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PubMed2026

Clinical implementation of next-generation sequencing in tertiary health system: the Rijeka retrospective study.

OBJECTIVE: This study aimed to assess the diagnostic yield, clinical indications, and utility of next-generation sequencing (NGS) testing since its implementation through collaboration between the University of Rijeka Faculty of Medicine and the Clinical Hospital Centre Rijeka. MATERIALS AND METHODS: This retrospective study included patients referred between 2018 and 2023 from the Clinical Hospital Centre Rijeka to the University of Rijeka Faculty of Medicine for genetic testing, primarily using exome sequencing. RESULTS: Between April 2018 and December 2023, 412 patients were referred for exome sequencing, of whom 353 (85.7%) underwent diagnostic genetic testing. A notable increase in tests ordered was observed over time. Patients were most frequently referred from Pediatrics (55.0%), Neurology (29.5%), Cardiology (7.4%), Ophthalmology (3.4%), and others (4.7%). A diagnosis was confirmed in 103/353 patients, corresponding to an overall diagnostic yield of 29.2%, and an adjusted diagnostic yield of 27.2% after collapsing related individuals into single family units. In these confirmed cases, 83 distinct disorders involving 71 unique genes were identified, with most patients showing heterozygous variants and several recurrent disorders and genes. Variants of uncertain significance were reported in 35/353 (9.9%) patients. CONCLUSION: The 27.2% diagnostic yield demonstrates effective integration of NGS into tertiary clinical practice. The recent introduction of medical genetics specialization is expected to further improve referral quality, variant interpretation, and overall diagnostic outcomes.

exome sequencing↗

PubMed2025

Estimation of demography and mutation rates from one million haploid genomes.

As genetic sequencing costs have plummeted, datasets with sizes previously unthinkable have begun to appear. Such datasets present opportunities to learn about evolutionary history, particularly via rare alleles that record the very recent past. However, beyond the computational challenges inherent in the analysis of many large-scale datasets, large population-genetic datasets present theoretical problems. In particular, the majority of population-genetic tools require the assumption that each mutant allele in the sample is the result of a single mutation (the "infinite-sites" assumption), which is violated in large samples. Here, we present DR EVIL, a method for estimating mutation rates and recent demographic history from very large samples. DR EVIL avoids the infinite-sites assumption by using a diffusion approximation to a branching-process model with recurrent mutation. This approach results in tractable likelihoods that are accurate for rare alleles. We show that DR EVIL performs well in simulations and apply it to rare-variant data from one million haploid samples. We identify mutation-rate heterogeneity even after accounting for trinucleotide context and methylation status. We also predict that at modern sample sizes, the alleles at most polymorphic sites with high mutation rates represent the descendants of multiple mutation events.

Haploidy↗

PubMed2023

Dominant negative variants in KIF5B cause osteogenesis imperfecta via down regulation of mTOR signaling.

BACKGROUND: Kinesin motor proteins transport intracellular cargo, including mRNA, proteins, and organelles. Pathogenic variants in kinesin-related genes have been implicated in neurodevelopmental disorders and skeletal dysplasias. We identified de novo, heterozygous variants in KIF5B, encoding a kinesin-1 subunit, in four individuals with osteogenesis imperfecta. The variants cluster within the highly conserved kinesin motor domain and are predicted to interfere with nucleotide binding, although the mechanistic consequences on cell signaling and function are unknown. METHODS: To understand the in vivo genetic mechanism of KIF5B variants, we modeled the p.Thr87Ile variant that was found in two patients in the C. elegans ortholog, unc-116, at the corresponding position (Thr90Ile) by CRISPR/Cas9 editing and performed functional analysis. Next, we studied the cellular and molecular consequences of the recurrent p.Thr87Ile variant by microscopy, RNA and protein analysis in NIH3T3 cells, primary human fibroblasts and bone biopsy. RESULTS: C. elegans heterozygous for the unc-116 Thr90Ile variant displayed abnormal body length and motility phenotypes that were suppressed by additional copies of the wild type allele, consistent with a dominant negative mechanism. Time-lapse imaging of GFP-tagged mitochondria showed defective mitochondria transport in unc-116 Thr90Ile neurons providing strong evidence for disrupted kinesin motor function. Microscopy studies in human cells showed dilated endoplasmic reticulum, multiple intracellular vacuoles, and abnormal distribution of the Golgi complex, supporting an intracellular trafficking defect. RNA sequencing, proteomic analysis, and bone immunohistochemistry demonstrated down regulation of the mTOR signaling pathway that was partially rescued with leucine supplementation in patient cells. CONCLUSION: We report dominant negative variants in the KIF5B kinesin motor domain in individuals with osteogenesis imperfecta. This study expands the spectrum of kinesin-related disorders and identifies dysregulated signaling targets for KIF5B in skeletal development.

Animals↗

PubMed2022

TTC5 syndrome: Clinical and molecular spectrum of a severe and recognizable condition.

Biallelic mutations in the TTC5 gene have been associated with autosomal recessive intellectual disability (ARID) and subsequently with an ID syndrome including severe speech impairment, cerebral atrophy, and hypotonia as clinical cornerstones. A TTC5 role in IDs has been proposed based on the physical interaction of TTC5 with p300, and possibly reducing p300 co-activator complex activity, similarly to what was observed in Menke-Hennekam 1 and 2 patients (MKHK1 and 2) carrying, respectively, mutations in exon 30 and 31 of CREBBP and EP300, which code for the TTC5-binding region. Recently, TTC5-related brain malformation has been linked to tubulinopathies due to the function of TTC5 in tubulins' dynamics. We reported seven new patients with novel or recurrent TTC5 variants. The deep characterization of the molecular and phenotypic spectrum confirmed TTC5-related disorder as a recognizable, very severe neurodevelopmental syndrome. In addition, other relevant clinical aspects, including a severe pre- and postnatal growth retardation, cryptorchidism, and epilepsy, have emerged from the reversal phenotype approach and the review of already published TTC5 cases. Microcephaly and facial dysmorphism resulted in being less variable than that documented before. The TTC5 clinical features have been compared with MKHK1 published cases in the hypothesis that clinical overlap in some characteristics of the two conditions was related to the common p300 molecular pathway.

Exons↗

PubMed2025

Identification of a novel heterozygous GPD1 missense variant in a Chinese adult patient with recurrent HTG-AP consuming a high-fat diet and heavy smoking.

BACKGROUND: Glycerol-3-phosphate dehydrogenase 1 (GPD1) gene defect can cause hypertriglyceridemia (HTG), which usually occurs in infants. The gene defect has rarely been reported in adult HTG patients. In the present study, we described the clinical and functional analyses of a novel GPD1 missense variant in a Chinese adult patient with recurrent hypertriglyceridemia‑related acute pancreatitis (HTG-AP), consuming a high-fat diet and smoking heavily. METHODS: Exome sequencing was used to analyze the DNA of the adult patient's blood sample. It was found that there was a new variant of GPD1 gene-p.K327N, which was verified by gold standard-sanger sequencing method. In vitro, the corresponding plasmid was constructed and transfected into human renal HEK-293T cells, and GPD1 protein levels were detected. A biogenic analysis was performed to study the population frequency, conservation, and electric potential diagram of the new variant p.K327N. Finally, the previously reported GPD1 variants were sorted and their phenotypic relationships were compared. RESULTS: A novel heterozygous variant of GPD1, p.K327N (c.981G > C), was found in the proband. Furthermore, the patient's daughter carried this variant, whereas his wife did not carry the variant. The proband with obesity suffered eight episodes of HTG-AP from the age of 36 years, and each onset of AP was correlated to high-fat diet consumption and heavy smoking. In vitro, this variant exerted a relatively mild effect on GPD1 functions, which were associated with its effect upon secretion (~ 25% of secretion decreased compared with that of the wild-type); thus, eventually impairing protein synthesis. Additionally, 36 patients with GPD1 variants found in previous studies showed significant transient HTG in infancy. The proband carrying the GDP1 variant was the first reported adult with recurrent HTG-AP. CONCLUSION: We identified a novel GPD1 variant, p.K327N, in a Chinese adult male patient with recurrent HTG-AP. The variant probably exerted a mild effect on GPD1 functions. The heterozygosity of this GPD1 variant, in addition to high-fat diet consumption and heavy smoking, probably triggered HTG-AP in the patient.

Adult↗

PubMed2025

Recurrent FGFR2 and PIK3CA Mutations in Sialoblastoma.

PURPOSE: Sialoblastoma is an extremely rare low-grade malignant salivary gland neoplasm that presents at birth or early infancy and has heterogeneous clinical behavior. Due to its rarity, the molecular landscape remains incompletely characterized. We aimed to expand the current understanding of the genetic alterations in sialoblastoma through comprehensive molecular analysis. METHODS: Five sialoblastoma cases were retrieved from four institutional archives. Clinical and pathologic review was performed, and targeted next-generation sequencing was conducted using clinically validated panels. Copy number analysis was performed on four cases. RESULTS: The cohort included five patients with tumors located in parotid gland (n = 2), minor salivary glands (n = 2), and submandibular gland (n = 1). Four patients were diagnosed before 6 months of age. Histologically, all tumors showed solid organoid nests with primitive basaloid cells, dense fibrous stroma, and mitotic activity ranging from 8 to 25 per 10 high-power fields. Recurrent FGFR2 p.C382R variants were identified in 80% (4/5) of cases. Additional alterations were seen in FGFR2 p.C382R mutated tumors, including PIK3CA hotspot mutations in two cases (p.R88Q, p.R38H) and a truncating FGFR2 variant (p.L776Rfs) in one. The single tumor that lacked FGFR2 mutations harbored a CTNNB1 p.I35T variant and showed more favorable histologic features. Copy number analysis revealed recurrent whole-chromosome gains of chromosomes 8, 10, and 11. CONCLUSION: A distinct subset of sialoblastoma has FGFR2 p.C382R hotspot mutation as the predominant driver mutation. Tumors with this mutation tend to have solid growth pattern, aggressive histologic features, and clinical behavior. The identification of concurrent genomic alterations expands the molecular landscape of this rare tumor. The detection of alternative drivers, such as CTNNB1 hotspot mutations typical of basal cell adenoma, also suggests that a subset of sialoblastoma may represent other salivary gland tumors presenting in infancy.

Humans↗

PubMed2026

"Tissue-specific mitochondrial dysfunction in keratoconus: An integrated structural, genomic, and functional analysis".

PURPOSE: Keratoconus (KC) is a progressive corneal ectasia characterized by stromal thinning, conical protrusion, and irregular astigmatism, leading to visual impairment. Although oxidative stress is implicated in KC, the role of mitochondrial dysfunction remains unclear. We evaluated mitochondrial structural, genomic, and functional abnormalities in corneal tissues and blood from KC patients. METHODS: This prospective study enrolled 110 KC patients and 55 controls. Transmission electron microscopy (TEM) and immunohistochemistry (IHC) were performed on epithelial and stromal tissues from 10 KC to 5 control corneas assessing mitochondrial morphology, oxidative phosphorylation (OXPHOS) complexes and pro-apoptotic protein NOXA. Whole mitochondrial DNA (mtDNA) sequencing and relative mtDNA copy number analysis were performed on paired blood and corneal tissues from 50 KC patients and 35 controls including both epithelial and stromal samples. Gene expression of mitochondrial biogenesis and oxidative stress-related genes was analysed by qRT-PCR in corneal epithelium from independent 50 KC patients and 15 controls. RESULTS: TEM revealed cristolysis, membrane disruption, and reduced mitochondrial density in KC corneas. IHC showed reduced expression of OXPHOS complexes and increased NOXA expression (p < 0.05). Sequencing identified 1107 mtDNA variants, with more variants in corneal tissues than matched blood (929 vs. 576; p = 0.0002). Recurrent likely pathogenic variants were enriched in complex I-encoding genes (ND4, ND5). KC corneas showed reduced mtDNA copy number, downregulated POLRMT, upregulated NOX4, and significant downregulation of multiple antioxidant genes (p < 0.0001). CONCLUSION: KC patients exhibit tissue-specific mitochondrial abnormalities and impaired oxidative stress regulation, supporting a role for mitochondrial dysfunction in disease pathogenesis and highlighting potential therapeutic targets.

Corneal pathology↗

PubMed2026

Longitudinal ctDNA tracking in early and recurrent breast cancer using an ultrasensitive structural variant-based assay: an extended analysis from the TRACER study.

BACKGROUND: Detection of circulating tumor DNA (ctDNA) following curative-intent therapy is prognostic of disease recurrence in early-stage breast cancer (EBC). An ultrasensitive structural variant (SV)-based ctDNA assay was evaluated previously in a 100-patient EBC cohort treated with neoadjuvant therapy, demonstrating high sensitivity, specificity, and a long lead-time to relapse. The stability of primary tumor-specific SVs at and after metastatic recurrence and their utility for longer-term ctDNA monitoring had not been established. PATIENTS AND METHODS: An updated retrospective analysis of ctDNA dynamics was conducted in an expanded cohort of 121 patients with EBC treated with neoadjuvant therapy. Plasma samples were collected at key clinical timepoints and serially in several patients who experienced metastatic recurrence. Clinical variables were abstracted from medical records. Associations between ctDNA detection, dynamics, and clinical outcomes were evaluated in the early-stage and metastatic settings. RESULTS: Thirty of 121 patients experienced clinical recurrence (28 distant, 2 local) over a median follow-up of 4.2 years (range 0.5-8.8; 25 ctDNA evaluable with adjuvant timepoints). All patients with detectable ctDNA in the adjuvant setting developed metastatic recurrence (22/22). Median lead time from ctDNA detection to metastatic recurrence was 346 days (range 0-1937). Among recurrent cases, 79% of primary tumor-specific SVs (n = 17 patients, tumor fraction ≥0.1%) remained detectable in plasma [range 7% (1/14 SV)-100% (15/15); median: 92%]. ctDNA dynamics in the recurrent metastatic setting demonstrated a strong relationship with radiographic outcomes in evaluable patients (n = 9). CONCLUSION: This SV-based digital PCR assay provided ultrasensitive ctDNA detection in an expanded EBC cohort, maintaining 100% positive predictive value for metastatic recurrence. In patients with recurrence, ctDNA dynamics were concordant with radiographic outcomes. Prospective studies evaluating the clinical utility of longitudinal ctDNA monitoring are warranted.

MRD↗

PubMed2023

H4C5 missense variant leads to a neurodevelopmental phenotype overlapping with Angelman syndrome.

Recurrent de novo missense variants in H4 histone genes have recently been associated with a novel neurodevelopmental syndrome that is characterized by intellectual disability and developmental delay as well as more variable findings that include short stature, microcephaly, and facial dysmorphisms. A 4-year-old male with autism, developmental delay, microcephaly, and a happy demeanor underwent evaluation through the Undiagnosed Disease Network. He was clinically suspected to have Angelman syndrome; however, molecular testing was negative. Genome sequencing identified the H4 histone gene variant H4C5 NM_003545.4: c.295T>C, p.Tyr99His, which parental testing confirmed to be de novo. The variant met criteria for a likely pathogenic classification and is one of the seven known disease-causing missense variants in H4C5. A comparison of our proband's findings to the initial description of the H4-associated neurodevelopmental syndrome demonstrates that his phenotype closely matches the spectrum of those reported among the 29 affected individuals. As such, this report corroborates the delineation of neurodevelopmental syndrome caused by de novo missense H4 gene variants. Moreover, it suggests that cases of clinically suspected Angelman syndrome without molecular confirmation should undergo exome or genome sequencing, as novel neurodevelopmental syndromes with phenotypes overlapping with Angelman continue to be discovered.

Male↗

PubMed2026

Baseline Plasma Cell-Free and Circulating Tumor DNA Across Lymphoma Subtypes and Its Prognostic Impact in Diffuse Large B-Cell Lymphoma.

BACKGROUND: Circulating tumor DNA (ctDNA) analysis enables real‑time assessment of the tumor burden and genomic complexity in lymphomas. However, real‑world evidence across lymphoma subtypes is limited. METHODS: We analyzed cell‑free DNA (cfDNA) and ctDNA data from 336 consecutive patients with newly diagnosed Hodgkin or non-Hodgkin lymphoma in 2022 and evaluated their prognostic impact in diffuse large B‑cell lymphoma (DLBCL). RESULTS: We detected somatic alterations in 248 of 336 patients (73.8%). DLBCL and follicular lymphoma showed the highest variant prevalences and ctDNA burdens. Epigenetic regulators, including KMT2D, CREBBP, TET2, and HIST1H1E, constituted the dominant class of genes with recurrent alterations. Plasma variant profiles closely mirrored publicly available, tissue‑based next-generation sequencing datasets. The baseline ctDNA burden correlated with adverse clinical features, and ctDNA positivity was associated with failure to achieve complete remission. In DLBCL, elevated cfDNA (top quartile) and a high International Prognostic Index (IPI) were independently associated with shorter overall and progression‑free survival. However, the total variant count per patient was not significantly associated with survival after adjustment. CONCLUSIONS: Baseline plasma cfDNA and ctDNA assessments are feasible in routine practice and recapitulate tissue-variant landscapes. Elevated cfDNA concentrations-but not the total variant count-were independently associated with survival in DLBCL, providing prognostic information beyond the IPI and supporting integration of plasma-based biomarkers into multiparameter risk models. Gene‑level ctDNA associations should be regarded as exploratory and hypothesis‑generating.

Cell-free DNA↗

PubMed2025

Osteogenesis imperfecta, intellectual disability and recurrent infections in a male with a pathogenic SASH3 variant.

Src Homology 3 Domain-containing Adaptor Protein 3 (SASH3) deficiency is an X-linked immune disorder. Here we identified a male case with a pathogenic SASH3 variant (c.1039C>T [p.Arg347Cys]) who presented with osteogenesis imperfecta, intellectual disability and recurrent infections. While immunological features in this case were characterized, further studies are needed to determine the association between the SASH3 variant and the skeletal or neurological manifestations.

Journal Article↗

PubMed2026

Clinical and Functional Characterization of Gain-of-Function ABL1 Variants Expands the Phenotypic Spectrum of CHDSKM.

Germline gain-of-function (GOF) variants in ABL1 cause congenital heart defects and skeletal malformations syndrome (CHDSKM), a multisystem developmental disorder characterized by congenital heart disease, skeletal abnormalities, dysmorphic features, and variable developmental delay. More recently, biallelic loss-of-function variants and ABL haploinsufficiency have been associated with distinct phenotypes, expanding the allelic spectrum of ABL1-related disorders. We report three individuals with ABL1 variants. A female infant with tetralogy of Fallot, critical pulmonary stenosis, covered omphalocele, and a lethal outcome was found by rapid trio genome sequencing to harbor a de novo likely pathogenic ABL1 variant, NM_007313.2:c.354G>T p.(Trp118Cys). We also provide updated clinical follow-up of a previously reported individual and describe a third individual, both carrying the recurrent p.(Tyr245Cys) variant. Functional studies were performed and support a GOF mechanism. Similar activation was observed for Tyr245Cys despite the differences in clinical severity. Our findings expand the phenotypic spectrum of ABL1-related CHDSKM to include severe conotruncal heart disease and covered omphalocele. The comparison of two biochemically activating ABL1 variants demonstrates substantial clinical variability despite a shared molecular mechanism. Furthermore, the overlap between ventral body wall abnormalities in GOF disease and omphalocele associated with ABL1 haploinsufficiency suggests that precise regulation of ABL1 signaling is critical for normal ventral body wall formation.

ABL1↗

PubMed2026

Prominent Movement Disorders in RNU2-2-Related Spliceosomopathy.

Pediatric movement disorders often overlap with neurodevelopmental diseases, suggesting shared molecular mechanisms. Variants in small nuclear RNA (snRNA) genes encoding spliceosome components have recently been associated with neurodevelopmental disorders, termed "RNUopathies." We analyzed genome sequencing data from 14 patients with undiagnosed pediatric movement disorders for pathogenic variants in snRNA genes. We identified recurrent de novo RNU2-2 variants (n.35A > G and n.4G > A) in two patients with intellectual disability, epilepsy, and hyperkinetic movement disorders. RNA sequencing of fibroblasts in one patient showed no characteristic transcriptomic signature. Spliceosomopathies should be considered in neurodevelopmental disorders and developmental and epileptic encephalopathies with hyperkinetic features.

Humans↗

PubMed2026

Microglial GRB2 is essential for brain ventriculogenesis and CSF homeostasis.

Microglia play essential yet poorly understood roles in brain development, including axon guidance, regulation of neurogenesis, and pruning of neuronal projections. Congenital hydrocephalus (CH), characterized by enlarged cerebrospinal fluid (CSF)-filled ventricles, is a leading cause of pediatric brain surgery, but its molecular mechanisms remain unclear. We have identified what we believe to be novel, recurrent, damaging missense variants in the SH3-binding domain of the adaptor protein Growth Factor Receptor-Bound Protein 2 (GRB2) in unrelated patients with CH. GRB2 is significantly co-expressed with one of its known upstream receptor tyrosine kinase partners, CSF1R, in the developing human brain, particularly in a microglial subtype associated with regulation of neural stem cells. Immunoprecipitation validated GRB2-CSF1R binding in mouse microglial cells and human monocyte cell line. Cx3cr1-Grb2fl/fl mice engineered with conditional deletion of Grb2 in microglia exhibit congenital absence of microglia and early postnatal severe communicating (non-obstructive) hydrocephalus, mimicking GRB2-mutant patients. The severe ventriculomegaly of Cx3cr1-Grb2fl/fl mice is associated with both depletion of cerebral cortical neurons and impairment of glia-lymphatic-mediated CSF flow. Together, these findings implicate a role of GRB2 in microglia that could be essential for brain development and CSF homeostasis.

Genetics↗

PubMed2026

A Novel De Novo STAG1 Variant at the RAD21 Binding Interface Is Associated With Hypoglycemia, Recurrent Fever, Immunodeficiency and Features of Classical Cohesinopathies.

The cohesin complex, composed of SMC1, SMC3, RAD21, and STAG1/STAG2, is essential for chromosome cohesion, DNA repair, and transcriptional regulation. Pathogenic variants in cohesin components cause cohesinopathies. The classical characteristics of cohesinopathies include developmental delay (DD), intellectual disability (ID), feeding difficulties, hypotonia, short stature, hearing loss, and dysmorphic features. Here, we present a 5-year-old boy with classical cohesinopathy features, including DD/ID and feeding difficulties, along with non-classical features such as hypoglycemia, recurrent fever, and immunodeficiency. Trio exome sequencing identified a novel de novo missense variant of uncertain significance (NM_005862.3:c.643G>A(p.Val215Ile)) in the STAG1 gene. The variant localizes to the RAD21 interaction interface, and molecular dynamics (MD) simulations revealed conformational changes comparable to other STAG1 variants reported as likely pathogenic in patients, supporting a deleterious effect which may disrupt the STAG1-RAD21 interaction interface. This case expands the phenotypic and molecular spectrum of STAG1-related cohesinopathy and advances our understanding of the disease mechanism.

STAG1↗

PubMed2026

Prevalence of BRCA1/2 variants in an Ovarian Cancer Cohort: outcomes from a Nationwide Testing Program.

Poly(ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the management of BRCA1- and BRCA2-associated ovarian cancer (OC). In 2020, Ireland implemented a nationwide, oncology-led pathway for mainstreamed BRCA1/2 testing in patients with OC. This study evaluated the pathway and characterised the BRCA1/2 landscape in an Irish cohort of patients with OC. Samples collected between January 2020 and December 2023 were tested in two national molecular diagnostic laboratories. Single-molecule molecular inversion probe sequencing was used to detect single nucleotide variants, while multiplex ligation-dependent probe amplification assessed large genomic rearrangements. Variants were classified according to the American College of Medical Genetics and Genomics and Association for Clinical Genomic Science 2020 guidelines and CanVIG-UK specifications. In total, 535 patients were included, with a median age of 65.5 years (range, 27-89 years). Of these, 455/535 (85.0%) underwent germline BRCA1/2 (gBRCA) testing using peripheral blood, and 360/535 (67.2%) underwent tumour BRCA1/2 (tBRCA) testing, resulting in 292/535 (54.6%) patients having paired testing. Among gBRCA-tested patients, 10.3% (47/455) had a clinically actionable variant (CAV), while 2.1% (10/455) had a variant of uncertain significance. Of the 262 patients who underwent paired testing and had negative gBRCA results, 9.5% (25/262) had a somatic BRCA CAV. Recurrent germline BRCA CAVs were identified in regional clusters, including BRCA1 c.5266dup, BRCA1 c.1175_1214del, and BRCA2 c.4398_4402del. This nationwide real-world study demonstrates that mainstreamed germline and somatic BRCA1/2 testing is feasible in Ireland and reports the prevalence of BRCA CAVs in a cohort of patients with OC. Although the observed prevalence of germline BRCA CAVs was lower than anticipated, it is consistent with UK real-world data. The identification of recurrent, regionally clustered germline variants further enhances the characterisation of the Irish genomic landscape.

Journal Article↗

PubMed2026

Tumor Mutational Concordance and Recurrence Timing in Hepatocellular Carcinoma.

INTRODUCTION: In hepatocellular carcinoma (HCC), intrahepatic recurrence includes true recurrence from clonal relapse and multicentric recurrence from de novo tumorigenesis. Recurrence timing is used to distinguish these types; however, its accuracy remains unclear. This study aimed to classify recurrent tumors based on somatic mutational concordance and assess the validity of recurrence timing. METHODS: Whole-exome sequencing was performed on paired primary and recurrent HCC tumors from 49 patients enrolled in a prospective institutional omics project. Tumors with ≥ 10 shared somatic mutations were classified as true recurrence. Clinicopathological features, recurrence timing, driver mutation patterns, and survival outcomes were compared between recurrence types. Mutational concordance was quantified using shared variant counts and the Jaccard similarity index. RESULTS: Of the 49 patients, 22 (44.9%) showed true recurrence and 27 (55.1%) had multicentric recurrence. Multicentric recurrence tumors harbored no shared variants or only a single shared variant with the primary tumor. True recurrence was associated with significantly higher concordance in histological differentiation and Edmondson-Steiner grading and greater retention of CTNNB1, TP53, ARID1A, and KEAP1 mutations. The number of shared variants (median: 115 vs. 0, and p < 0.001) and the Jaccard index (median: 0.44 vs. 0.00 and p < 0.001) were significantly higher in the true recurrence group. Recurrence timing was inconsistently correlated with mutational concordance, although a 3-year cutoff yielded significant separation. CONCLUSION: Recurrence timing alone insufficiently reflects clonal relationships. Genomic profiling offers a reliable framework for distinguishing between recurrence types and guiding HCC management.

clonal relapse↗

PubMed2024

Genomic insights from a deeply phenotyped highly consanguineous neurodevelopmental disorders cohort.

PURPOSE: The genetic underpinning of neurodevelopmental disorders (NDDs) in diverse ethnic populations, especially those with high rates of consanguinity, remains largely unexplored. Here, we aim to elucidate genomic insight from 576 well-phenotyped and highly consanguineous (16%) NDD cohort. METHODS: We used chromosomal microarray (CMA; N:247), exome sequencing (ES; N:127), combined CMA and ES (N:202), and long-read genome sequencing to identify genetic etiology. Deep clinical multivariate data were coupled with genomic variants for stratification analysis. RESULTS: Genetic diagnosis rates were 17% with CMA, 29.92% with ES, and 37.13% with combined CMA and ES. Notably, children of consanguineous parents showed a significantly higher diagnostic yield (P < .01) compared to those from nonconsanguineous parents. Among the ES-identified pathogenic variants, 36.19% (38/105) were novel, implicating 35 unique genes. Long-read sequencing of seizure participants unresolved by combined test identified expanded FMR1 trinucleotide repeats. Additionally, we identified 2 recurrent X-linked variants in the G6PD in 3.65% (12/329) of NDD participants. These variants were absent in large-population control cohorts and cohort comprising neurodevelopmental and neuropsychiatric populations of European descendants, indicating a possible associated risk factor potentially resulting from ancient genetic drift. CONCLUSION: This study unveils unique clinical and genomic insights from a consanguinity rich Bangladeshi NDD cohort.

Humans↗