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PubMed2026

Further Support for Association of DAND5 with Autosomal Recessive Laterality Disorders.

BACKGROUND: Laterality defects are rare congenital malformations that encompass congenital heart defects (CHDs) together with abnormalities of visceral organ arrangement (situs inversus or situs ambiguous). These defects may be isolated or part of a syndromic presentation with multisystem involvement. While over 50 genes have been implicated in laterality disorders, across multiple modes of inheritance, many cases remain molecularly undiagnosed. We sought to elucidate the molecular basis of dextrocardia, CHDs and visceral heterotaxy in two unrelated individuals of Arab-Muslim descent. METHODS: Detailed clinical phenotyping and exome sequencing (ES) were performed for each of the probands, followed by familial segregation analysis. RESULTS: ES revealed a shared homozygous variant in the Dan Domain Family Member 5 (DAND5) gene (NM_152654.3): c.396_397dup, p.(Tyr133SerfsTer11). DAND5 encodes a member of the Cerberus-related DAN protein family, which is involved in the establishment of left body asymmetry. This frameshift variant introduces a premature stop codon within the final exon, which is predicted to escape nonsense-mediated decay (NMD), resulting in a truncated protein lacking the functional DAN domain. CONCLUSIONS: DAND5 has recently been suggested as a candidate gene in heterotaxy and CHDs. Our findings further support biallelic loss of function variants in DAND5 autosomal recessive laterality defects.

Female↗

PubMed2026

Unraveling a Diagnostic Enigma: A TECPR2 Case Solved Through Multi-Omic Genomics.

TECPR2 is a key regulator of autophagy, encoded by the TECPR2 gene. Pathogenic variants in this gene have been linked to a rare hereditary sensory and autonomic neuropathy with intellectual disability (HSAN9). We report a teenage female with a syndromic intellectual disability disorder associated with neuromuscular abnormalities. Multi-omics analysis including genomics, transcriptomics, and proteomics, together with muscle biopsy from the affected individual, were used in this clinical case. Through trio exome sequencing we identified two heterozygous variants in the TECPR2 gene, NM_014844.4: c.480G>A; p.(Gln160=) and c.2846C>A; p.(Ala949Glu). Both were classified as variants of uncertain significance due to the lack of supporting evidence for pathogenicity. Subsequent long-read sequencing phased the variants and confirmed they were in trans. Additional functional studies using RNAseq and proteomics analyses verified the pathogenicity of the variants. This case study demonstrated the value of a multi-omics assisted analysis, which complemented the traditional phenotype-first approach in reaching a definitive clinical diagnosis.

Humans↗

PubMed2024

Effect of the OPHN1 novel variant c.1025+1 G>A on RNA splicing: insights from a minigene assay.

This research analyzes the clinical data, whole-exome sequencing results, and in vitro minigene functional experiments of a child with developmental delay and intellectual disability. The male patient, aged 4, began experiencing epileptic seizures at 3 months post-birth and has shown developmental delay. Rehabilitation training was administered between the ages of one and two. There were no other significant family medical histories. Through comprehensive family exome genetic testing, a hemizygous variant in the 11th exon of the OPHN1 gene was identified in the affected child: c.1025 + 1G > A. Family segregation analysis confirmed the presence of this variant in the patient's mother, which had not been previously reported. According to the ACMG guidelines, this variant was classified as a likely pathogenic variant. In response to this variant, an in vitro minigene functional experiment was designed and conducted, confirming that the mutation affects the normal splicing of the gene's mRNA, resulting in a 56 bp retention on the left side of Intron 11. It was confirmed that OPHN1: c.1025 + 1G > A is the pathogenic cause of X-linked intellectual disabilities in the child, with clinical phenotypes including developmental delay and seizures.

Humans↗

PubMed2026

Unveiling clinical and genetic landscapes of MMA and CBS: insights from whole exome sequencing in a tertiary care setting.

BACKGROUND: MMA and CBS deficiency are rare autosomal recessive metabolic disorders caused by defects in cobalamin metabolism and cystathionine-beta-synthase activity, respectively. Advanced molecular genetic techniques, have become essential for diagnosing these conditions. This study aimed to analyze the genetic variations in three MMA and four CBS deficiency cases using WES and correlate the findings with clinical, biochemical, and treatment outcomes. METHODS: Clinical evaluation, biochemical testing, neuroimaging, and WES were performed. WES data were analyzed using the reference genome GRCh37, and variants were classified according to ACMG guidelines. Treatment outcomes were monitored for three months post-intervention. RESULTS: In MMA cases, a homozygous pathogenic variant (c.394 C > T, p.Arg132Ter) in MMACHC was identified in all three patients. Biochemical abnormalities included methylmalonic aciduria, elevated homocysteine, and megaloblastic anemia. Hydroxycobalamin therapy improved behavioral, cognitive, and dermatological symptoms, though residual neuropathy persisted in one case. In CBS deficiency, pathogenic variants in CBS (c.992 C > T, p.Ala331Val; c.862 G > A, p.Ala288Thr; c.700 G > A, p.Asp234Asn) were identified. Clinical features included developmental delayed milestones, lens dislocation, and vascular complications. Treatment outcomes varied based on early diagnosis and compliance. CONCLUSION: This study highlights the importance of newborn screening program with WES in diagnosing and managing MMA and CBS deficiency, facilitating early intervention, improving clinical outcomes, and supporting precision medicine approaches. IMPACT: Early newborn screening and diagnosis are critical for effective treatment and improved patient outcomes. Novel clinical and pathogenic variants will expand the current understanding of these disorders. WES enhances the diagnostic precision for MMA and CBS deficiency, facilitating timely intervention and superior clinical management. Accurate and early detection of treatable IEMs through NBS can significantly reduce disease burden and healthcare costs.

Child, Preschool↗

PubMed2026

ATM Variants and Breast Cancer Risk in North Macedonia: Focus on the Regionally Enriched p.(Leu2492Arg) Variant.

BACKGROUND: Germline pathogenic variants (PVs) in the ataxia-telangiectasia mutated (ATM) gene are established moderate-risk factors for breast cancer (BC), however, population-specific variant spectra and the clinical significance of many missense variants remain incompletely characterized. AIMS: To evaluate the prevalence of ATM variants in a large cohort of patients with BC from North Macedonia and compare it with that in the general population, with a particular focus on the frequency of the p.(Leu2492Arg) variant and its distribution relative to global genomic datasets. STUDY DESIGN: Retrospective case–control study. METHODS: ATM variants were analyzed in 1,211 patients with BC from North Macedonia using a targeted hereditary cancer gene panel. These findings were compared with those from 1,303 population-based controls analyzed by clinical exome or whole-exome sequencing. RESULTS: Pathogenic ATM variants were identified in 1.9% of BC cases and 0.4% of controls, indicating a significantly increased risk of BC [odds ratio (OR) = 5.02, p = 0.0006]. Most PVs were protein-truncating, with six recurrent variants accounting for over 70% of detections, suggesting regional enrichment. Carriers showed a significantly higher prevalence of human epidermal growth factor receptor 2-positive tumors (OR = 2.92, p = 0.0189). Variants of uncertain significance were observed at comparable frequencies in cases and controls. The p.(Leu2492Arg) missense variant was more frequently detected in cases than in controls (1.9% vs. 1.1%; OR = 1.78, p = 0.086) and exhibited a markedly higher allele frequency in this population than in global databases. CONCLUSION: These findings confirm ATM as a clinically relevant BC susceptibility gene in North Macedonia and highlight the population-specific enrichment of both PVs and the p.(Leu2492Arg) missense variant. The results emphasize the importance of using population-matched controls and regional genomic data for accurate risk assessment and variant interpretation.

Humans↗

PubMed2026

Costello Syndrome Associated With Somatic Mosaicism of Rare p.Gly13Asp HRAS Variant: Expanding the Phenotypic Spectrum.

BACKGROUND: Costello syndrome (CS) is a rare RASopathy, mostly caused by de novo heterozygous pathogenic variants in the HRAS gene. Over 80% of cases involve the germline p.Gly12Ser variant, resulting in a fairly uniform phenotype of neuro-cardio-facio-cutaneous involvement with an increased risk of malignancy. Consequences of other rare HRAS variants are less well understood due to the limited number of reported cases. METHODS: An adult, young woman was referred due to sparse, slow-growing scalp hair, Blaschko-linear hyperpigmentation, acanthosis nigricans, palmoplantar hyperkeratosis, and joint hyperlaxity. Molecular, imaging, and detailed laboratory studies were performed. RESULTS: Although initial clinical exome- and whole-exome sequencing (WES) were inconclusive, indicating possible mosaicism, subsequent WES from hair-derived DNA samples revealed somatic mosaicism for the rare HRAS p.Gly13Asp variant. Brain MRIs showed a cerebral cavernoma, while cardiological evaluation, urinalysis, abdominal, and pelvic ultrasound were unremarkable. Nevertheless, she remains under close follow-up. CONCLUSION: Among the ten reported individuals carrying the p.Gly13Asp variant, our patient is only the second with confirmed mosaicism and the fifth mosaic CS case described to date. This case expands the phenotypic spectrum of CS and highlights the need for multi-tissue analysis in attenuated or atypical presentations to ensure a correct diagnosis, oncological risk assessment, and informed genetic and reproductive counseling.

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↗

PubMed2026

Identification of autosomal and sex chromosome aneuploidies using next generation sequencing.

MOTIVATION: Chromosomal abnormalities, referred to as aneuploidies, occur in approximately 0.3% of live births. While the majority of aneuploidies in humans are incompatible with life, well-characterized exceptions include Down syndrome (47,+21), Patau syndrome (47,+13), Edwards syndrome (47,+18), Turner syndrome (45,X0), Klinefelter syndrome (47,XXY), and triple X syndrome (47,XXX). These chromosomal alterations disrupt gene expression and cellular function, leading to genetic and developmental disorders. With the increasing adoption of next generation sequencing (NGS) in clinical diagnostics, this study aims to explore the potential use of NGS for aneuploidies detection. RESULTS: Using data derived from clinical exomes (CES) and whole exomes (WES) sequencing we have been able to detect autosomal as well as sex chromosome aneuploidies with high specificity. Moreover, we have also been able to identify mosaic aneuploidies proving the high sensibility of this methodological approach. Thus, we present NGS as a cost-effective first line approach to detect chromosomal aneuploidies in routine diagnostic practice. AVAILABILITY AND IMPLEMENTATION: Scripts are available at https://github.com/B-R-I-D-G-E/AneuploidiesStudies.

Humans↗

PubMed2024

Leveraging clinical intuition to improve accuracy of phenotype-driven prioritization.

PURPOSE: Clinical intuition is commonly incorporated into the differential diagnosis as an assessment of the likelihood of candidate diagnoses based either on the patient population being seen in a specific clinic or on the signs and symptoms of the initial presentation. Algorithms to support diagnostic sequencing in individuals with a suspected rare genetic disease do not yet incorporate intuition and instead assume that each Mendelian disease has an equal pretest probability. METHODS: The LIkelihood Ratio Interpretation of Clinical AbnormaLities (LIRICAL) algorithm calculates the likelihood ratio of clinical manifestations represented by Human Phenotype Ontology terms to rank candidate diagnoses. The initial version of LIRICAL assumed an equal pretest probability for each disease in its calculation of the posttest probability (where the test is diagnostic exome or genome sequencing). We introduce Clinical Intuition for Likelihood Ratios (ClintLR), an extension of the LIRICAL algorithm that boosts the pretest probability of groups of related diseases deemed to be more likely. RESULTS: The average rank of the correct diagnosis in simulations using ClintLR showed a statistically significant improvement over a range of adjustment factors. CONCLUSION: ClintLR successfully encodes clinical intuition to improve ranking of rare diseases in diagnostic sequencing. ClintLR is freely available at https://github.com/TheJacksonLaboratory/ClintLR.

Humans↗

PubMed2026

Intramuscular patient-derived xenografts achieve high engraftment rates in gastric cancer: implications for pharmacodynamic testing and genomic biomarker discovery.

BACKGROUND: Gastric cancer (GC) exhibits marked inter-patient heterogeneity, limiting empirical chemotherapy efficacy. Patient-derived xenograft (PDX) models preserve the molecular features of parental tumors and can serve as pharmacodynamic surrogates, but conventional subcutaneous PDX suffers from low engraftment rates. This study evaluated an optimized intramuscular PDX platform for individualized drug testing in GC and applied whole exome sequencing (WES) for biomarker identification (Clinical trial registry: ChiCTR-OOC-17012731). MATERIALS AND METHODS: Ninety-eight treatment-naive GC patients were enrolled between April 2018 and December 2020. Fresh tumor tissues were engrafted into NCG mice by intramuscular transplantation. Drug efficacy was evaluated using tumor cell necrosis rate and Ki-67 expression. WES was performed on 32 engrafted tumorgrafts to characterize driver mutations in fast- and slow-growing subgroups. RESULTS: An engraftment rate of 71.7% (43/60) was achieved, substantially exceeding rates reported in prior studies. Clinical characteristics were independent of engraftment success and outgrowth time (all p > 0.05). Fast- and slow-growing tumorgrafts diverged in frequently altered genes: KMT2C, APOB, CDK12 and MSH2 predominated in fast-growing grafts, whereas TP53, CHD3 and TET2 were enriched in slow-growing grafts. Slow-growing tumorgrafts correlated with longer progression-free survival (p = 0.02). PDX-guided treatment was associated with improved prognosis. CONCLUSIONS: Intramuscular transplantation into NCG mice yields high engraftment rates for GC PDX. PDX-guided chemotherapy selection is associated with favorable outcomes. Driver mutation divergence between fast- and slow-growing tumorgrafts provides candidate prognostic biomarkers.

Animals↗

PubMed2025

Opportunistic screening for broad range of medically relevant secondary findings: Laboratory benefits and burdens.

PURPOSE: Exome and genome sequencing enable opportunistic screening for secondary findings (SFs). We report on exome analysis for a broad range of medically relevant SFs in the setting of the Incidental Genomics randomized clinical trial (NCT03597165). METHODS: Participants had exome sequencing and were randomized to receive only primary cancer findings (control) or cancer findings and a choice of SFs (intervention). RESULTS: Across 279 participants, there were 4441 unique variants in SF genes: 5.0% (221) were reportable pathogenic/likely pathogenic variants, and 81.4% (3615) were nonreportable variants of uncertain significance (VUS). Intervention arm participants had on average 2.6 (SD 1.66, range 0-9) pathogenic/likely pathogenic variants and 29.5 VUS (SD 13.2, range 2-74). SFs for monogenic disease risk were reported in 35.3% (49/139) of participants (American College of Medical Genetics and Genomics non-cancer subset in 1.4%) and carrier status in 89.3% (117/131). In the intervention arm, variant filtration was 7.7 times longer per case (95% CI 5.3 to 11.3, P < .0001), variant classification was 13.3 times longer (95% CI 10.6 to 16.5, P < .0001), and report preparation was 3.3 times longer (95% CI 2.6 to 4.1, P < .0001). CONCLUSION: Although the yield of reportable SFs was high, this was accompanied by many nonreportable VUS and increased efforts for exome analysis.

Humans↗

PubMed2026

Clinical, genetic and bioinformatic analysis of Saudi families with Joubert syndrome and related disorders.

BACKGROUND: Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies caused by pathogenic variants in over 40 genes, mainly encoding ciliary proteins. However, data on JSRD in the Saudi population remain limited. This study aimed to identify novel and reported JSRD-causing variants in Saudi families and analyze their potential functional impact on protein structure using advanced computational tools. METHODS: Patients with genetically or clinically confirmed/suspected JSRD were recruited according to ethical protocols. Clinical data were collected, and exome sequencing was performed, followed by Sanger validation of identified variant. Pathogenicity was assessed using bioinformatics tools, while conservation, expression and RNA structure analyses were conducted to evaluate the potential functional consequences. RESULTS: Homozygous variants were identified in three consanguineous Saudi families, including a novel stop-gain variant in KIF7 (c.2992 C > T; p.(Gln998Ter)), and novel splice-site variant in CEP104 (c.489 + 1G > A) and a previously reported splice-site variant in TMEM237 (c.869 + 1G > A). All variants were predicted to be pathogenic as per ACMG criteria and located in highly conserved regions, suggesting potential functional impact. RNA analysis suggested possible alterations in folding. CONCLUSION: This study identified three pathogenic variants in JSRD-related genes in Saudi families, including two novel variants. These findings expand the variant spectrum for JSRD, particularly in the Saudi population. Establishing a comprehensive regional variant database is essential for improving molecular diagnosis and genetic counseling in population with high consanguinity. Finally, these results highlight the need for further functional studies to validate their pathogenicity and elucidate their role in JSRD pathogenesis.

Humans↗

PubMed2026

Integrating Optical Genome Mapping into the Genetic Diagnostic Algorithm: Clinical Utility in Unresolved Autosomal Recessive Disorders from a Large Cohort.

INTRODUCTION: The identification of precise genetic etiologies is indispensable for the clinical management of monogenic disorders. However, conventional diagnostic methods and exome sequencing (ES) frequently fail to identify complex structural variations (SVs), leaving the genetic basis unexplained in approximately 30-60% of suspected cases. Optical genome mapping (OGM) emerges as a high-resolution technology capable of detecting cryptic SVs inaccessible to standard methodologies. METHODS: In this study, we evaluated the clinical utility of integrating OGM into the diagnostic algorithm for unresolved monogenic diseases. Following negative or inconclusive results from standard ES pipelines, OGM was applied to a targeted subset of patients (n = 7) selected from a comprehensive clinical cohort of 1,257 individuals with suspected genetic disorders. RESULTS: The integration of OGM identified candidate SVs that may represent the second allelic alteration in two distinct cases; however, confirmation through parental segregation analysis remains pending. Specifically, OGM identified an intronic insertion in the TTLL5 gene and a deletion in a putative regulatory region approximately 400 kb upstream of the NMNAT1 gene, both of which were missed by prior diagnostic testing. CONCLUSION: Our findings suggest that OGM has potential value in investigating the missing heritability of autosomal recessive disorders. By detecting candidate SVs invisible to conventional methods, OGM may warrant consideration as a complementary diagnostic approach following inconclusive ES; however, larger cohorts and confirmatory functional studies are needed to establish its clinical utility.

Autosomal recessive disorders↗

PubMed2026

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

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

Humans↗

PubMed2024

Comprehensive molecular profiling of multiple myeloma identifies refined copy number and expression subtypes.

Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundation's Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.

Humans↗

PubMed2025

Prematurity and Genetic Liability for Autism Spectrum Disorder.

BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by diverse presentations and a strong genetic component. Environmental factors, such as prematurity, have also been linked to increased liability for ASD, though the interaction between genetic predisposition and prematurity remains unclear. This study aims to investigate the impact of genetic liability and preterm birth on ASD conditions. METHODS: We analyzed phenotype and genetic data from two large ASD cohorts, the Simons Foundation Powering Autism Research for Knowledge (SPARK) and Simons Simplex Collection (SSC), encompassing 78,559 individuals for phenotype analysis, 12,519 individuals with genome sequencing data, and 8,104 individuals with exome sequencing data. Statistical significance of differences in clinical measures was evaluated between individuals with different ASD and preterm status. We assessed the rare variants burden using generalized estimating equations (GEE) models and polygenic load using ASD-associated polygenic risk score (PRS). Furthermore, we developed a machine learning model to predict ASD in preterm children using phenotype and genetic features available at birth. RESULTS: Individuals with both preterm birth and ASD exhibit more severe phenotypic outcomes despite similar levels of genetic liability for ASD across the term and preterm groups. Notably, preterm ASD individuals showed an elevated rate of de novo variants identified in exome sequencing (GEE model, p=0.005) in comparison to the non-ASD preterm group. Additionally, a GEE model showed that a higher ASD PRS, preterm birth, and male sex were positively associated with a higher predicted probability for ASD, reaching a probability close to 90% in SPARK. Lastly, we developed a machine learning model using phenotype and genetic features available at birth with limited predictive power (AUROC = 0.65). CONCLUSIONS: Preterm birth may exacerbate the multimorbidity present in ASD, which was not due to the ASD genetic factors. However, increased genetic factors may elevate the likelihood of a preterm child being diagnosed with ASD. Additionally, a polygenic load of ASD-associated variants had an additive role with preterm birth in the predicted probability for ASD, especially for boys. We propose that incorporating genetic assessment into neonatal care could benefit early ASD identification and intervention for preterm infants.

Autism Spectrum Disorder↗

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↗

PubMed2024

Clinical characteristics and genetic analysis of four pediatric patients with Kleefstra syndrome.

BACKGROUND: Kleefstra syndrome spectrum (KLEFS) is an autosomal dominant disorder that can lead to intellectual disability and autism spectrum disorders. KLEFS encompasses Kleefstra syndrome-1 (KLEFS1) and Kleefstra syndrome-2 (KLEFS2), with KLEFS1 accounting for more than 75%. However, limited information is available regarding KLEFS2. KLEFS1 is caused by a subtelomeric chromosomal abnormality resulting in either deletion at the end of the long arm of chromosome 9, which contains the EHMT1 gene, or by variants in the EHMT1 gene and the KMT2C gene that cause KLEFS2. METHODS: This study was a retrospective analysis of clinical data from four patients with KLEFS. Exome sequencing (ES) and Sanger sequencing techniques were used to identify and validate the candidate variants, facilitating the analysis of genotype‒phenotype correlations of the EHMT1 and KMT2C genes. Protein structure modeling was performed to evaluate the effects of the variants on the protein's three-dimensional structure. In addition, real-time quantitative reverse transcription‒polymerase chain reaction (RT‒qPCR) and western blotting were used to examine the protein and mRNA levels of the KMT2C gene. RESULTS: Two patients with KLEFS1 were identified: one with a novel variant (c.2382 + 1G > T) and the other with a previously reported variant (c.2426 C > T, p.Pro809Leu) in the EHMT1 gene. A De novo deletion at the end of the long arm of chromosome 9 was also reported. Furthermore, a patient with KLEFS2 was identified with a novel variant in the KMT2C gene (c.568 C > T, p.Arg190Ter). The RT‒qPCR and western blot results revealed that the expression of the KMT2C gene was downregulated in the KLEFS2 sample. CONCLUSION: This study contributes to the understanding of both KLEFS1 and KLEFS2 by identifying novel variants in EHMT1 and KMT2C genes, thereby expanding the variant spectrum. Additionally, we provide the first evidence of how a KMT2C variant leads to decreased gene and protein expression, enhancing our understanding of the molecular mechanisms underlying KLEFS2. Based on these findings, children exhibiting developmental delay, hypotonia, distinctive facial features, and other neurodevelopmental abnormalities should be considered for ES to ensure early intervention and treatment.

Child↗