{"title":"Loss of Different Domains of TDRD12 Leads to Distinct Male Infertility-Related Phenotypes.","authors":"Xinyao Tang, Jinhui Li, Yunchuan Tian, Chanjuan Zhao, Xiaohui Jiang, Chuan Jiang, Xiang Wang, Jun Ma, Yingteng Zhang, Tiechao Ruan, Guicheng Zhao, Yihong Yang, Ying Shen","doi":"10.1111/cge.70034","DOIUrl":"https://doi.org/10.1111/cge.70034","url":null,"abstract":"<p><p>Tdrd12 is known to play an important role in spermatogenesis in mice. However, evidence linking TDRD12 mutations to male azoospermia is limited, and no cases of TDRD12-related teratozoospermia have been reported. We identified two novel homozygous TDRD12 mutations (c.3378dupG and c.2463C>G) in two unrelated infertile men, respectively. Patient 1 carried a TDRD12 frameshift mutation (c.3378dupG), resulting in a truncated protein lacking the cysteine-rich domain. This patient presented with teratozoospermia, characterized by abnormal sperm morphology, including defects in the head and flagellum. Patient 2 carried a TDRD12 nonsense mutation (c.2463C>G), resulting in complete degradation of the protein. This patient exhibited azoospermia, characterized by germ cell maturation arrest at the spermatocyte stage. Mechanistically, TDRKH, TDRD9, PIWIL2, and PIWIL1, key piRNA biogenesis proteins, are predicted to interact with TDRD12. Notably, PIWIL1 fluorescence was reduced in Patient 1's sperm, while PIWIL2 and TDRD9 signals were diminished and LINE-1 signal was increased in Patient 2's testicular tissue. Furthermore, Intracytoplasmic sperm injection using Patient 1's sperm was unsuccessful. Our study first identified that the loss of different domains of TDRD12 results in distinct male infertility-related phenotypes. These findings revealed novel genetic insights into male infertility, demonstrated the critical role of TDRD12 in human spermatogenesis, and are helpful for diagnosis and genetic counseling.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Khemika K Sudnawa, Alexa Geltzeiler, Cara H Kanner, Kyle Zreibe, Nicolò Pini, Celia Tam, Robert J Fee, Sean Calamia, Emily Callejo, Holli Sharples, Catherine E Serianni, Michela Fagiolini, Ellen Hanson, Jacqueline Montes, April Levin, Wendy K Chung
{"title":"Comprehensive Clinical Characteristics, Longitudinal Adaptive Functioning, and Electroencephalogram Activity in MAPK8IP3-Related Neurodevelopmental Disorder.","authors":"Khemika K Sudnawa, Alexa Geltzeiler, Cara H Kanner, Kyle Zreibe, Nicolò Pini, Celia Tam, Robert J Fee, Sean Calamia, Emily Callejo, Holli Sharples, Catherine E Serianni, Michela Fagiolini, Ellen Hanson, Jacqueline Montes, April Levin, Wendy K Chung","doi":"10.1111/cge.70032","DOIUrl":"https://doi.org/10.1111/cge.70032","url":null,"abstract":"<p><p>Mitogen-activated protein kinase 8-interacting protein 3-related neurodevelopmental disorder (MAPK8IP3-related NDD) results from heterozygous pathogenic or likely pathogenic variants in MAPK8IP3. We report on 32 individuals (median age 7.5 years, range 1.3-22.0), all of whom had heterozygous pathogenic/likely pathogenic MAPK8IP3 variants, including missense (62.5%) and predicted loss-of-function (LOF) variants (34.4%). Common symptoms included cognitive impairment, hypotonia, motor difficulties, strabismus, microcephaly, and attention deficits. Corpus callosum thinning was reported in 62.1%. Nearly all individuals walked independently but demonstrated slower gait speed and a wider base of support compared to controls. The mean DAS-II General Conceptual Ability score was 62.5 ± 26.5. EEG analysis suggested a trend toward lower power accentuated frequency compared to typically developing individuals. Missense variants were associated with more severe symptoms than LOF variants. This study provides valuable insights into the clinical characteristics, patient management, and preparation for future clinical trials.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S Rehan Ahmad, Abdullah M AlShahrani, Natchimuthu Vijayakumar, Anupriya Kumari
{"title":"Pathogenic DDX39A Variant Disrupts Nuclear Homeostasis and Causes an Early-Onset Neurodegenerative Disorder With Cerebral Atrophy.","authors":"S Rehan Ahmad, Abdullah M AlShahrani, Natchimuthu Vijayakumar, Anupriya Kumari","doi":"10.1111/cge.70033","DOIUrl":"https://doi.org/10.1111/cge.70033","url":null,"abstract":"<p><p>Neurodevelopmental disorders arising from mutations in RNA-processing factors are increasingly recognized but remain mechanistically underexplored. Here, we identify that variant (c.485A>C; p.Lys137Gln) in DDX39A in a 7-month-old proband presenting with global developmental delay, microcephaly, seizures, hypotonia, and brain atrophy with corpus callosum thinning. DDX39A encodes a DEAD-box RNA helicase essential for mRNA splicing and export via the TREX complex. Functional studies in proband-derived fibroblasts revealed that while transcript and protein levels of DDX39A-K137Q were unaffected, the mutant protein displayed aberrant nuclear clumping and failed to interact with the TREX component THOC1. Structural modeling demonstrated that Lys137 mediates critical inter- and intra-molecular interactions, which are disrupted by the K137Q substitution. This loss destabilizes the DDX39A-THOC1 interface, impairing TREX complex integrity. The mutant cells exhibited severe nuclear morphological abnormalities, disrupted nuclear lamina organization, and increased cell death. Transcriptomic network analysis and gene ontology revealed enrichment of DDX39A interactions in mRNA export, splicing, and nucleocytoplasmic transport-functions essential for neuronal development. Temporal and regional brain expression data showed that DDX39A is highly expressed during early postnatal life and across multiple brain regions, indicating its importance in early brain maturation. Our findings establish DDX39A-K137Q as a pathogenic variant that impairs nuclear RNA processing and structural homeostasis, leading to a severe neurodegenerative phenotype. This study identifies the role of RNA helicases in neurodevelopment and explores DDX39A as a novel gene implicated in pediatric neurodegenerative disease.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144728417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zeynep Esener, Mehmet Akif Yücesoy, Alper Gezdirici, Mustafa Dogan, Ayberk Turkyilmaz, Ibrahim Tekedereli, Hasan Bas, Aysel Tekmenuray-Unal, Sinem Kocagil, Senol Citli, Murat Ozturk, Emine Ipek Ceylan, Volkan Karaman, Ayca Dilruba Aslanger
{"title":"Hypohidrotic Ectodermal Dysplasias: Phenotypic and Genotypic Findings in 32 Cases.","authors":"Zeynep Esener, Mehmet Akif Yücesoy, Alper Gezdirici, Mustafa Dogan, Ayberk Turkyilmaz, Ibrahim Tekedereli, Hasan Bas, Aysel Tekmenuray-Unal, Sinem Kocagil, Senol Citli, Murat Ozturk, Emine Ipek Ceylan, Volkan Karaman, Ayca Dilruba Aslanger","doi":"10.1111/cge.70030","DOIUrl":"https://doi.org/10.1111/cge.70030","url":null,"abstract":"<p><p>Hypohidrotic ectodermal dysplasias are a genetic condition affecting ectoderm-derived structures such as hair, teeth, nails, and sweat glands, resulting from variations in the EDA, EDAR, EDARADD, and WNT10A genes. This study examined 32 cases from 25 unrelated families from Türkiye, identifying seven novel variants in the EDA, EDAR, and WNT10A genes. The distribution of genetic alterations across the cohort revealed that 44% of the families (11/25) harbored variants in EDA, whereas EDAR and WNT10A variants were identified in 32% (8/25) and 24% (6/25) of families, respectively. Clinical evaluation revealed the characteristic hypohidrotic ectodermal dysplasia triad of hypotrichosis, hypodontia, and hypohidrosis was observed in 87.5% of cases, along with other symptoms such as dry skin, atopic dermatitis, and developmental delays. All cases presented with hair, eyebrow, and eyelash abnormalities, ranging in severity from subtle thinning to marked hypotrichosis. Among the cohort, one case exhibited severe atopic dermatitis as the predominant symptom. Targeted next-generation sequencing and clinical exome sequencing were employed to determine the genetic basis of the condition, emphasizing the importance of early diagnosis for targeted interventions. This study expands the genetic and phenotypic spectrum of hypohidrotic ectodermal dysplasia, presenting a comprehensive overview of molecular findings and genotype-phenotype correlations in the population from the Turkish population.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"French Guidelines of the AchroPuce Network for the Interpretation and Reporting of Constitutional Copy Number Variants.","authors":"Céline Pebrel-Richard, Paul Kuentz, Anne-Claude Tabet, Jean-Michel Dupont, Chantal Missirian, Serge Romana, Detlef Trost, Caroline Rooryck, Valérie Malan, Matthieu Egloff","doi":"10.1111/cge.70027","DOIUrl":"https://doi.org/10.1111/cge.70027","url":null,"abstract":"<p><p>Over the past 15 years, molecular methods for human genome analysis have evolved significantly, becoming integral to routine genetic diagnostics. Among various genomic alterations, copy-number variations (CNVs) are particularly important as sources of both benign and pathogenic variants. Accurate assessment of these variants' clinical implications is critical, especially for rare, non-recurrent CNVs and for susceptibility loci linked to neurodevelopmental disorders (NDDs). To address these challenges, the French AchroPuce CNV Interpretation Working Group proposes a novel classification termed \"PIEV,\" referring to CNVs associated with NDDs characterized by incomplete penetrance and variable expressivity. This category complements the existing five-tier ACMG classification system, supporting genetic professionals in harmonizing practice through standardized French national guidelines, thereby enhancing genetic counseling and clinical interpretation precision. Distinguishing clearly pathogenic variants from those with incomplete penetrance is crucial, and the consistent classification of these CNVs independently of the clinical context is essential. Clinical significance assessments should entail collaboration between biologists and multidisciplinary clinical teams, especially in prenatal diagnostics. The working group maintains an annually reviewed curated list of recurrent neurodevelopmental CNVs with reduced penetrance and provides consensus recommendations with a customized interpretation tool to enhance national consistency in CNVs reporting.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Humeroradial Synostosis: An Updated Classification and Differential Diagnosis Based on Genetic Aetiology.","authors":"Fiona Leduc, Clémence Vanlerberghe, Fabienne Escande, Perrine Brunelle, Florence Petit, Anne Dieux","doi":"10.1111/cge.70023","DOIUrl":"https://doi.org/10.1111/cge.70023","url":null,"abstract":"<p><p>Humeroradial synostosis (HRS) is a rare congenital limb malformation, characterised by fusion of the humeral and radial bones, leading to functional disability of the elbow joint. HRS may be reported in familial or sporadic cases and observed either isolated or as part of a syndromic condition. According to an extensive review of the literature, a dozen known conditions may comprise an HRS. The present review aims to propose an updated classification based on molecular pathways (chondrogenesis and osteogenesis; limb development and patterning; genome regulation), combined with a concise overview of the conditions associated with HRS. This knowledge could guide molecular analyses, patient management and genetic counselling. As some cases remain unexplained, further genetic and epidemiological studies are required to evaluate the contribution of genetic and environmental factors in HRS physiopathology.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Molecular and Clinical Landscape of Osteogenesis Imperfecta: Unraveling Autosomal Recessive Forms, Therapeutic Outcomes, and Bone Mineral Density in Carriers.","authors":"Haseena Sait, Naik Adarsha, Amita Moirangthem, Deepti Saxena, Lokesh Sharma, Preeti Dabadgao, Avantika Gupta, Shubha R Phadke","doi":"10.1111/cge.70003","DOIUrl":"https://doi.org/10.1111/cge.70003","url":null,"abstract":"<p><p>Osteogenesis imperfecta (OI) is a heritable disorder characterized by bone fragility and marked genetic and phenotypic heterogeneity. This study explores the molecular and clinical spectrum of OI, with a focus on autosomal recessive (AR) forms, therapeutic outcomes, and bone mineral density (BMD) in carriers of AR OI-associated gene variants from the Indian population. A total of 78 clinically suspected OI patients were analyzed, yielding a high diagnostic rate of 92.3%. Exome sequencing was performed in all cases, with whole-genome sequencing in selected exome-negative cases. Autosomal dominant (AD) and AR OI accounted for 66% and 34% of cases, respectively. P3H1 (n = 11) was the most frequently implicated AR gene causing OI, followed by SERPINF1 (n = 5) and WNT1 (n = 4), with 79% of AR variants being novel. Phenotypic evaluation (n = 67) revealed fractures, short stature (87%), and bony deformities (84%) as predominant features. A rare homozygous COL1A1 variant was identified in one patient, while another patient harbored additional variants in AD OI genes, suggesting a potential digenic or modifier effect. Phenotypic severity followed the order from most to least severe: AR genes > COL1A2 (substitution and non-substitution) > COL1A1 (substitution > non-substitution). A self-designed, preliminary clinical severity scoring system ranked CRTAP followed by P3H1, as the AR genes associated with the most severe phenotypes. Therapeutic assessment showed a significant reduction in fracture incidence following zoledronate therapy only in the COL1A1 group, with no notable improvements in the COL1A2 or AR groups. Additionally, BMD evaluation in carrier parents of AR gene causing OI indicated a higher predisposition to low BMD among WNT1 gene carriers. However, these findings are preliminary and limited by small sample size. This study provides an extensive genotypic and phenotypic characterization of OI in the Indian population, with a focus on AR OI. It documents differential therapeutic responses among genetic subgroups and provides preliminary observations on BMD in carrier parents of AR OI-an aspect that has been less explored previously and suggest the need for tailored management strategies. The findings in this study also raise the possibility of genetic modifiers contributing to phenotypic variability, warranting further investigation.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144616610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Areej Alatawi, Omamah Alshehri, Aminah Alessa, Fuad Al Mutairi, Norah AlSaleh, Wafaa Eyaid, Ali Alsamri, Eissa Faqeih, Aziza Mushiba, Mohammed Saleh, Maha Alotaibi, Brahim Tabarki, Yaser I Aljadhai, Panagiotis Katsonis, Olivier Lichtarge, Fowzan S Alkuraya, Majid Alfadhel, Mohammed Almannai
{"title":"SLC25A42-Related Mitochondrial Disorder: New Cases and Literature Review.","authors":"Areej Alatawi, Omamah Alshehri, Aminah Alessa, Fuad Al Mutairi, Norah AlSaleh, Wafaa Eyaid, Ali Alsamri, Eissa Faqeih, Aziza Mushiba, Mohammed Saleh, Maha Alotaibi, Brahim Tabarki, Yaser I Aljadhai, Panagiotis Katsonis, Olivier Lichtarge, Fowzan S Alkuraya, Majid Alfadhel, Mohammed Almannai","doi":"10.1111/cge.70021","DOIUrl":"https://doi.org/10.1111/cge.70021","url":null,"abstract":"<p><p>SLC25A42 encodes a mitochondrial carrier that is responsible for the import of CoA into mitochondria. Biallelic pathogenic variants in SLC25A42 have been associated with a recently described mitochondrial disorder characterized by encephalomyopathy with variable severity. To date, 24 affected individuals from 16 different families have been reported. Most are of Arab descent who harbor the founder variant in SLC25A42 (c.871A>G, p.Asn291Asp). In this report, we present 23 additional individuals from 19 unrelated families and their clinical, radiological, and molecular findings. We show again that SLC25A42-related mitochondrial disorder is associated with extremely variable severity. Some individuals with mild presentation may be unrecognized, while others are prone to metabolic decompensations with neuro-regression and irreversible neurological insult, making early diagnosis important.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S Rehan Ahmad, Md Zeyaullah, Abdullah M AlShahrani, Danish Qavi, Abdelrhman A G Altijani, Mohammad Suhail Khan, Khursheed Muzammil
{"title":"An Unstable ATG2A Variant Causes a Neurodegenerative Disorder via Impaired Autophagy and Proteotoxic Stress in Brain Atrophy.","authors":"S Rehan Ahmad, Md Zeyaullah, Abdullah M AlShahrani, Danish Qavi, Abdelrhman A G Altijani, Mohammad Suhail Khan, Khursheed Muzammil","doi":"10.1111/cge.70019","DOIUrl":"https://doi.org/10.1111/cge.70019","url":null,"abstract":"<p><p>Autophagy is a critical cellular process for maintaining proteostasis and neuronal health. Disruption of this pathway is increasingly recognized in pediatric neurodegenerative disorders. Here, we study a novel previously uncharacterized homozygous and autosomal recessive missense variant, c.1372G>C (p.Gly433Ala), in the autophagy gene ATG2A, identified in a 3-year-old female proband presenting with developmental regression, seizures, cerebellar ataxia, and MRI-confirmed diffuse cerebral and cerebellar atrophy. The affected residue, Gly433, is evolutionarily conserved across eukaryotes and predicted to be structurally and functionally critical. Computational modeling and molecular dynamics simulations revealed that the G433A substitution induces local β-sheet extension, increased protein flexibility, higher aggregation propensity, and global structural destabilization. Proband-derived fibroblasts expressing ATG2A-G433A showed normal transcript and protein levels, but exhibited mislocalization of ATG2A to the cytosol, reduced colocalization with LC3B, loss of autophagosome formation, and a marked increase in protein aggregates. Proteotoxic stress was further evidenced by significant accumulation of Proteostat- and SQSTM1-positive granules. Additionally, transcript levels of unfolded protein response markers (GRP78, PERK, ATF4, and CHOP) were significantly upregulated, suggesting increased ER stress signaling. Cell cycle analysis revealed a substantial increase in cell death in proband fibroblasts. Overall, our findings identify ATG2A as a potentially novel disease gene and its G433A variant as a pathogenic substitution that disrupts autophagy and proteostasis, driving neurodegeneration via aggregation-prone misfolding and autophagy failure. This work depicts the first clinical spectrum of ATG2A-related neurodegenerative disorders and highlights the importance of autophagy maintenance in pediatric neurodevelopmental processes.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Seyedeh Saideh Daryabari, Sylvie Giroux, André Caron, Jean-Claude Forest, Sylvie Langlois, Emmanuel Bujold, François Rousseau
{"title":"Prenatal Cell-Free DNA Screening With Fetal Enrichment Enables Sampling From 8 Weeks of Gestational Age.","authors":"Seyedeh Saideh Daryabari, Sylvie Giroux, André Caron, Jean-Claude Forest, Sylvie Langlois, Emmanuel Bujold, François Rousseau","doi":"10.1111/cge.70020","DOIUrl":"https://doi.org/10.1111/cge.70020","url":null,"abstract":"<p><p>Cell-free DNA (cfDNA) screening for fetal aneuploidy is typically offered from 10 weeks of gestational age (GA) onward. Fetal fraction (FF) enrichment may enable screening before 10 weeks with a low failure rate. This study aimed to assess the feasibility of cfDNA screening with in vitro enrichment before 10 weeks of gestation. 435 pregnant women were recruited between 7w0d and 9w6d of GA (EARLY samples) and scheduled for a second cfDNA sample after 11 weeks of GA (12w+ samples). 371 women provided both an EARLY and a 12w+ sample, and we compared cfDNA results between EARLY and 12w+ samples and sex at birth. For sex determination using cfDNA, EARLY, and 12w+ samples were 100% concordant with clinical sex at birth. In 170 male pregnancies, EARLY samples 5.9% had FF < 4% after enrichment. Seven aneuploidies were observed early, but eight at 12+ weeks (one false positive after invasive diagnostic testing). We observed 4.4% spontaneous abortions between the EARLY and 12w+ sampling. Our findings suggest that in vitro fetal enrichment provides sufficient cfDNA for reliable prenatal cfDNA screening results as early as 8 weeks, but one limitation lies in the high proportion of spontaneous abortions before 12w0d.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}