Molecular Genetics & Genomic Medicine最新文献

{"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":"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":"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":"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}

{"title":"Novel Variants in KMT2C Further Support a Neurodevelopmental Disorder Distinct From Kleefstra and Kabuki Syndromes.","authors":"Lucie Sedláčková, Dana Šafka Brožková, Markéta Havlovicová, Petra Laššuthová","doi":"10.1002/mgg3.70209","DOIUrl":"10.1002/mgg3.70209","url":null,"abstract":"<p><strong>Background: </strong>Heterozygous loss-of-function variants in the KMT2C gene were only recently recognized as a cause of neurodevelopmental disorder distinct from Kleefstra and Kabuki 1 syndromes. KMT2C-related neurodevelopmental disorder is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, seizures, craniofacial dysmorphism, and other comorbidities. Here we describe detailed phenotypes of three additional patients with novel variants in the KMT2C gene.</p><p><strong>Methods and results: </strong>Using exome sequencing, we found two heterozygous variants c.3212G>A, p.(Trp1071*) and c.13204_13205delinsA, p.(Cys4402Ilefs*11) leading to premature stop codon and one heterozygous missense variant c.6517C>T, p.(Pro2173Ser) in the KMT2C gene (NM_170606.3) in patients with unrecognized neurodevelopmental disorder. Our patients suffer from developmental delay, speech delay, autism spectrum disorder, cognitive impairment, seizures, and/or craniofacial dysmorphism.</p><p><strong>Conclusion: </strong>After detailed phenotype analysis and by comparison with previous reports, we found that our patients have very similar phenotypes as described before and thus further extend the list of KMT2C causal variants. Therefore, we believe that they fit into these previously described phenotypes of KMT2C-related Kleefstra syndrome 2 as well.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 4","pages":"e70209"},"PeriodicalIF":1.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13140550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581877","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 Exome Diagnostic Yield, Syndromic Landscape and Secondary Findings.","authors":"Kayleigh Avello, Shawn Gessay, Megan Nelson, Connie Schultz, Natalie Jacob","doi":"10.1002/mgg3.70207","DOIUrl":"10.1002/mgg3.70207","url":null,"abstract":"<p><strong>Objective: </strong>Exome sequencing (ES) has become increasingly more prevalent across maternal fetal medicine spaces when anomalies are visualized on ultrasound. As such, Prevention Genetics implemented secondary finding categories into their prenatal exome based on professional recommendations in June of 2021. This study aimed to determine the diagnostic yield and syndromic landscape of reported variants during that timeframe.</p><p><strong>Methods: </strong>Prenatal ES cases from June 2021 to June 2023 were retrospectively reviewed for secondary finding opt-ins, overall result outcomes, variant nomenclature, and inheritance/segregation patterns. From this data, quantitative and descriptive statistical methods were used to determine the frequency of positive primary and secondary results, including cases in which multiple molecular diagnoses were detected.</p><p><strong>Results: </strong>Of 520 fetal samples included in the cohort, 131 (25.2%) had a positive molecular result consistent with the clinical indication for exome. Within those 131 cases, 81 (61.8%) were caused by a de novo variant. From the total 520-sample cohort, 260 (50%) cases opted into at least one SF category. Among the 222 fetuses tested in which ACMG guideline-recommended genes were opted into, 14 (6.3%) were found to carry a reportable variant in genes associated with cardiovascular, metabolic, pediatric tumor-predisposition, or connective-tissue disorders. Four fetuses in the COD opt-in cohort were discovered to carry a deleterious variant in two separate SF genes, constituting comorbid pediatric molecular diagnoses. Unlike the primary reporting category, the majority (N = 25/30, 83.3%) of COD SF variants were inherited from a carrier parent.</p><p><strong>Conclusion: </strong>The aim of this study is to provide meaningful information that can aid in the exome consenting process as improvements in testing technologies and laboratory offerings evolve in response to developments in genetic understanding and professional guidelines. As such, it is crucial for healthcare teams to stay abreast of the increased scope of testing, potential test outcomes, and the phenotypic expansion of various genetic disorders.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 4","pages":"e70207"},"PeriodicalIF":1.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13057406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147633915","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":"Implementing a Tiered Genetic Testing Strategy for Muscular Dystrophies in Morocco: From Targeted Assays to Exome Sequencing.","authors":"Yasmina Rahmuni, Ilham Ratbi, Jaber Lyahyai, Imane Cherkaoui Jaouad, Ourayna Batta, Aziza Sbiti, Maryem Sahli, Omar Askander, Zineb Rchiad, Abdelaziz Sefiani","doi":"10.1002/mgg3.70192","DOIUrl":"10.1002/mgg3.70192","url":null,"abstract":"<p><strong>Introduction: </strong>Muscular dystrophies (MDs) are a heterogeneous group of inherited neuromuscular disorders. In Morocco, where consanguinity is common, recurrent variants have been reported; however, the overall molecular landscape remains underexplored.</p><p><strong>Methods: </strong>We analyzed 716 patients referred over 32 years for suspected limb-girdle muscular dystrophy (LGMD) or dystrophinopathy using a stepwise approach. Multiplex PCR (MPCR) for DMD deletions and targeted Sanger sequencing of the SGCG:c.525delT variant were performed as first-line tests. Unsolved patients underwent next-generation sequencing (NGS), either via a customized gene panel or whole-exome sequencing (WES).</p><p><strong>Results: </strong>Multiplex PCR for DMD deletions and targeted Sanger sequencing of the SGCG:c.525delT variant resolved nearly half of cases, demonstrating the efficiency of these cost-effective first-line tests. Unsolved patients underwent next-generation sequencing (NGS), via a customized gene panel or whole-exome sequencing (WES), though resource limitations prevented full coverage. Among tested cases, SGCA, CAPN3, and FKRP were the most frequently mutated genes after DMD and SGCG, with several novel or recurrent variants suggesting population-specific alleles.</p><p><strong>Conclusions: </strong>These results highlight the genetic heterogeneity of MDs in Morocco and the value of combining targeted and broad genomic approaches, while underscoring the need to extend NGS to fully characterize unresolved patients.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 3","pages":"e70192"},"PeriodicalIF":1.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12936390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147307810","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}