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At least 19 recordsLinked to original sources

PubMed2024

Diagnosing missed cases of spinal muscular atrophy in genome, exome, and panel sequencing data sets.

PURPOSE: We set out to develop a publicly available tool that could accurately diagnose spinal muscular atrophy (SMA) in exome, genome, or panel sequencing data sets aligned to a GRCh37, GRCh38, or T2T reference genome. METHODS: The SMA Finder algorithm detects the most common genetic causes of SMA by evaluating reads that overlap the c.840 position of the SMN1 and SMN2 paralogs. It uses these reads to determine whether an individual most likely has 0 functional copies of SMN1. RESULTS: We developed SMA Finder and evaluated it on 16,626 exomes and 3911 genomes from the Broad Institute Center for Mendelian Genomics, 1157 exomes and 8762 panel samples from Tartu University Hospital, and 198,868 exomes and 198,868 genomes from the UK Biobank. SMA Finder's false-positive rate was below 1 in 200,000 samples, its positive predictive value was greater than 96%, and its true-positive rate was 29 out of 29. Most of these SMA diagnoses had initially been clinically misdiagnosed as limb-girdle muscular dystrophy. CONCLUSION: Our extensive evaluation of SMA Finder on exome, genome, and panel sequencing samples found it to have nearly 100% accuracy and demonstrated its ability to reduce diagnostic delays, particularly in individuals with milder subtypes of SMA. Given this accuracy, the common misdiagnoses identified here, the widespread availability of clinical confirmatory testing for SMA, and the existence of treatment options, we propose that it is time to add SMN1 to the American College of Medical Genetics list of genes with reportable secondary findings after genome and exome sequencing.

Humans↗

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↗

PubMed2026

Whole-Exome Sequencing in a Consanguinity-Enriched South Indian Retinitis Pigmentosa Cohort: Diagnostic Yield and Molecular Spectrum.

PURPOSE: To determine the molecular diagnostic yield, variant spectrum, inheritance architecture, and influence of consanguinity on whole-exome sequencing outcomes in a South Indian retinitis pigmentosa (RP) cohort. DESIGN: Prospective, registry-based cohort study. SUBJECTS: A total of 113 affected participants were enrolled through the Aravind Registry for Inherited Diseases of the Eye, including 109 unrelated probands and 4 affected relatives from already represented families. Primary analyses were restricted to the 109 unrelated probands. METHODS: Whole-exome sequencing was performed using a clinical exome workflow. Variants were interpreted using American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria and cases were categorized as solved, possibly solved, inconclusive, or unsolved using prespecified inheritance-aware rules. MAIN OUTCOME MEASURES: Molecular diagnostic yield, distribution of implicated genes and variant classes, inheritance architecture, and diagnostic yield stratified by consanguinity status. RESULTS: Among the 109 unrelated probands, mean age at testing was 39.3 ± 14.1 years and 58.7% were male. Whole-exome sequencing identified 186 distinct rare variants across 92 inherited retinal disease genes, including 26 pathogenic and 33 likely pathogenic variants. A molecular diagnosis was established in 50 of 109 probands (45.9%), including 42 solved and 8 possibly solved cases; 45 (41.3%) were inconclusive and 14 (12.8%) remained unsolved, including 4 (3.7%) in whom no candidate variant was identified. EYS, USH2A, and ADGRV1 were the most frequently implicated genes. Autosomal recessive (AR) disease predominated (44/50, 88.0%). Consanguineous AR cases were exclusively homozygous (17/17); notably, 68.0% of nonconsanguineous AR cases were also homozygous (P = 0.013). Diagnostic yield was higher in consanguineous probands (51.4% vs. 41.7%), without reaching significance. Recurrent alleles included an established South Asian founder variant (MFSD8 c.1361T>C) and candidate founder alleles in EYS (c.4321C>T) and ADGRV1 (c.14329C>T). CONCLUSIONS: Whole-exome sequencing established a molecular diagnosis in nearly half of this South Indian RP cohort and revealed a predominantly recessive, homozygosity-enriched architecture shaped by consanguinity. These findings define a region-specific variant landscape to support clinical interpretation, genetic counseling, and future trial enrollment in this underrepresented population. FINANCIAL DISCLOSURES: The authors have no proprietary or commercial interest in any materials discussed in this article.

Consanguinity↗

PubMed2026

Genetic landscape of pediatric seizures in Southeast China: identification of a novel GLI3 frameshift variant through whole-exome sequencing.

BACKGROUND: Pediatric seizure disorders are clinically and genetically heterogeneous. Whole-exome sequencing has improved the detection of rare genetic variants in childhood epilepsy; however, data from pediatric populations in Southeast China remain limited. This study aimed to characterize the genetic landscape of pediatric seizure disorders in Southeast China and to evaluate the clinical diagnostic yield of whole-exome sequencing. MATERIALS AND METHODS: This retrospective observational study included 21 pediatric patients with seizure disorders who were recruited at the Fifth Hospital of Xiamen, Fujian, China, between January 2021 and June 2024. Clinical data were extracted from medical records. Whole-exome sequencing was performed on DNA extracted from peripheral blood. Sequence variants were annotated, filtered, and classified according to the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Copy-number variants were evaluated using exome-based algorithms. Descriptive statistics were used because of the limited sample size. RESULTS: WES identified three clinically relevant, likely pathogenic findings in 3 of 21 patients, corresponding to a provisional diagnostic yield of 14.3%. The remaining 62 of 65 variants were of uncertain significance (VUS). The three retained variants included a GLI3 frameshift variant (exon 2: c.90_91insCAGATGTGAGC; p.Glu31Glnfs*3) and two copy-number variants (16p13.12-16p13.11 duplication and Xp22.31 deletion) with established clinical significance. Functional analysis of all 65 variants revealed that ion channel genes and neurodevelopmental genes were the most frequently affected categories. CONCLUSION: Whole-exome sequencing identified clinically relevant genetic findings in a subset of Southeast Chinese children with seizure disorders. The novel GLI3 frameshift variant may suggest an expansion of the GLI3-associated phenotypic spectrum, but further segregation, functional validation, and larger cohort studies are needed. The high proportion of variants of uncertain significance highlights the ongoing challenges of genetic interpretation in pediatric seizure disorders.

GLI3 frameshift variant↗

PubMed2024

Diagnostic yield of exome sequencing-based copy number variation analysis in Mendelian disorders: a clinical application.

Next-generation sequencing (NGS) coupled with bioinformatic tools has revolutionized the detection of copy number variations (CNVs), which are implicated in the emergence of Mendelian disorders. In this study, we evaluated the diagnostic yield of exome sequencing-based CNV analysis in 449 patients with suspected Mendelian disorders. We aimed to assess the diagnostic yield of this recently utilized method and expand the clinical spectrum of intragenic CNVs. The cohort underwent whole exome sequencing (WES) and clinical exome sequencing (CES). Using GATK-gCNV, we identified 12 pathogenic CNVs that correlated with their clinical findings and resulting in a diagnostic yield of 2.67%. Importantly, the study emphasizes the role of CNVs in the etiology of Mendelian disorders and highlights the value of exome sequencing-based CNV analysis in routine diagnostic processes.

Humans↗

PubMed2026

Integrated exome and mitochondrial genome sequencing reveals the genetic landscape of primary mitochondrial diseases: findings from a large Tunisian cohort.

Primary mitochondrial diseases are a heterogeneous group of neurometabolic disorders recognized as the most common metabolic genetic diseases. They manifest at any age, affecting any tissue or organ, especially those with high energy demands, and are caused by pathogenic variants in both mitochondrial and nuclear genomes. Here, we aimed to describe the genetic spectrum of a Tunisian pediatric cohort with suspected mitochondrial diseases. We recruited 47 unrelated families who underwent exome sequencing as a first-tier test followed by whole mitochondrial genome sequencing for unsolved cases. Dedicated bioinformatic pipelines and prediction tools were used to determine the potential disease-causing variants. Sanger sequencing confirmed the presence and segregation within parents. For the newly identified variants, structural modeling was conducted to study the impact of these variants on protein structure and motions. Dual genome sequencing yielded a molecular diagnosis in 33/47 families (70%) and 18/47 (38%) showed disease-causing variants in genes encoding mitochondrial proteins. Among them, four families disclosed novel variants in FASTKD2, SERAC1 and GATB, which were supported by in-depth in silico and structural analyses demonstrating their deleterious effect. The remaining families (32%, 15/47) disclosed other metabolic and neurological disorders. An exome-first strategy delivers a high diagnostic yield in Tunisia, where consanguinity remains high and simultaneously captures mitochondrial and non-mitochondrial etiologies. Mitochondrial sequencing remains indispensable in the case of an inconclusive exome. Thus, our data expand the clinical and genetic spectrum of primary mitochondrial diseases in Tunisia, an underrepresented and admixed population.

Humans↗

PubMed2022

Feasibility of a novel non-invasive swab technique for serial whole-exome sequencing of cervical tumors during chemoradiation therapy.

BACKGROUND: Clinically relevant genetic predictors of radiation response for cervical cancer are understudied due to the morbidity of repeat invasive biopsies required to obtain genetic material. Thus, we aimed to demonstrate the feasibility of a novel noninvasive cervical swab technique to (1) collect tumor DNA with adequate throughput to (2) perform whole-exome sequencing (WES) at serial time points over the course of chemoradiation therapy (CRT). METHODS: Cervical cancer tumor samples from patients undergoing chemoradiation were collected at baseline, at week 1, week 3, and at the completion of CRT (week 5) using a noninvasive swab-based biopsy technique. Swab samples were analyzed with whole-exome sequencing (WES) with mutation calling using a custom pipeline optimized for shallow whole-exome sequencing with low tumor purity (TP). Tumor mutation changes over the course of treatment were profiled. RESULTS: 216 samples were collected and successfully sequenced for 70 patients (94% of total number of tumor samples collected). A total of 33 patients had a complete set of samples at all four time points. The mean mapping rate was 98% for all samples, and the mean target coverage was 180. Estimated TP was greater than 5% for all samples. Overall mutation frequency decreased during CRT but mapping rate and mean target coverage remained at >98% and >180 reads at week 5. CONCLUSION: This study demonstrates the feasibility and application of a noninvasive swab-based technique for WES analysis which may be applied to investigate dynamic tumor mutational changes during treatment to identify novel genes which confer radiation resistance.

Exome↗

PubMed2025

Monogenic disorders associated with motor speech phenotypes in children and adolescents undergoing clinical exome sequencing.

PURPOSE: Prior studies investigating the genetic architecture of pediatric motor speech disorders (MSDs) have been limited by small sample sizes and an exclusive focus on apraxia. We aimed to identify pathogenic genomic variants associated with MSDs in a large pediatric population referred for exome sequencing (ES). METHODS: We identified pediatric patients with MSDs who had clinical ES between 2012 and 2022. The rate of pathogenic/likely pathogenic (P/LP) findings considered causative of the MSD phenotype was determined and delineated by sex and neurodevelopmental comorbidity. Gene-based burden testing compared the rate of P/LP variants in each gene in MSD cases with a comparison clinical ES cohort. RESULTS: Positive diagnostic results were detected in 527 of 2004 (26.3%) patients with MSDs, with higher diagnostic rates in females and individuals with neurodevelopmental comorbidities. P/LP sequence variants were detected in 262 genes. Gene-based case-referent burden analysis revealed that 30 genes were nominally associated with MSDs, 2 of which (SETBP1 and ADCY5) survived exome-wide correction. CONCLUSION: Over 25% of patients with MSDs were found to harbor P/LP variants in 262 genes, many of which have not previously been associated with MSDs. Potential clinical implications include early implementation of intensive speech therapy for children diagnosed with monogenic causes of MSDs.

Humans↗

PubMed2025

Trio exome sequencing identifies de novo variants in novel candidate genes in 19.62% of CAKUT families.

PURPOSE: Congenital anomalies of the kidney and urinary tract (CAKUT) encompass heterogenous malformations arising from defective nephrogenesis. To date, approximately 50 monogenic genes are known to cause CAKUT if mutated. Recent studies show the impact of de novo variants in genetic disease etiology. Trio exome sequencing identifies de novo variants in novel candidate genes in 19.62% of CAKUT families. METHODS: We performed trio-based exome sequencing in 209 families with CAKUT to detect novel candidate disease genes. RESULTS: Trio analysis yielded in the identification of CAKUT candidate genes in 96 of 209 trio families (45.93%). In 41 of 209 cases, we detected strong de novo variants in 45 potential novel CAKUT candidate genes (19.62%). We developed a prioritization approach that highlights a truncating de novo variant in SOX13 (HGNC:11192) as a promising cause for CAKUT. In addition, further allele carriers for the candidate gene CHD1L (HGNC:1916) were identified, thus supporting the role of CHD1L in the pathogenesis of CAKUT. CONCLUSION: We conclude that de novo variants in potential novel CAKUT candidate genes contribute to the disease etiology and present SOX13 as a potential novel cause for CAKUT.

Humans↗

PubMed2024

Exome sequencing reveals neurodevelopmental genes in simplex consanguineous Iranian families with syndromic autism.

BACKGROUND AND OBJECTIVE: Autosomal recessive genetic disorders pose significant health challenges in regions where consanguineous marriages are prevalent. The utilization of exome sequencing as a frequently employed methodology has enabled a clear delineation of diagnostic efficacy and mode of inheritance within multiplex consanguineous families. However, these aspects remain less elucidated within simplex families. METHODS: In this study involving 12 unrelated simplex Iranian families presenting syndromic autism, we conducted singleton exome sequencing. The identified genetic variants were validated using Sanger sequencing, and for the missense variants in FOXG1 and DMD, 3D protein structure modeling was carried out to substantiate their pathogenicity. To examine the expression patterns of the candidate genes in the fetal brain, adult brain, and muscle, RT-qPCR was employed. RESULTS: In four families, we detected an autosomal dominant gene (FOXG1), an autosomal recessive gene (CHKB), and two X-linked autism genes (IQSEC2 and DMD), indicating diverse inheritance patterns. In the remaining eight families, we were unable to identify any disease-associated genes. As a result, our variant detection rate stood at 33.3% (4/12), surpassing rates reported in similar studies of smaller cohorts. Among the four newly identified coding variants, three are de novo (heterozygous variant p.Trp546Ter in IQSEC2, heterozygous variant p.Ala188Glu in FOXG1, and hemizygous variant p.Leu211Met in DMD), while the homozygous variant p.Glu128Ter in CHKB was inherited from both healthy heterozygous parents. 3D protein structure modeling was carried out for the missense variants in FOXG1 and DMD, which predicted steric hindrance and spatial inhibition, respectively, supporting the pathogenicity of these human mutants. Additionally, the nonsense variant in CHKB is anticipated to influence its dimerization - crucial for choline kinase function - and the nonsense variant in IQSEC2 is predicted to eliminate three functional domains. Consequently, these distinct variants found in four unrelated individuals with autism are likely indicative of loss-of-function mutations. CONCLUSIONS: In our two syndromic autism families, we discovered variants in two muscular dystrophy genes, DMD and CHKB. Given that DMD and CHKB are recognized for their participation in the non-cognitive manifestations of muscular dystrophy, it indicates that some genes transcend the boundary of apparently unrelated clinical categories, thereby establishing a novel connection between ASD and muscular dystrophy. Our findings also shed light on the complex inheritance patterns observed in Iranian consanguineous simplex families and emphasize the connection between autism spectrum disorder and muscular dystrophy. This underscores a likely genetic convergence between neurodevelopmental and neuromuscular disorders.

Humans↗

PubMed2023

Exome-wide evidence of compound heterozygous effects across common phenotypes in the UK Biobank.

Exome-sequencing association studies have successfully linked rare protein-coding variation to risk of thousands of diseases. However, the relationship between rare deleterious compound heterozygous (CH) variation and their phenotypic impact has not been fully investigated. Here, we leverage advances in statistical phasing to accurately phase rare variants (MAF ~ 0.001%) in exome sequencing data from 175,587 UK Biobank (UKBB) participants, which we then systematically annotate to identify putatively deleterious CH coding variation. We show that 6.5% of individuals carry such damaging variants in the CH state, with 90% of variants occurring at MAF < 0.34%. Using a logistic mixed model framework, systematically accounting for relatedness, polygenic risk, nearby common variants, and rare variant burden, we investigate recessive effects in common complex diseases. We find six exome-wide significant () and 17 nominally significant () gene-trait associations. Among these, only four would have been identified without accounting for CH variation in the gene. We further incorporate age-at-diagnosis information from primary care electronic health records, to show that genetic phase influences lifetime risk of disease across 20 gene-trait combinations (FDR < 5%). Using a permutation approach, we find evidence for genetic phase contributing to disease susceptibility for a collection of gene-trait pairs, including FLG-asthma () and USH2A-visual impairment (). Taken together, we demonstrate the utility of phasing large-scale genetic sequencing cohorts for robust identification of the phenome-wide consequences of compound heterozygosity.

Preprint↗

PubMed2026

Whole-exome characterization of host genetic variation in HIV-associated genes across the high-prevalence Mizo population, Northeast India.

BACKGROUND: The Mizoram state of Northeast India has one of the highest HIV prevalence rates in Asia, yet the host genetic factors influencing HIV susceptibility in this Tibeto-Burman population remain uncharacterised. METHODS: We performed whole-exome sequencing using Illumina NovaSeq 6000, mean coverage 100X on 76 HIV-negative Mizo individuals. Variants were called using GATK HaplotypeCaller v4.3 against GRCh38p14, annotated with ANNOVAR, and filtered using hard-quality thresholds (QD ≥ 2, SOR ≤ 3, MQ ≥ 40, DP ≥ 10, GQ ≥ 20). The allele frequencies were compared against gnomAD v2.1.1 population databases. Hardy-Weinberg equilibrium was assessed using the Wigginton exact test with Bonferroni correction. RESULTS: Post-quality filtering resulted in 12,011 sample-variants across 2,821 unique positions from 36 HIV-associated loci (33 protein-coding genes, 2 chemokine ligands, and 3 lncRNA targets). Of these, 784 observations (51 unique positions) were high-impact nonsynonymous or loss-of-function variants. ADAR rs2229857 (p.K384R, NM_015840) was the most frequently observed variant (Mizo carrier frequency = 0.895; 95% CI: 0.806-0.946). CXCR1 rs16858808 (p.R335C) showed the greatest population enrichment (Mizo carrier frequency = 0.197; 95% CI: 0.123-0.300; 7.65-fold carrier-frequency enrichment versus gnomAD South Asian; CADD = 15.60). Sixteen of 20 tested variants deviated from Hardy-Weinberg equilibrium after Bonferroni correction (p < 0.0025), predominantly showing excess homozygosity consistent with the endogamous Mizo population. The protective variant CCR5-Δ32 was absent in all the 76 individuals tested. CONCLUSION: This first whole-exome characterization of HIV host genes in the Mizo population identifies CXCR1 rs16858808 as the most population-enriched functional variant and reveals a pervasive endogamy signature. These findings provide a population-specific genetic framework for future HIV susceptibility studies and ART pharmacogenomics research.

Humans↗

PubMed2026

WxS-QC-a quality control pipeline for human germline short-variant Whole-Genome and Whole-Exome cohorts for population-scale analyses.

SUMMARY: Whole-exome (WES) and whole-genome (WGS) sequencing are rapidly becoming preferred methods for population-scale analysis of the human genetic landscape. However, there are currently no standardized quality control (QC) pipelines for human WES and WGS datasets. In this paper, we present WxS-QC, a powerful, scalable, and convenient pipeline for the QC of human germline short-variant WGS and WES cohorts for population-scale analyses. Our pipeline is suitable for both rare-variant discovery and common-variant association studies. It is based on deeply refactored gnomAD v3 and v4 quality control pipelines, contains several methods we have developed de novo, and is aligned with current best practices in WGS/WES germline cohort QC. We provide all methods in a single codebase, aligned to work together and controlled via a single YAML config, with automatic export of resulting graphs and summary tables, excellent performance and scalability, and comprehensive documentation. The pipeline can run in any UNIX-like environment and can efficiently process cohorts of up to 200 000 whole-exome samples, with the potential to handle bigger datasets. AVAILABILITY AND IMPLEMENTATION: The pipeline code is written in Python using the Hail library and is freely available under the BSD-3 license here: https://github.com/wtsi-hgi/wxs-qc. The detailed description of the pipeline is available in the pipeline documentation: https://github.com/wtsi-hgi/wxs-qc/blob/main/README.md. We also provide an open dataset with all required metadata, which is available at https://wxs-qc-data.cog.sanger.ac.uk/wxs-qc_public_dataset_v3.tar. An example of test dataset analysis is available in the supplementary materials.

Humans↗

PubMed2024

Genomic landscape of hepatocellular carcinoma in Egyptian patients by whole exome sequencing.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Chronic hepatitis and liver cirrhosis lead to accumulation of genetic alterations driving HCC pathogenesis. This study is designed to explore genomic landscape of HCC in Egyptian patients by whole exome sequencing. METHODS: Whole exome sequencing using Ion Torrent was done on 13 HCC patients, who underwent surgical intervention (7 patients underwent living donor liver transplantation (LDLT) and 6 patients had surgical resection}. RESULTS: Mutational signature was mostly S1, S5, S6, and S12 in HCC. Analysis of highly mutated genes in both HCC and Non-HCC revealed the presence of highly mutated genes in HCC (AHNAK2, MUC6, MUC16, TTN, ZNF17, FLG, MUC12, OBSCN, PDE4DIP, MUC5b, and HYDIN). Among the 26 significantly mutated HCC genes-identified across 10 genome sequencing studies-in addition to TCGA, APOB and RP1L1 showed the highest number of mutations in both HCC and Non-HCC tissues. Tier 1, Tier 2 variants in TCGA SMGs in HCC and Non-HCC (TP53, PIK3CA, CDKN2A, and BAP1). Cancer Genome Landscape analysis revealed Tier 1 and Tier 2 variants in HCC (MSH2) and in Non-HCC (KMT2D and ATM). For KEGG analysis, the significantly annotated clusters in HCC were Notch signaling, Wnt signaling, PI3K-AKT pathway, Hippo signaling, Apelin signaling, Hedgehog (Hh) signaling, and MAPK signaling, in addition to ECM-receptor interaction, focal adhesion, and calcium signaling. Tier 1 and Tier 2 variants KIT, KMT2D, NOTCH1, KMT2C, PIK3CA, KIT, SMARCA4, ATM, PTEN, MSH2, and PTCH1 were low frequency variants in both HCC and Non-HCC. CONCLUSION: Our results are in accordance with previous studies in HCC regarding highly mutated genes, TCGA and specifically enriched pathways in HCC. Analysis for clinical interpretation of variants revealed the presence of Tier 1 and Tier 2 variants that represent potential clinically actionable targets. The use of sequencing techniques to detect structural variants and novel techniques as single cell sequencing together with multiomics transcriptomics, metagenomics will integrate the molecular pathogenesis of HCC in Egyptian patients.

Humans↗

PubMed2025

Exome sequencing revealed a novel homozygous variant in TRMT61 A in a multiplex family with atypical Cornelia de Lange Syndrome from Rwanda.

BACKGROUND: In 30% of patients who exhibit the clinical profile of Cornelia de Lange Syndrome (CdLS), the genetic cause remains undetermined. This proportion tends to be higher in low-resource settings including Africa. We performed a molecular characterization of CdLS in a multiplex Rwandan family. METHODS: After a clinical evaluation of two affected siblings, DNA isolated from peripheral whole blood of the affected patients and their parents underwent Exome Sequencing (ES). Sanger sequencing validated the variant segregating with CdLS. In silico predictive tools, protein modelling, and cell-based experiments using HEK293T cells were used to investigate the pathogenicity of the variant found. RESULTS: We identified a family with two parents and their two offspring (male and female), who were referred for hearing impairment. The 17-year-old female presented bilateral profound hearing impairment with moderate hypertelorism, progressive visual impairment, and secondary amenorrhea. The 14-year-old male displayed intellectual disability and a bilateral profound hearing impairment with no noticeable facial dysmorphism. Following exome sequencing (ES) of DNA samples obtained from the four family members, we found that the siblings harbored a novel likely pathogenic homozygous missense variant in the TRMT61 A gene [NM_152307.3:c.665C > T p.(Ala222Val)] inherited from both heterozygous parents. In silico analysis suggested that the variant substitutes a highly conserved amino acid, and 2-D structure modelling revealed a significant decrease in the stability of the protein. Cell-based experiment in HEK293T showed that the variant significantly affected the TRMT61 A protein localization which is thought to impact the mitochondrial and cytosolic functions. CONCLUSION: We reported a novel biallelic variant in TRMT61 A, [NM_152307.3:c.665C > T p.(Ala222Val)], which is associated with autosomal recessive atypical CdLS in a multiplex Rwandan family, the first report from Africa, and the second globally. The study emphasizes the need to expand the availability of ES for molecular characterization of rare diseases for the understudied genetically diverse population of Africa.

Humans↗

PubMed2026

Whole-exome Sequencing Identifies Novel Candidate PCNT Variants in a Child With Overlapping MOPD II Features: A Case Report.

A 7-year-old Chinese boy presented with severe postnatal growth failure (height <3rd percentile at age 7 years), global developmental delay, moderate intellectual disability, and characteristic dysmorphic features including hypertelorism, short palpebral fissures, low-set ears, and a broad nasal bridge. A single electrocardiogram demonstrated a borderline corrected QT interval (QTc = 450 ms). No arrhythmias, QT-prolonging medications, electrolyte abnormalities, or relevant family cardiac history were identified. This finding warrants longitudinal cardiology follow-up and should not be interpreted as definitive Long QT syndrome. Whole-exome sequencing identified two novel missense variants in the PCNT gene (NM_006031.5): c.5675A>G (p.Glu1892Gly) in exon 28 and c.9734G>T (p.Arg3245Ile) in exon 45. Both variants were absent from gnomAD, ExAC, the 1000 Genomes Project database, and Chinese population databases, fulfilling ACMG criterion PM2. Although classified as variants of uncertain significance (VUS) because of limited functional evidence and conflicting in silico predictions, the variants occur in a gene associated with primordial dwarfism and are accompanied by partial phenotypic overlap with Microcephalic Osteodysplastic Primordial Dwarfism Type II (MOPD II). However, parental segregation analysis was unavailable; therefore, the variant phase could not be confirmed, and a recessive disease mechanism could not be established. These findings support the presence of candidate PCNT variants in an atypical primordial dwarfism phenotype and illustrate the utility of whole-exome sequencing for generating testable molecular hypotheses in genetically heterogeneous growth disorders. A definitive molecular diagnosis cannot be established at present, and the isolated borderline QTc finding requires further clinical evaluation.

Humans↗

PubMed2026

T-rex: standardized analysis of germline variants in whole-exome sequencing trios.

Whole-exome sequencing (WES) enables the identification of rare germline variants contributing to pediatric diseases. Trio-based sequencing, comparing affected children with their parents, is particularly effective for rare disease genetics. However, WES data analysis requires bioinformatics expertise, varies across institutions, and is often incompatible with clinical workflows. We developed T-Rex (Trio Rare variant analysis of EXomes), a cross-platform desktop application that enables the standardized and local analysis of WES germline Trio data without the need for programming knowledge. T-Rex integrates state-of-the-art tools for alignment, dual-variant calling (GATK HaplotypeCaller + VarScan2), annotation (SNPEff/SNPSift), rare-variant filtering based on population frequencies (gnomAD), and family-based statistical testing, including the Transmission Disequilibrium Test with multiple-testing correction. Benchmarking of the dual-caller strategy on the Genome in a Bottle Ashkenazim Trio demonstrates high precision (99.2%) while maintaining robust sensitivity (91.1%). User testing (n = 13) confirmed quick learning across clinicians and researchers. Application to a cohort of n = 121 pediatric cancer Trio datasets, filtering for rare protein-coding variants (MAF ≤ 0.1% in gnomAD v4.1), validated all assessable previously reported pathogenic variants. Overall, T-Rex enables clinicians to robustly analyze WES Trio data in compliance with data protection regulations without requiring additional software licenses. As one of the first platforms for comprehensive WES Trio analysis that requires no programming expertise while providing reproducible, end-to-end workflows for clinical genomics, T-Rex facilitates collaborative research between clinics and reduces reliance on external providers.

Humans↗

PubMed2025

Exome sequencing identifies a homozygous splice site variant in RP1 as the underlying cause of autosomal recessive retinitis pigmentosa in a Pakistani family.

BACKGROUND: Mutations in RP1 gene are the third leading cause of inherited retinal dystrophies (IRDs) in Pakistani families. PATIENTS: A two-generation consanguineous Pakistani family underwent both clinical and genetic analyses. Clinical examinations included visual acuity test, visual field, fundoscopy, and ocular coherence tomography (OCT). Whole exome sequencing (WES) was performed on the proband's DNA, and Sanger sequencing was performed to validate the WES findings. Splicing prediction tools such as Human Splicing Finder (HSF), NNSplice predictor, SpliceAI, MaxENTScan, and SpliceRover were used. RESULTS: A nuclear family of seven children, comprising five affected individuals (four males and one female) and two healthy siblings, was recruited from northwestern Pakistan. The proband was a 49-years old male who was presented with complaints of decreased visual acuity and night blindness since early childhood. Upon clinical evaluation, the proband appeared to have severely reduced visual acuity of hand movement (HM), bilateral visual field constriction, a waxy pale disc with vascular attenuation, pigmentary bone spicules at the periphery associated with chorioretinal degeneration, diffuse macular atrophy, and horizontal nystagmus in both of his eyes. Exome sequencing (ES) in the proband identified a homozygous splice site variant (NM_006269.2: c.615 + 1G > A) in RP1 gene. In-silico analysis, genotype-phenotype co-segregation study, and literature survey strongly supported the causality of the detected variant. CONCLUSIONS: We report a previously known pathogenic splice site variant of RP1 as the underlying cause of early-onset autosomal recessive retinitis pigmentosa (arRP) in a Pakistani family. We contemplate that the detected allele might constitute a mutational hotspot in RP1.

Humans↗