Molecular Genetics & Genomic Medicine最新文献

{"title":"Multi-Level Genomic and Computational Analyses Identify a Novel IFT122 Variant Associated With Cranioectodermal Dysplasia 1 in a Consanguineous Saudi Family.","authors":"Deema Aljeaid, Abdulrahman Almadiny, Khalidah K Nasser, Mahmoud Almutadares, Noha M Issa","doi":"10.1002/mgg3.70230","DOIUrl":"10.1002/mgg3.70230","url":null,"abstract":"<p><strong>Background: </strong>Cranioectodermal dysplasia (CED) is a rare autosomal recessive ciliopathy characterized by craniofacial, skeletal, and ectodermal anomalies. Significant phenotypic heterogeneity often results in clinical overlap with other skeletal dysplasias, including Robinow syndrome. In consanguineous populations, the presence of multiple rare variants can further complicate the molecular diagnosis. This study aimed to clarify the genetic basis of a complex syndromic presentation in a consanguineous Saudi family exhibiting features suggestive of both disorders using an integrated phenotypic, genomic, and computational approach.</p><p><strong>Methods: </strong>Exome sequencing was performed on two affected siblings, followed by Sanger sequencing for the familial segregation analysis. Detailed phenotypic evaluation was combined with structural and bioinformatics analyses, including in silico pathogenicity prediction tools, three-dimensional protein modeling, protein-protein interaction analysis, and molecular docking to assess the structural and functional impact of candidate variants.</p><p><strong>Results: </strong>Exome sequencing identified a homozygous missense variant in IFT122 gene (c.94G > A; p.Gly32Arg), associated with cranioectodermal dysplasia 1, and a heterozygous frameshift variant in DVL3 gene (c.1949_1950del; p.His650Profs*60), associated with Robinow syndrome. Segregation analysis excluded the DVL3 variant as the primary cause, while the IFT122 variant segregated with the phenotype in an autosomal recessive manner. Computational analyses demonstrated that the p.Gly32Arg substitution affects a highly conserved residue and is consistently predicted to be deleterious. Structural modeling revealed the disruption of local hydrogen bonding, increased solvent accessibility, and reduced protein stability. Protein-protein interaction and molecular docking analyses further indicated altered interactions with key IFT-A components, including TTC21B, IFT140, TULP3, and IFT43, suggesting impaired intraflagellar transport complex integrity and ciliary protein trafficking.</p><p><strong>Conclusion: </strong>This study identifies a novel homozygous IFT122 (c.94G > A; p.Gly32Arg) variant underlying CED1, thereby expanding the molecular spectrum of IFT122-related ciliopathies. These findings emphasize the value of integrating phenotypic, genomic, segregation, and structural analyses to resolve diagnostically challenging cases, particularly in consanguineous populations. Further functional studies are warranted to confirm this molecular mechanism.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 5","pages":"e70230"},"PeriodicalIF":1.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13180794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147964259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exclusion of CLIC5 as a Candidate Gene and Identification of NEFM as a Possible Novel Gene Correlated With Autosomal Recessive Pure Cerebellar Ataxia in a Highly Consanguineous Family.","authors":"Paolo Enrico Maltese, Gabriele Bonetti, Elena Manara, Benedetta Tanzi, Andrea Bernini, Mark A Berryman, Soichi Tanda, Corinne Nielsen, Silvia Casagrande, Amanda Ferrero, Salvatore Stano, Riccardo Zuccarino, Andrea Barp, Pietro Chiurazzi, Matteo Bertelli","doi":"10.1002/mgg3.70199","DOIUrl":"10.1002/mgg3.70199","url":null,"abstract":"<p><strong>Background: </strong>Pure cerebellar ataxia is a neurological disorder characterised by isolated cerebellar dysfunction, arising from either developmental anomalies or progressive degenerative processes. Precise genetic diagnosis remains challenging.</p><p><strong>Methods: </strong>The aim of this study was to use a whole-exome sequencing approach to study a large, highly consanguineous Italian family in order to identify a new gene correlated with pure cerebellar ataxia.</p><p><strong>Results: </strong>Sequencing excluded the presence of mutations in known-related genes but revealed a homozygous missense variant in CLIC5; however in vivo analysis of a CLIC5 KO mouse model showed vestibular dysfunction without cerebellar involvement, suggesting that CLIC5 is not directly involved in pure cerebellar ataxia onset. Further analysis identified two compound heterozygous variants in NEFM, and in silico analysis showed that they dysregulate NEFM phosphorylation. Phosphorylation of neurofilaments and subsequent formation of aggregates has already been linked to conditions such as ageffing and neurodegeneration. Moreover, in vivo studies on mice transgenic for human NEFM have correlated NEFM phosphorylation and aggregation with neurodegeneration. Finally, neurofilaments have been proposed to be correlated to ataxia and autoimmune cerebellar ataxia.</p><p><strong>Conclusion: </strong>We therefore propose NEFM as a possible new candidate gene for hereditary cerebellar ataxia. These findings could be useful for advancing the genetic diagnosis of hereditary pure cerebellar ataxia, possibly enabling the screening of healthy carriers.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 4","pages":"e70199"},"PeriodicalIF":1.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13140635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prenatal Diagnosis of Autosomal Recessive Primary Microcephaly Type 2 Caused by Compound Heterozygous WDR62 Variants in a Family With Two Recurrent Cases.","authors":"Yan-Fang Li, Song-Hui Zhang, Li Zhen, Lan-Zhen Zhang","doi":"10.1002/mgg3.70203","DOIUrl":"10.1002/mgg3.70203","url":null,"abstract":"<p><strong>Objective: </strong>Autosomal recessive microcephaly type 2 (MCPH2), caused by biallelic WDR62 variants, is a rare neurodevelopmental disorder typically described postnatally. We aimed to delineate its prenatal phenotype via data from two affected fetuses in a family.</p><p><strong>Methods: </strong>Trio whole-exome sequencing (WES) was performed on one fetus and his parents. Variants were prioritized via population databases, computational predictions, and segregation analysis, which were confirmed via Sanger sequencing.</p><p><strong>Results: </strong>Prenatal imaging revealed microcephaly, agenesis of the corpus callosum, and neuronal migration defects (lobar holoprosencephaly and lissencephaly) in two fetuses. Trio-WES identified compound heterozygous WDR62 variants (c.1128C > A/p.Cys376* and c.643A > C/p.Thr215Pro) in one fetus, each inherited from a heterozygous parent. Sanger sequencing confirmed variants in both fetuses and parents.</p><p><strong>Conclusions: </strong>Trio-WES is crucial for the prenatal diagnosis of fetuses with unresolved sonographic anomalies. We report the prenatal features and molecular diagnoses of MCPH2, expanding its prenatal phenotypic spectrum and enhancing its clinical genomic database utility.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 4","pages":"e70203"},"PeriodicalIF":1.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13092497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147723443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implementation of an Inherited Diseases Gene Panel to Accelerate Precision Medicine in the South African Public Healthcare System.","authors":"Nadia Carstens, Maria Mudau, Fahmida Essop, Amanda Krause","doi":"10.1002/mgg3.70213","DOIUrl":"10.1002/mgg3.70213","url":null,"abstract":"<p><strong>Background: </strong>While whole genome and exome sequencing is already being implemented in clinics across the globe, there is still very little uptake of these technologies in African healthcare facilities. Significant hurdles remain that impede the translation of these highly effective mutation screening strategies into appropriate and effective clinical services in low- and middle-income countries.</p><p><strong>Methods: </strong>We developed, validated, and implemented a phenotype-driven genetic testing platform using a 500-gene Ion AmpliSeq Inherited Diseases Panel (IDP) within the South African State healthcare system. This panel enables testing for over 1000 Mendelian disorders using a single laboratory workflow, followed by selective, phenotype-guided analysis to minimize the risk of incidental or secondary findings. A pooled sequencing strategy was used to optimize resource efficiency, achieving an average coverage of 200-400× per sample.</p><p><strong>Results: </strong>Among 276 patients tested during the validation phase, a molecular diagnosis was identified in 46% (127/276) of cases. All pathogenic and likely pathogenic variants were submitted to ClinVar to support global data sharing and variant interpretation. The high coverage achieved reduced the need for additional validation testing, supporting the panel's efficiency and reliability in a clinical diagnostic setting.</p><p><strong>Discussion: </strong>This IDP enables us to improve genetic counselling, identify patients with well-described genetic disorders for whom appropriate interventions are needed and/or available and identify patients that would benefit from whole exome or genome-based testing, and allow for risk clarification for close relatives. This system has laid the foundation for rare disease genetic testing in the South African public healthcare system and can be used as a point of departure for genetic service implementation in resource-constrained environments.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 4","pages":"e70213"},"PeriodicalIF":1.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13062639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147639345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PDXK-Related Neuropathy: A Case With a Novel Splice-Altering Missense Variant and Literature Review.","authors":"Dmitrii Subbotin, Daria Akimova, Elena Dadali, Kristina Mikhalchuk, Artem Borovikov, Vitaly Kadyshev, Mikhail Skoblov, Aysylu Murtazina","doi":"10.1002/mgg3.70210","DOIUrl":"10.1002/mgg3.70210","url":null,"abstract":"<p><strong>Background: </strong>PDXK-related neuropathy is a rare form of hereditary motor and sensory neuropathy with optic atrophy, caused by biallelic variants in the PDXK gene. To date, only four missense variants have been reported in 13 patients from six families. Unlike most inherited neuropathies, which currently have only symptomatic treatments, this type of neuropathy can be managed with pyridoxal 5'-phosphate supplementation.</p><p><strong>Methods: </strong>The clinical presentation of the patient was evaluated twice, at ages 14 and 15 years. The whole-exome sequencing was performed for the proband followed by functional studies using RNA extracted from the proband's and proband's mother's peripheral blood mononuclear cells.</p><p><strong>Results: </strong>In this study, we provided a brief literature review on PDXK-related neuropathy and reported a female patient with a novel missense variant (c.826G>C, p.(Ala276Pro)) found in compound heterozygous state with a previously reported variant (c.659G>A, p.[Arg220Gln]) in the PDXK gene. Additionally, she carried a novel likely pathogenic missense variant (c.1180C>T, p.[Arg394Cys]) in the GCK gene, associated with MODY2, which was segregated with hyperglycemia in her family. The novel variant c.826G>C in the PDXK gene was predicted to disrupt splicing that was confirmed by our functional studies. The patient exhibited typical peripheral neuropathy but no optic atrophy, likely due to her young age.</p><p><strong>Conclusions: </strong>Here we report a novel splice-altering missense variant in PDXK that induces aberrant transcript degradation, revealing a new disease mechanism for PDXK-related neuropathy.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 4","pages":"e70210"},"PeriodicalIF":1.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13140640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147521418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Complex Neurodevelopmental Phenotype Resembling a Chromatinopathy With Concurrent 7p Duplication and 10p Deletion Involving ZMYND11: A Case Report and Literature Review.","authors":"Elia Marco Paolo Minale, Stefania Martone, Chiara Criscuolo, Roberta Marra, Vito Alessandro Lasorsa, Raffaella Ruggiero, Teresa Suero, Mario Capasso, Immacolata Andolfo, Achille Iolascon, Roberta Russo, Michele Pinelli","doi":"10.1002/mgg3.70164","DOIUrl":"10.1002/mgg3.70164","url":null,"abstract":"<p><strong>Background: </strong>The complex pathogenetic mechanisms of rare genetic diseases make the diagnostic process highly challenging. Advances in molecular genomic techniques, such as exome sequencing, have improved the identification of copy number variants (CNVs), increasing diagnostic yield.</p><p><strong>Methods: </strong>We report the case of a female patient with global developmental delay, growth alterations, and dysmorphic features. Clinical exome sequencing did not reveal point mutations. CNV analysis from exome data identified a 6 Mb microdeletion in 10p15.3p14, involving the ZMYND11 gene, and a 7.6 Mb microduplication in 7p22.3p21.3; both rearrangements were subsequently confirmed by chromosomal microarray analysis. Conventional karyotyping revealed a derivative chromosome 10 [46,XX,der (10)], a finding consistent with the possibility of an unbalanced translocation involving chromosomes 7 and 10. The combined cytogenetic and molecular findings are consistent with the possibility that the duplicated 7p segment is inserted into the short arm of chromosome 10.</p><p><strong>Results: </strong>ZMYND11, a dosage-sensitive gene, has been associated with Cornelia de Lange Syndrome (CdLS)-like phenotypes, and its haploinsufficiency is linked to 10p15.3 microdeletion syndrome. Our patient presented a complex phenotype due to the concurrent 7p duplication and 10p deletion, highlighting the importance of ZMYND11 in chromatinopathies. A review of similar cases supports considering ZMYND11 in evaluating chromatinopathy-related features. Notably, she also exhibited unique characteristics that have not been previously described in association with either CNV.</p><p><strong>Conclusion: </strong>Next-generation sequencing, capable of detecting both single nucleotide variants and CNVs, is a critical tool for diagnosing neurodevelopmental disorders and uncovering diverse causative variants. This case emphasizes how NGS facilitates the identification of co-occurring CNVs and expands the phenotypic spectrum associated with chromatinopathies. Detailed characterization of such complex phenotypes using NGS is essential for advancing our understanding of rare genetic conditions and improving diagnostic accuracy.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 4","pages":"e70164"},"PeriodicalIF":1.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13093532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147723438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of the Phenotype and Gene Mutations of Two Families With Combined Mutations of Anticoagulant Protein Genes.","authors":"Yueli Guo, Tingting Shan, Wenjieying Zheng, Chun Zhao, Wanzhong Kong, Xiaojing Zou","doi":"10.1002/mgg3.70191","DOIUrl":"10.1002/mgg3.70191","url":null,"abstract":"<p><strong>Background: </strong>AT and PC are key components of the anticoagulant system. Mutations in their encoding genes, SERPINC1 and PROC, can lead to insufficient protein levels or impaired function, thereby increasing an individual's susceptibility to venous thromboembolism (VTE). In this study, we describe the clinical characteristics and functional effects of compound heterozygous mutations in SERPINC1 and PROC in two pedigrees.</p><p><strong>Methods: </strong>Anticoagulant protein activity and antigen levels were evaluated in family members. Targeted sequencing was performed using next-generation sequencing (NGS) and CNVplex technology. The identified variants were assessed for evolutionary conservation, pathogenic potential, and their impact on protein structure. Thrombin generation was measured using the calibrated automated thrombogram (CAT) assay.</p><p><strong>Results: </strong>The PC:A and PC:Ag of proband 1 were decreased to 57% and 59.2%, and PC:A of proband 2 was decreased to 68%. The SERPINC1 (OMIM#:613118) and PROC (OMIM#:176860) gene analysis indicated that there were c.400+5G>A and c.883G>A in proband 1, c.811C>T and c.880C>T in proband 2, respectively. These mutation sites are highly conserved across homologous species. Bioinformatics analysis predicts their potential pathogenicity, suggesting that they may alter the three-dimensional structures of both AT and PC proteins, thereby compromising their functional integrity. Thrombin generation assays revealed that two AT mutation carriers exhibited varying degrees of elevated ETP. In the presence of sTM, two PC mutation carriers showed significantly impaired plasma anticoagulant function without a significant reduction in thrombin generation.</p><p><strong>Conclusion: </strong>In both pedigrees, we identified two distinct mutations in AT and PC. Dual mutations in SERPINC1 and PROC confer markedly increased VTE susceptibility.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 4","pages":"e70191"},"PeriodicalIF":1.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13140201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147521463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association Between Cerebellar Metabolic Markers and Activities of Daily Living in Patients With Spinocerebellar Ataxia Type 3.","authors":"Mei Ye, Xiao Ping Qiu, Shengnan Zhang, Ling Wang, Zhongming Gao, Mengyu Liu, Yaping Feng","doi":"10.1002/mgg3.70197","DOIUrl":"10.1002/mgg3.70197","url":null,"abstract":"<p><strong>Background: </strong>Spinocerebellar ataxia type 3 (SCA3) is a progressive neurodegenerative disorder that results in the impaired ability to perform activities of daily living (ADLs). However, there is a lack of objective neuroimaging indices to assess functional decline. In this study, we investigated the association between cerebellar metabolic rate as detected by magnetic resonance spectroscopy (MRS) and ADL performance in patients with SCA3.</p><p><strong>Methods: </strong>A total of 23 SCA3 patients underwent multivoxel MRS scans of the cerebellar cortex, dentate nucleus, and vermis and were analyzed for associations between the metabolic ratio and the ability to perform activities of daily living (ADL). Metabolic ratios were quantified and correlated with Barthel Index scores. The predictive value of metabolic ratio was assessed using multiple regression and least absolute shrinkage and selection operator (LASSO) analysis.</p><p><strong>Results: </strong>Our results showed that the NAA/Cr and Cho/Cr ratios in all three brain regions were significantly correlated with higher Barthel Index scores (r = 0.66), indicating a link between neuronal integrity, membrane metabolism, and functional independence. Regression analyses confirmed these associations, and the exploratory LASSO analysis suggested that the combined markers may have potential predictive value in patients' daily lives.</p><p><strong>Conclusion: </strong>Cerebellar NAA/Cr and Cho/Cr ratios may serve as candidate neuroimaging biomarkers of functional status in patients with SCA3. These preliminary results warrant validation in future studies using advanced MRS quantitative analysis.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 4","pages":"e70197"},"PeriodicalIF":1.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13080496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147691093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Compound Heterozygous Variants in the COG5 Gene Causing Fetal Hydrops and Skeletal Dysplasia.","authors":"Qi Yang, Wei He, Qiang Zhang, Sheng Yi, Xunzhao Zhou, Linlin Wang, Shang Yi, Zailong Qin, Jingsi Luo","doi":"10.1002/mgg3.70215","DOIUrl":"10.1002/mgg3.70215","url":null,"abstract":"<p><strong>Introduction: </strong>Congenital Disorders of Glycosylation (CDG) are a complex and highly heterogeneous group of rare metabolic disorders characterized by defects in enzymes and transporter proteins crucial for glycosylation pathways, including N-linked, O-linked, and glycolipid glycosylation. To date, over 160 distinct subtypes have been identified. CDG are characterized by significant clinical heterogeneity, which presents substantial challenges for diagnosis, especially in the prenatal setting. While prenatal ultrasound serves as a crucial tool for screening potential cases, the intricate nature of CDG often necessitates the use of advanced techniques such as whole-exome sequencing (WES) to obtain more precise molecular genetic evidence.</p><p><strong>Methods: </strong>To investigate the genetic causes of suspected CDG in a Chinese fetus, WES was performed. Subsequently, the detected variants and their origins were validated by Sanger sequencing and classified according to the guidelines of the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP).</p><p><strong>Results: </strong>A non-consanguineous couple had previously experienced fetal hydrops with skeletal dysplasia during midpregnancy. In their subsequent pregnancy, second-trimester ultrasonography again revealed fetal hydrops, a previously unreported complication. Fetal WES revealed two novel heterozygous variants in the COG5 gene (NM_006348.5), namely c.1972del(p.Val658Serfs*23) and c.2168_2168+4delinsCATAAAA. Sanger sequencing confirmed that the c.1972del(p.Val658Serfs*23) variant was paternally inherited, while the c.2168_2168+4delinsCATAAAA variant was maternal inherited. Both variants were classified as likely pathogenic according to the ACMG/AMP guidelines.</p><p><strong>Conclusions: </strong>This study further expands the phenotypic and mutational spectrum of the COG5 gene, enhancing our understanding of COG5-CDG. Clinically, intellectual disability, developmental delay, brain abnormalities, skeletal deformities, microcephaly, short stature, vision abnormalities, and hepatic lesions are crucial diagnostic criteria for COG5-CDG. Other variable phenotypes of COG5-CDG can provide supporting information for prenatal diagnosis. The combined application of prenatal ultrasound and WES enables a more comprehensive and precise diagnosis of COG5-CDG, which will facilitate the implementation of early intervention and treatment.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 4","pages":"e70215"},"PeriodicalIF":1.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13062644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147639295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Genetic Landscape of Euploid Miscarriages From Couples With Recurrent Pregnancy Loss Through Whole Exome Sequencing.","authors":"Fanjuan Kong, Zhaochu Yin, Haiyan Zhou, Zhiyu Liu, Wanqin Xie","doi":"10.1002/mgg3.70220","DOIUrl":"10.1002/mgg3.70220","url":null,"abstract":"<p><strong>Background: </strong>This study aimed to identify candidate genes for recurrent pregnancy loss (RPL).</p><p><strong>Methods: </strong>Trio-whole exome sequencing (WES) analysis was performed with blood samples and euploid miscarriage tissues from 55 couples.</p><p><strong>Results: </strong>Overall, 117 de novo protein-altering variants of 83 genes from 38 miscarriages were identified, with three alterations per embryo on average. A vast majority of the de novo variants were missense/indel and classified as variants of uncertain significance. The de novo variants preferentially hit the intolerant genes and impacted the functional pathways such as Pol II transcription, heart development, and p53 signaling. In search of recessive variants associated with embryo lethality, six autosomal and four X-chromosomal genes, which are functionally clustered into the pathways such as cilium assembly and regulation of cell morphogenesis, were prioritized for 12 family trios. Of the recessive variants, a large majority were missense and of uncertain significance. Notably, there were miscarriages having inherited biallelic variants and coincidental de novo variants. In perspective of maternal effect genes, homozygous or compound heterozygous missense variants of the MEI4 gene were identified.</p><p><strong>Conclusions: </strong>Our findings reveal a significant heterogeneity and complexity in exomic variants contributing to RPL.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 4","pages":"e70220"},"PeriodicalIF":1.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13096722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147729517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}