PURPOSE: Advancements in sequencing technologies have significantly improved clinical genetic testing; yet, the diagnostic yield remains around 30% to 40%. Emerging technologies are now being deployed to address the remaining diagnostic gap. METHODS: We tested whether short-read genome sequencing could increase the diagnostic yield in individuals enrolled into the UCI-GREGoR research study, who had suspected Mendelian conditions and prior inconclusive testing. Two other collaborative research cohorts, focused on aortopathy and dilated cardiomyopathy, consisted of individuals who were undiagnosed but had not undergone harmonized prior testing. RESULTS: We sequenced 353 families (754 participants) and found a molecular diagnosis in 54 (15.3%) of them. Of these diagnoses, 55.5% were previously missed because the causative variants were in regions not originally interrogated. In 5 cases, they were deep intronic variants, all of which led to abnormal splicing and pseudoexons, as directly shown by RNA sequencing. All 5 of these variants had inconclusive spliceAI scores. In 26% of newly diagnosed cases, the causal variant could have been detected by exome sequencing reanalysis. CONCLUSION: Genome sequencing can overcome limitations of clinical genetic testing, such as the inability to call intronic variants. Our findings highlight pseudoexons as a common mechanism via which deep intronic variants cause Mendelian disease.

Humans↗
PubMed2026

First-line drug-resistant tuberculosis among children under 15 years in Ethiopia: insights from phenotypic and whole-genome sequencing approaches.

BACKGROUND: Childhood drug-resistant tuberculosis is often underdiagnosed and inadequately characterized due to the paucibacillary nature of the disease. This study aimed to assess resistance to first-line anti-tuberculosis drugs in children using phenotypic drug susceptibility testing and whole-genome sequencing. METHODS: A retrospective-prospective study was conducted on culture-confirmed childhood tuberculosis cases in Ethiopia (2017&#x2013;2023). Phenotypic drug susceptibility testing was performed on 110 Mycobacterium tuberculosis complex isolates. Whole-genome sequencing was completed for 85 of these isolates, which were analyzed using the TB-Profiler and MTBSeq pipelines. We assessed the sensitivity, specificity, predictive values, and kappa agreement of whole-genome sequencing compared with phenotypic drug susceptibility testing. RESULTS: Phenotypic resistance to at least one first-line anti-TB drug was observed in 26/110 (23.6%) of the examined isolates, with isoniazid resistance being the most frequent, 23/110 (20.9%), followed by rifampicin resistance, 18/110 (16.4%). TB-Profiler showed almost perfect agreement with phenotypic drug susceptibility testing for rifampicin (sensitivity 94.4%, kappa&#x2009;=&#x2009;0.96) and isoniazid (sensitivity 91.3%, kappa&#x2009;=&#x2009;0.91), whereas MTBSeq showed slightly lower performance. Both pipelines demonstrated moderate to weak agreement with phenotypic drug susceptibility testing for detecting resistance to ethambutol, pyrazinamide, and streptomycin. The most frequently observed resistance mutations among phenotypically resistant isolates were rpoB (Ser450Leu), katG (S315Thr), embB (Met306Ile), and pncA (C-11&#xa0;A&#x2009;>&#x2009;G) for rifampicin, isoniazid, ethambutol, and pyrazinamide, respectively. Discrepancies between genotypic and phenotypic drug susceptibility testing were observed across all first-line anti-TB drug-resistant isolates, particularly for ethambutol and pyrazinamide. CONCLUSION: We found a high prevalence of isoniazid resistance, along with rifampicin resistance, underscoring the need for early detection in vulnerable groups. Whole-genome sequencing showed good accuracy for these drugs, with TB-Profiler performing best. CLINICAL TRIAL NUMBER: Not applicable.

Humans↗
PubMed2024

Critically unwell infants and children with mitochondrial disorders diagnosed by ultrarapid genomic sequencing.

PURPOSE: To characterize the diagnostic and clinical outcomes of a cohort of critically ill infants and children with suspected mitochondrial disorders (MD) undergoing ultrarapid genomic testing as part of a national program. METHODS: Ultrarapid genomic sequencing was performed in 454 families (genome sequencing: n&#xa0;= 290, exome sequencing&#xa0;+/- mitochondrial DNA sequencing: n&#xa0;= 164). In 91 individuals, MD was considered, prompting analysis using an MD virtual gene panel. These individuals were reviewed retrospectively and scored according to modified Nijmegen Mitochondrial Disease Criteria. RESULTS: A diagnosis was achieved in 47% (43/91) of individuals, 40% (17/43) of whom had an MD. Seven additional individuals in whom an MD was not suspected were diagnosed with an MD after broader analysis. Gene-agnostic analysis led to the discovery of 2 novel disease genes, with pathogenicity validated through targeted functional studies (CRLS1 and MRPL39). Functional studies enabled diagnosis in another 4 individuals. Of the 24 individuals ultimately diagnosed with an MD, 79% had a change in management, which included 53% whose care was redirected to palliation. CONCLUSION: Ultrarapid genetic diagnosis of MD in acutely unwell infants and children is critical for guiding decisions about the need for additional investigations and clinical management.

Humans↗
PubMed2025

Identification of a novel non-coding deletion in Allan-Herndon-Dudley syndrome by long-read HiFi genome sequencing.

BACKGROUND: Allan-Herndon-Dudley syndrome (AHDS) is an X-linked disorder caused by pathogenic variants in the SLC16A2 gene. Although most reported variants are found in protein-coding regions or adjacent junctions, structural variations (SVs) within non-coding regions have not been previously reported. METHODS: We investigated two male siblings with severe neurodevelopmental disorders and spasticity, who had remained undiagnosed for over a decade and were negative from exome sequencing, utilizing long-read HiFi genome sequencing. We conducted a comprehensive analysis including short-tandem repeats (STRs) and SVs to identify the genetic cause in this familial case. RESULTS: While coding variant and STR analyses yielded negative results, SV analysis revealed a novel hemizygous deletion in intron 1 of the SLC16A2 gene (chrX:74,460,691&#x2009;-&#x2009;74,463,566; 2,876&#xa0;bp), inherited from their carrier mother and shared by the siblings. Determination of the breakpoints indicates that the deletion probably resulted from Alu/Alu-mediated rearrangements between homologous AluY pairs. The deleted region is predicted to include multiple transcription factor binding sites, such as Stat2, Zic1, Zic2, and FOXD3, which are crucial for the neurodevelopmental process, as well as a regulatory element including an eQTL (rs1263181) that is implicated in the tissue-specific regulation of SLC16A2 expression, notably in skeletal muscle and thyroid tissues. CONCLUSIONS: This report, to our knowledge, is the first to describe a non-coding deletion associated with AHDS, demonstrating the potential utility of long-read sequencing for undiagnosed patients. Although interpreting variants in non-coding regions remains challenging, our study highlights this region as a high priority for future investigation and functional studies.

Humans↗