Application of Clinical Genetics最新文献

{"title":"Clinical Feasibility of Early First-Trimester Non-Invasive Prenatal Testing: Associations Between Gestational Age, Fetal Fraction, and No-Call Rates.","authors":"Trinh The Son, Sang Trieu Tien, Tran Van Khoa, Hung Sy Ho, Hien Le Thi Thu, Nhat Ngoc Nguyen, Dang Thai Son, Phong Nguyen Van, Minh Duc Pham, Hang Thi Doan","doi":"10.2147/TACG.S599716","DOIUrl":"https://doi.org/10.2147/TACG.S599716","url":null,"abstract":"<p><strong>Background: </strong>Non-invasive prenatal testing (NIPT) based on cell-free fetal DNA (cffDNA) is widely used for screening common fetal aneuploidies. Although fetal fraction (FF) increases with gestational age, the feasibility and performance of NIPT in the early first-trimester, particularly before 10 weeks of gestation, remain incompletely defined.</p><p><strong>Methods: </strong>This retrospective cohort study included 9,708 singleton pregnancies undergoing first-trimester NIPT between 9 weeks 0 days and 13 weeks 6 days of gestation, which was determined by ultrasound using crown-rump length (CRL) measurement. Participants were stratified into two groups based on gestational age at testing (< 10 weeks and ≥ 10 weeks). Multivariable linear regression was used to assess factors associated with fetal fraction, and multivariable logistic regression was applied to evaluate predictors of no-call results (non-reportable NIPT outcome primarily attributed to fetal fraction <4%), adjusting for maternal age and body mass index (BMI).</p><p><strong>Results: </strong>Fetal fraction increased significantly with advancing gestational age. After adjustment for maternal age and BMI, testing performed at ≥ 10 weeks was associated with a higher fetal fraction compared with testing at < 10 weeks (β = 1.58; 95% CI, 1.31 to 1.85; <i>p</i> < 0.001). However, gestational age was not independently associated with the risk of a no-call result (adjusted OR 0.88; 95% CI, 0.68 to 1.16; <i>p</i> = 0.40), and no significant difference in no-call rates was observed between the two gestational age groups (3.78% vs. 3.76%).</p><p><strong>Conclusion: </strong>Although fetal fraction increases after 10 weeks of gestation, gestational age is not an independent determinant of no-call results once fetal fraction adequacy is achieved. NIPT performed in the early first-trimester (< 10 weeks of gestation) demonstrates acceptable analytical feasibility and reliable performance, supporting its use for early prenatal screening under appropriate clinical conditions.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"19 ","pages":"599716"},"PeriodicalIF":2.6,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135759/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Outcomes and Management of Pregnancies Screening Positive for Microdeletions 22q11.2, 15q11.2, 1p36, 4p, or 5p: A Retrospective Cohort Study.","authors":"D Claire Miller, Devika Chawla, Summer Pierson, Katherine Johansen Taber","doi":"10.2147/TACG.S591410","DOIUrl":"https://doi.org/10.2147/TACG.S591410","url":null,"abstract":"<p><strong>Purpose: </strong>To compare pregnancy outcomes and management between patients screening positive for five microdeletions (microdeletion screen-positive, MDS+) and patients screening negative (microdeletion screen-negative, MDS-).</p><p><strong>Patients and methods: </strong>Patients who received a prenatal cell-free DNA (pcfDNA) test that screens for microdeletions 22q11.2, 15q11.2, 1p36, 4p, and 5p and results were linked to de-identified insurance claims. Diagnosis and procedure codes were used to assess outcomes. Logistic and Poisson regression with adjustment for prior high-risk pregnancy and payer type were used to compare pregnancy outcomes and management in those with MDS+ and MDS- results.</p><p><strong>Results: </strong>A total of 119 MDS+ patients and 287,169 MDS- patients were eligible for analysis. During pregnancy, MDS+ patients were more likely than MDS- patients to have polyhydramnios (18.5% in MDS+ vs. 3.4% in MDS-; OR=6.3 [95% CI: 3.8-10.1]; p<0.001) and fetal growth restriction (22.2% in MDS+ vs. 10.4% in MDS-; OR=2.4 [95% CI: 1.5-3.7]; p<0.001). MDS+ patients were more likely to experience pregnancy loss (OR=3.2; 95% CI: 1.3-6.3; p=0.004) or terminate the pregnancy (OR=22.2 [95% CI: 8.6-46.8]; p<0.001). Among patients with a live birth, MDS+ were more likely to have a preterm delivery (25.0% in MDS+ vs. 15.4% in MDS-; OR=1.8 [95% CI: 1.0-3.0]; p=0.04). MDS+ patients had increased pregnancy management, including more invasive diagnostic testing (13.4% in MDS+ vs. 0.5% in MDS-; OR=31.0 [95% CI: 17.5-51.1]; p<0.001) and more frequent echocardiograms (RR=1.5 [95% CI: 1.2, 1.9]; p<0.001) compared to MDS- pregnancies.</p><p><strong>Conclusion: </strong>MDS+ pregnancies had elevated rates of ultrasound abnormalities, pregnancy loss, preterm birth, and pregnancy management as compared to an MDS- control group. These findings support the clinical utility of microdeletion screening in prenatal care.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"19 ","pages":"591410"},"PeriodicalIF":2.6,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13094567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147784239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two Distinct Clinical Presentations of Primary Ciliary Dyskinesia (PCD): Diagnostic Utility of Whole-Exome Sequencing in a Genetically Heterogeneous Disorder.","authors":"Mateusz Górecki, Ilona Jaszczuk, Monika Lejman","doi":"10.2147/TACG.S549665","DOIUrl":"https://doi.org/10.2147/TACG.S549665","url":null,"abstract":"<p><p>Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous disorder with variable clinical presentation. In cases where traditional diagnostic tools such as transmission electron microscopy (TEM) or nasal nitric oxide (nNO) measurement are inconclusive/unavailable, molecular diagnostics via whole-exome sequencing (WES) may provide essential insights. In this case report, we present two male infants with diverse phenotypes and genotypes. 1st patient was ultimately diagnosed with PCD thanks to WES, while 2nd patient was strongly suggestive of PCD. The 1st patient portrayed in his clinical history symptoms such as perinatal respiratory distress, situs inversus, and recurrent otitis media. He was found to carry a known pathogenic homozygous variant c.461A>C (p.His154Pro), in the <i>CCDC103</i> gene. The second patient exhibited more complex phenotype, including diaphragmatic hernia, absence of the pericardium, significant delay in the motor development. WES identified two variants in both <i>DNAH5</i> and <i>DNAH9</i>. Parental testing identified the maternal origin for the c.10243-6C>T (p.?) and c.308del (p.Phe103Serfs*31) variants in the <i>DNAH9</i> gene and a paternal origin for the c.1206T>A (p.Asn402Lys) variant in the <i>DNAH5</i> gene. The second variant c.5124G>T (p.Glu1708Asp) in the <i>DNAH5</i> gene in the proband arose de novo. At the time of analysis, these variants were classified as variants of uncertain significance (VUS) or likely benign, with limited segregation data and no definitive functional validation. Although the genetic findings were not diagnostic on their own, the clinical picture (situs inversus, neonatal respiratory distress, recurrent infections) was strongly suggestive of PCD. Both cases illustrate the crucial role of WES in establishing a molecular diagnosis of PCD, particularly when the use of traditional diagnostic methods is inconclusive. Moreover, they demonstrate the value of genomic testing in guiding the clinical management and informing about prognosis in diseases like PCD.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"19 ","pages":"549665"},"PeriodicalIF":2.6,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13052831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147634350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prenatal Ultrasound and Genetic Diagnosis of <i>EFTUD2</i> Haploinsufficiency in Two Fetuses: A Case Series.","authors":"Agata Kucińska, Lech Dudarewicz, Beata Anna Nowakowska, Maciej Geremek, Urszula Wysocka, Łukasz Przesór, Dobromiła Barańska, Piotr Grzelak, Agnieszka Gach","doi":"10.2147/TACG.S579472","DOIUrl":"https://doi.org/10.2147/TACG.S579472","url":null,"abstract":"<p><p>Mandibulofacial dysostosis with microcephaly (MFDM) is caused by haploinsufficiency of <i>EFTUD2</i> gene. This syndrome is characterized by microcephaly, malar and mandibular hypoplasia, ear abnormalities, developmental delay, and intellectual disability. In this study, we report two cases of fetuses presenting a phenotype consistent with MFDM and confirmed <i>EFTUD2</i> gene variants. The patients were referred following abnormal ultrasound findings. Genetic diagnostics in both cases revealed heterozygous variants in the <i>EFTUD2</i> gene that had not been previously reported prenatally. In the first patient, exome sequencing identified a c.2698_2701del p.(Val865Serfs*34), while in the second a novel large deletion involving multiple genes, including the entire <i>EFTUD2</i> gene, was detected by microarray analysis. Prenatal diagnosis of MFDM requires precise ultrasound assessment. Therefore, consideration of characteristic features observed in fetuses with MFDM is essential for differential diagnosis and guiding targeted genetic testing.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"19 ","pages":"579472"},"PeriodicalIF":2.6,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13037503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147595335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Case Report: Schaaf-Yang Syndrome Milder Phenotype Due to Potential Pathogenic Novel Missense Variant as an Unusual Cause of Obesity in a Pediatric Patient.","authors":"Dalibor Pastucha, Darina Aleksijevic, Jiri Hyjanek, Ondrej Vesely, Eva Klaskova, Kristyna Kolarikova, Radek Vodicka","doi":"10.2147/TACG.S584482","DOIUrl":"https://doi.org/10.2147/TACG.S584482","url":null,"abstract":"<p><p>According to OMIM and Orphanet databases, Schaaf-Yang syndrome (SYS) (OMIM: 615547, ORPHA: 398069) is a rare genetic disorder that shares certain clinical features with Prader-Willi syndrome (PWS), including hypotonia, developmental delay, and early-onset obesity. However, SYS often exhibits a more complex and variable phenotype. Missense variants in MAGEL2 have been reported only rarely, and their phenotypic spectrum appears milder and more variable than that of truncating mutations. Data on early-onset obesity as a dominant feature in such patients are limited. In this case report, we describe a child with mild phenotype (SYS) carrying the novel missense variant <i>MAGEL2(NM_019066.5)</i>:c.1265C>T (p.Pro422Leu) presenting with severe early-onset obesity and a comparatively neurodevelopmental phenotype. We present a case of a boy with neonatal hypotonia, diagnosed with (SYS) at age 9 years, with follow-up to age 11 years. The boy was born at 34+3 weeks of gestation with hypotonia, feeding difficulties, and a persistent ductus arteriosus that required surgical ligation in early infancy. In the following years, he developed severe early-onset obesity, already evident by age 2 despite multidisciplinary care. Genetic testing performed at age 9 years identified a novel missense variant (NM_019066.5)c.1265C>T in the <i>MAGEL2</i> gene, which was not inherited from his mother, thereby confirming the diagnosis of (SYS). At the time of the most recent evaluation, at age 11 years, he remained under long-term follow-up. Clinical management over this period included endocrine therapy, cardiac surgery, physical rehabilitation, and dietary interventions, and despite the complexity of his condition, long-term stabilization of his BMI percentile was achieved with consistent non-pharmacological interventions. This case highlights the importance of early multidisciplinary investigation and intervention in SYS, particularly when obesity is the dominant feature. Effective long-term weight stabilization is possible through structured lifestyle management.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"19 ","pages":"584482"},"PeriodicalIF":2.6,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13047383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147623976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hearing, Voice and Speech Disorders in 10-Year-Old-Boy with Facio-Scapulo-Humeral Dystrophy (FSHD) - Case Study.","authors":"Emilia Duchnowska, Bożena Kosztyła-Hojna, Maciej Zdrojkowski, Sarah Burton-Jones, Wojciech Kułak","doi":"10.2147/TACG.S574913","DOIUrl":"https://doi.org/10.2147/TACG.S574913","url":null,"abstract":"<p><strong>Purpose: </strong>The aim of the study was to evaluate hearing, voice, and speech in 10-year-old boy with fascio-scapulo-humeral dystrophy (FSHD).</p><p><strong>Patients and methods: </strong>Hearing, voice, and speech were assessed in a 10-year-old boy with FSHD due to scarcity of detailed audiophonological assessment in this disorder. Evaluation of muscle tension in upper and lower limb posture, gait, muscle enzyme activity, ECG, USG, bone densitometry, lower limb muscles MRI, handgrip strength were conducted. Hearing was examined using pure-tone, impedance, speech audiometry, and DPOAE. Voice assessment included GRBAS and endoscopic laryngeal examinations. Speech evaluation was conducted using Child Speech Assessment Cards (Karty Oceny Logopedycznej Dziecka, KOLD).</p><p><strong>Results: </strong>Diagnosis of FSHD was genetically confirmed by haplotype testing. Muscle hypotonia and atrophy were observed in limbs and face, along with gait disturbances. The 6-minute walk test (6MWT) result was 570 m, and the upper limb muscle strength was 9.3 kg (right limb) and 11.0 kg (left limb), both limbs: 15.7 kg. Audiological evaluation revealed severe bilateral sensorineural hearing (mean 73 dB HL). Bilateral type As tympanogram was recorded (right ear: 0.27 mL; left ear: 0.18 mL). Stapedial reflex was absent at high frequencies. DPOAE testing revealed sporadic bilateral cochlear responses. Speech audiometry showed reduced speech comprehension. Endoscopic examinations revealed edema of both vocal folds mucosa, preserved mobility. GRBAS scale showed G2R1B3A3S0. Acoustic analysis demonstrated slight reduction in fundamental frequency (F0) and elevated shimmer (10.566%). MPT was slightly shortened to 20 s. Speech evaluation revealed mouth breathing, shortened expiratory phase during phonation, bradylalia, articulation disorders with prolonged pauses between words, high-arched soft palate, shortened lingual frenulum, open bite, reduced tone of facial, lip, and tongue muscles.</p><p><strong>Conclusion: </strong>Genetic testing confirmed the presence of facio-scapulo-humeral muscular dystrophy (FSHD). Bilateral severe sensorineural hearing loss was documented. Speech disorders in FSHD were associated with reduced tension of articulatory muscles.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"19 ","pages":"574913"},"PeriodicalIF":2.6,"publicationDate":"2026-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12978010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147444175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>TNF-α</i> rs1800629 Polymorphism in Vietnamese COPD Patients: Exploratory Evidence for Recessive Protective Association and Clinical Correlates.","authors":"Ha Minh Nguyen, Duong Hoang Huy Le, Tham Thi Hong Ho, Phuc Doan Huynh Anh Nguyen, Thinh Hung Nguyen, Van Nguyen Thanh Phan, Tuan Huu Ngoc Nguyen","doi":"10.2147/TACG.S586977","DOIUrl":"https://doi.org/10.2147/TACG.S586977","url":null,"abstract":"<p><strong>Background: </strong>Chronic obstructive pulmonary disease (COPD) poses a significant health burden in Vietnam. The <i>TNF-α</i> rs1800629 (-308G/A) polymorphism is an influential factor in disease pathogenesis. However, its association is inconsistent across the studied populations. This study addresses this gap in Vietnam by examining allele frequencies and clinical associations in stable COPD patients.</p><p><strong>Methods: </strong>A cross-sectional study recruited 320 healthy controls and 266 stable COPD patients (per GOLD 2023 criteria) from October 2024 to August 2025. Clinical data were collected from medical records and direct interrogation. Genotyping was performed using PCR-RFLP. The dataset used for sensitivity analyses (2,660 observations) was created through multiple imputations to address missing clinical data. Associations of the rs1800629 with disease susceptibility and selected clinical management parameters were analyzed using Chi-square/Fisher's exact tests, multivariable logistic regression, and sensitivity analysis.</p><p><strong>Results: </strong>The A allele frequencies were 8.83% (COPD), 6.88% (controls), and 7.77% overall (<i>p</i> > 0.05). Patients were predominantly male smokers over 40 years, with moderate-severe symptoms (CAT ≥10, mMRC 3) and A/B severity groups. Under a recessive model, the AA genotype was associated with ~96% reduced susceptibility (adjusted OR 0.039, 95% CI 0.002-0.62, p=0.022). Regression identified smoking (OR 1.83-2.35), family history (OR 2.04), and onset ≥40 years (OR 2.88-3.36) as independent symptom influences. Sensitivity analysis further supported the protective effect of the AA genotype and revealed GA protective effects on symptomatic outcomes (OR<1, <i>p</i><0.05).</p><p><strong>Conclusion: </strong>Our findings suggest a possible protective recessive association of the <i>TNF-α</i> rs1800629 (-308G/A) polymorphism with COPD susceptibility, symptom burden, and exacerbation risk. However, the wide confidence intervals arising from the rarity of the AA genotype and the use of multiply imputed data mean these signals are exploratory. Larger multi‑center studies with comprehensive exposure assessment are needed to confirm these observations.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"19 ","pages":"586977"},"PeriodicalIF":2.6,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12948766/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147327563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variable Expressivity in Type 2 Familial Partial Lipodystrophy Related to a Pathogenic <i>LMNA</i> Variant R482: Maternal Transmission to Non-Identical Twins.","authors":"Paola Andrea Duque-Cordoba, Lorena Diaz-Ordoñez, Laura Carvajal-Del-Castillo, Daniela Marmolejo, Andres Felipe Leal, Harry Pachajoa","doi":"10.2147/TACG.S570428","DOIUrl":"https://doi.org/10.2147/TACG.S570428","url":null,"abstract":"<p><p>Familial partial lipodystrophy type 2 (FPLD2), or Dunnigan syndrome, is a rare autosomal dominant disorder caused by mutations in the lamin A (<i>LMNA)</i> gene, most frequently involving the p.R482W variant. It is characterized by regional loss of subcutaneous fat and severe metabolic abnormalities, particularly dyslipidemia, insulin resistance, and hepatic steatosis. We report a family with three individuals -mother and two siblings- carrying the same pathogenic <i>LMNA</i> c.1444C>T (p.R482W) variant but exhibiting distinct clinical and biochemical profiles. The proband (patient 1) is a 29-year-old male, presented with moderate metabolic disturbances, including hypertriglyceridemia, low levels of high density lipoprotein-cholesterol (HDL-C), and hepatic steatosis, accompanied by physical features such as dorsocervical fat accumulation and winged neck. His dizygotic female twin (patient 2) exhibited a more severe phenotype with triglycerides levels approached 700 mg/dL, insulin resistance, and polycystic ovarian morphology (PCOM). Their 68-year-old mother, also a carrier, showed only mild dyslipidemia and unstable angina. The comparison of dizygotic twins and their mother carrying the same <i>LMNA</i> variant provides a unique opportunity to illustrate how sex, age, and hormonal status modulate metabolic severity in FPLD2. These findings reinforce the clinical relevance of family-based evaluation and early metabolic surveillance, even in mildly affected or asymptomatic carriers.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"19 ","pages":"570428"},"PeriodicalIF":2.6,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12911963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146221321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Routine Excision, Rare Diagnosis: Solitary Neurofibroma Prompting NF1 Screening in an Adolescent.","authors":"Manal Mubarak Alquaimi","doi":"10.2147/TACG.S549653","DOIUrl":"10.2147/TACG.S549653","url":null,"abstract":"<p><p>A solitary plexiform neurofibroma in a 15-year-old girl prompted an unexpected referral for neurofibromatosis type 1 (NF1) evaluation. Initially excised under the impression of a lipoma, the lesion's histopathology revealed neural origin features with strong S100 and CD34 positivity. Dermatologic examination uncovered multiple café-au-lait macules, and subsequent referral to neurology raised clinical suspicion for NF1. This case emphasizes how incidental histological findings in a benign-appearing lesion can serve as the first clinical clue of a genetic disorder, triggering appropriate multidisciplinary evaluation.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"19 ","pages":"549653"},"PeriodicalIF":2.6,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13016114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147522421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional Validation of a Novel Deep Intronic <i>IMPG2</i> Variant Causing Pseudoexon Activation in Retinitis Pigmentosa with Macular Involvement.","authors":"Guobing Zheng, Chenxia Xu, Fenghua Xie, Qiaoli Li, Zhanhui Ou, Degang Wang, Haijun Li","doi":"10.2147/TACG.S573156","DOIUrl":"https://doi.org/10.2147/TACG.S573156","url":null,"abstract":"<p><strong>Objective: </strong>Retinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinal dystrophies often accompanied by macular involvement. Variants in <i>IMPG2</i> are known to cause RP type 56 and vitelliform macular dystrophy type 5, but the pathogenic role of deep intronic variants has rarely been characterized. This study aimed to identify and functionally validate a novel deep intronic <i>IMPG2</i> variant in a patient with RP.</p><p><strong>Methods: </strong>A comprehensive clinical, genetic, and functional assessment was performed. Ophthalmic evaluations included fundus photography, optical coherence tomography (OCT), OCT angiography (OCTA), and multifocal electroretinography (mfERG). Whole-genome sequencing followed by Sanger validation and segregation analysis was conducted. In silico splicing prediction and dual minigene assays (pcMINI and pcMINI-C) in HEK293T and HeLa cells were employed to evaluate the splicing effect of the variant.</p><p><strong>Results: </strong>A novel homozygous deep intronic variant in <i>IMPG2</i> (NM_016247.4:c.909-1659A>G), absent from public databases, was identified. Splice prediction tools suggested creation of a cryptic donor site. Functional assays demonstrated aberrant splicing with retention of a 132 bp pseudoexon, introducing a premature termination codon and thereby likely triggering nonsense-mediated decay rather than generating a stable truncated protein. Segregation analysis confirmed autosomal recessive inheritance. The proband exhibited lifelong night blindness, progressive peripheral visual field constriction, and macular structural and functional impairment, consistent with <i>IMPG2</i>-associated retinopathy.</p><p><strong>Conclusion: </strong>This study provides the first functional evidence that a deep intronic <i>IMPG2</i> variant causes pseudoexon activation leading to a premature termination codon and likely nonsense-mediated decay. These findings expand the <i>IMPG2</i> mutational spectrum, highlight the pathogenic potential of deep intronic variants, and emphasize the importance of functional assays for reclassifying variants of uncertain significance in inherited retinal diseases.</p>","PeriodicalId":39131,"journal":{"name":"Application of Clinical Genetics","volume":"19 ","pages":"573156"},"PeriodicalIF":2.6,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13003989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147500122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}