Molecular Genetics & Genomic Medicine最新文献

{"title":"A Novel De Novo MTM1 Insertion Frameshift Variant Causes X-Linked Myotubular Myopathy in a Chinese Female.","authors":"Lijun Chen, Yingxiao Bao, Gonglu Liu","doi":"10.1002/mgg3.70318","DOIUrl":"https://doi.org/10.1002/mgg3.70318","url":null,"abstract":"<p><strong>Background: </strong>MTM1-related X-linked myotubular myopathy (XLMTM) typically affects males; however, symptomatic female carriers may occur.</p><p><strong>Methods: </strong>We evaluated a 24-year-old woman with infantile hypotonia followed by slowly progressive, asymmetric proximal weakness with facial and ocular involvement. Clinical assessment, pulmonary function testing, electromyography, lower-limb muscle MRI, and muscle biopsy were performed. Next-generation sequencing and parental segregation analysis were conducted.</p><p><strong>Results: </strong>The patient developed progressive functional decline leading to wheelchair dependence. Investigations showed moderate-to-severe restrictive ventilatory impairment, a myopathic pattern on electromyography, and extensive fatty replacement on muscle MRI. Muscle biopsy demonstrated histopathological features consistent with centronuclear myopathy. Genetic testing identified a heterozygous MTM1 insertion, c.1266_1267insATGGTGATAAAAACCATTCA, predicted to cause a frameshift (p.Gly423MetfsTer48). The variant was absent in both parents, supporting a de novo event. To our knowledge, this MTM1 variant has not been previously reported.</p><p><strong>Conclusion: </strong>This case expands the MTM1 variant spectrum and highlights that de novo MTM1 frameshift variants can underlie clinically significant XLMTM manifestations in females, underscoring the value of genetic testing in symptomatic women with centronuclear myopathy features.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 10","pages":"e70318"},"PeriodicalIF":1.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112360","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":"Identification of Variants in Two Families With Congenital Cataract by Whole Exome Sequencing.","authors":"Yazhou Huang, Xinwei Leng, Jibo Zhang, Xingxin Fang, Ting He, Lihua Zhou, Zhenkai Wu, Yuankun Wang, Dan Peng","doi":"10.1002/mgg3.70313","DOIUrl":"10.1002/mgg3.70313","url":null,"abstract":"<p><strong>Background: </strong>Congenital cataract (CC) is an ophthalmic disorder diagnosed at birth or during early infancy, characterized by severe visual impairment and potential blindness. This study aimed to evaluate the pathogenicity of two variants: GJA8 c.201C>G (p.Asp67Glu) and CRYBB2 c.325A>T (p.Ile109Phe).</p><p><strong>Methods: </strong>The patient's lenses were examined using slit-lamp photography and B-ultrasound. Whole-exome sequencing (WES) and sanger sequencing were performed to identify the variants. Multiple sequence alignment was conducted using CLUSTALW to assess the evolutionary conservation of the affected residues. Structural modeling and conformational analyzes of wild-type (WT) and mutant-type (MT) proteins were conducted using AlphaFold2, PyMOL, and computational structural dynamics approaches, including root mean square fluctuation (RMSF) and normal mode analysis (NMA).</p><p><strong>Results: </strong>Two likely pathogenic missense variants were identified in two unrelated families: c.201C>G (p.Asp67Glu) in exon 2 of GJA8, which encodes Connexin 50 (Cx50) protein, was paternally inherited in family 1, whereas c.325A>T (p.Ile109Phe) in exon 4 of CRYBB2 occurred de novo in family 2. The c.201C>G (p.Asp67Glu) variant mapped to the first extracellular loop (EL1) of Cx50. Structural modeling revealed disruption of the Asp67-Arg185 ionic interaction (Cα-OD distance: 3.4 → 4.9 Å) alongside a novel hydrogen bond with Asn63. Reduced RMSF in the mutant indicated localized rigidification of EL1, potentially impairing channel gating and correlating with severe cataract in affected family members. The co-segregation of the variant with the affected phenotype within the family 1 was confirmed by sanger sequencing combined with phenotypic analysis. The c.325A>T variant (p.Ile109Phe) in CRYBB2 increased protein flexibility, and the bulky aromatic phenylalanine side chain perturbed the hydrophobic core of Greek key motif III, causing global dynamic instability. The CRYBB2 c.325A>T variant was further confirmed to be de novo by sanger sequencing in conjunction with phenotypic analysis in family 2. Furthermore, multiple sequence alignment demonstrated that both residues are highly evolutionarily conserved.</p><p><strong>Conclusions: </strong>This study expands the pathogenic spectrum of congenital cataract. Our findings provide novel insights into the molecular diagnosis of CC and have important implications for genetic counseling.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 10","pages":"e70313"},"PeriodicalIF":1.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112326","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 Heterozygous Variant in the GABBR2 Gene in a Girl With Clinical Classic Rett Syndrome.","authors":"Jenny Klintenstedt, Peter Baeck, Ingegerd Witt Engerström, Cecilia Gunnarsson","doi":"10.1002/mgg3.70303","DOIUrl":"10.1002/mgg3.70303","url":null,"abstract":"<p><strong>Background: </strong>Rett syndrome (RTT) is a neurodevelopmental disorder mainly affecting females and may start with seemingly normal early development but leads to developmental stagnation, regression, and characteristic neurological symptoms. While most cases involve MECP2 variants, other genes have been implicated in RTT and RTT-like phenotypes, but the underlying molecular mechanisms remain incompletely understood.</p><p><strong>Methods: </strong>We describe a girl fulfilling the clinical diagnostic criteria for classic RTT in whom standard genetic testing, including MECP2 and CDKL5, was normal. Trio-based whole-exome sequencing was used to identify an alternative genetic cause that was confirmed using Sanger sequencing.</p><p><strong>Results: </strong>A heterozygous de novo variant in GABBR2 (NM_005458.7:c.1699G>A; p.Ala567Thr) was identified as the only clinically relevant genetic finding. The patient fulfilled the clinical diagnostic criteria for classic RTT and exhibited developmental stagnation, progressive impairment of purposeful hand use, characteristic stereotypic movements, autonomic dysfunction, and behavioral disturbances.</p><p><strong>Conclusion: </strong>This patient expands the phenotypic spectrum associated with GABBR2 variants and, together with previously reported cases, provides further evidence that GABBR2-related disease may present with a clinical RTT phenotype. These findings support a role for GABBR2-mediated GABAergic signaling in the pathophysiology of RTT and highlight the importance of considering GABBR2 in the genetic evaluation of MECP2-negative patients with a clinical RTT phenotype.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 10","pages":"e70303"},"PeriodicalIF":1.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069991","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":"The Paradox of Progress: Genetic Counselling in a South African Context and the Challenges of Workforce Retention.","authors":"Samantha Schnell, Katryn Fourie, Elzette Gilfillan, Bianca Rossouw, Barry Shingwenyana, Jamey Thom, Monica Araujo","doi":"10.1002/mgg3.70310","DOIUrl":"10.1002/mgg3.70310","url":null,"abstract":"<p><p>This invited commentary explores the paradox of progress in genetic counselling in South Africa, where established training programmes and professional recognition have not yet translated into sustainable clinical genetic services. Drawing on workforce data and insights into training, employment and service delivery, the authors highlight how limited funded public-sector posts, geographic concentration of services and loss of professionals from patient-facing roles constrain equitable access to genetic counselling. The commentary aims to support coordinated workforce planning and investment to ensure that the expansion of genomic medicine is accompanied by accessible, sustainable and equitable genetic counselling services.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 10","pages":"e70310"},"PeriodicalIF":1.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081436","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 Novel Homozygous Variant Associated With Distinct Clinical Phenotypes of SDR9C7 Nonsyndromic Epidermal Differentiation Disorder in Two Affected Patients From a Consanguineous Saudi Family.","authors":"Faisal Almalki, Zaker Khoj, Essa Alharbi, Osama Alsharif","doi":"10.1002/mgg3.70322","DOIUrl":"10.1002/mgg3.70322","url":null,"abstract":"<p><strong>Background: </strong>Nonsyndromic Epidermal Differentiation Disorders (nEDD) are a group of heterogeneous disorders characterized by scaling and erythema. Pathogenic variants in SDR9C7 cause SDR9C7-nEDD. We report two affected siblings from a consanguineous Saudi family presenting with distinct clinical phenotypes. The older affected brother exhibited generalized xerosis with both white and brown scaling, neck hyperpigmentation, and a velvety texture on the posterior neck. The younger sister showed diffuse xerosis with fine white scaling and marked palmoplantar hyperlinearity.</p><p><strong>Methods: </strong>A family with two siblings suspected of a rare genetic disease was recruited. Given the phenotypic variability, whole-exome sequencing (WES) was carried out for the proband brother to identify the genetic cause. Sanger sequencing was used to confirm the finding in the proband and to examine segregation analysis for the family members. In silico prediction tools were also used to assess the variant's pathogenicity.</p><p><strong>Results: </strong>WES identified a novel homozygous SDR9C7 variant (NM_148897.3:c.154G>A; p.Val52Met). The affected sister was also homozygous for the variant. The variant was rare in global population databases, absent from the local database, and showed complete segregation within the family. Multiple prediction tools classified the variant as pathogenic and deleterious.</p><p><strong>Conclusion: </strong>This study expands the clinical spectrum of SDR9C7-nEDD, demonstrating its phenotypic variability even with the same novel variant. These findings highlight the contribution of additional modifying factors and emphasize the essential role of WES in diagnosing genetically heterogeneous skin disorders when genotype-phenotype correlation is uncertain.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 10","pages":"e70322"},"PeriodicalIF":1.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165714","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 and Postnatal Follow-Up of 19 Fetuses With 16p13.11 Microduplication in a Cohort of 12,038 Pregnancies From South Zhejiang.","authors":"Xiaoxiao Lv, Shufei Li, Lili Zhou, Ruipu Wang, Yuan Yu, Chenyang Xu, Xueqin Xu, Xiaohua Tang, Huanzheng Li","doi":"10.1002/mgg3.70324","DOIUrl":"10.1002/mgg3.70324","url":null,"abstract":"<p><strong>Background: </strong>Prenatal interpretation of 16p13.11 microduplication remains difficult in daily practice, mainly because the same duplication may be associated with very different clinical outcomes. In this study, we reviewed fetuses diagnosed with 16p13.11 microduplication at our center and summarized their prenatal findings, pregnancy outcomes, and postnatal development to provide data that may be useful in prenatal counseling.</p><p><strong>Methods: </strong>We retrospectively reviewed 12,038 pregnant women who underwent amniocentesis at Wenzhou Central Hospital between 2014 and 2025. Chromosomal microarray analysis was performed in all cases. For fetuses carrying 16p13.11 microduplication, we reviewed the indication for amniocentesis, ultrasound findings, pregnancy outcome, and available postnatal follow-up information.</p><p><strong>Results: </strong>Chromosomal microarray analysis (CMA) identified 16p13.11 microduplication in 19 fetuses, with duplication sizes ranging from 0.80 to 1.60 Mb. The main indications for prenatal diagnosis were advanced maternal age (n = 7), adverse pregnancy history (n = 5), ultrasound abnormalities (n = 4), and high-risk serum screening results (n = 3). Three pregnancies were terminated. Sixteen infants were live-born, of whom two were lost to follow-up. Among the remaining 14 children, the follow-up period ranged from 10 months to 10 years. One infant was hospitalized at birth for a ventricular septal defect, and one child showed growth and developmental delay. Five children showed better growth and development than their peers, whereas seven had no apparent abnormalities during follow-up.</p><p><strong>Conclusion: </strong>The follow-up results in our cohort are consistent with the incomplete penetrance and variable outcomes reported for 16p13.11 microduplication. In this cohort, most live-born children showed mild or no clinical manifestations. In prenatal counseling, this CNV should be discussed together with fetal imaging results, inheritance pattern, family history, and available follow-up data rather than interpreted as an isolated finding.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 10","pages":"e70324"},"PeriodicalIF":1.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149195385","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":"Clinical Epigenomics in Rare Diseases: Interpreting DNA Methylation Episignatures.","authors":"Himanshu Goel, Shuxiang Goh, Luke Stuart","doi":"10.1002/mgg3.70319","DOIUrl":"https://doi.org/10.1002/mgg3.70319","url":null,"abstract":"<p><strong>Background: </strong>Epigenomic testing complements sequence-based analysis by detecting downstream changes in epigenomic state associated with genetic variation. Genome-wide DNA methylation episignatures are reproducible molecular phenotypes that can serve as biomarkers of specific Mendelian disorders, particularly those involving chromatin regulators, DNA methylation machinery, and transcriptional regulatory pathways.</p><p><strong>Methods: </strong>We reviewed the biological basis, laboratory methodology, analytical approaches and clinical applications of DNA methylation episignature testing, with emphasis on neurodevelopmental disorders and rare diseases. We also considered current computational tools, limitations of clinical interpretation and emerging epigenomic and epitranscriptomic approaches.</p><p><strong>Results: </strong>DNA methylation episignature testing is now used clinically to support molecular diagnosis, assist interpretation of variants of uncertain significance and distinguish overlapping neurodevelopmental and chromatin-related disorders. Interpretation integrates methylation-array data, statistical and machine-learning classification, phenotype, genotype and assay-specific validation. Important limitations include tissue specificity, mosaicism, developmental effects, incomplete disorder coverage and dependence on reference datasets. Emerging approaches include tissue-agnostic classifiers, long-read methylation profiling, additional epigenomic signatures and multi-omic integration.</p><p><strong>Conclusion: </strong>DNA methylation episignatures provide a clinically useful functional layer of evidence by detecting downstream epigenomic consequences of genomic variation. They should be interpreted as an adjunct to sequence-based diagnosis and clinical assessment rather than as a replacement for either. Continued expansion of reference datasets and integration with other functional genomic approaches should broaden their diagnostic utility.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 10","pages":"e70319"},"PeriodicalIF":1.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112375","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":"Clinical Practice of Single-Molecule Real-Time Sequencing in the Diagnosis of Spinal Muscular Atrophy.","authors":"Hua Wei, Ya-Wen Zheng, Ning-Ke Zhang, Tie-Li Gao, Jie-Xiang Zheng, Tian-You Li, Shu-Rong Hong","doi":"10.1002/mgg3.70314","DOIUrl":"https://doi.org/10.1002/mgg3.70314","url":null,"abstract":"<p><strong>Objectives: </strong>To investigate the distribution proportions of the SMN1 gene in spinal muscular atrophy (SMA) using single-molecule real-time sequencing (SMRT), thereby providing supplementary evidence for SMA genotyping.</p><p><strong>Methods: </strong>A retrospective analysis was conducted on 771 subjects who underwent both real-time quantitative PCR and SMRT sequencing tests, followed by statistical analysis.</p><p><strong>Results: </strong>Among the 771 enrolled individuals, the male-to-female ratio was 2:3, with a median age of 31 years. The detection results obtained from real-time quantitative PCR and SMRT sequencing were consistent. Using SMRT sequencing, the proportions of samples with SMN1 copy numbers 1, 2, 3, and 4 were 2.33% (18/771), 91.18% (703/771), 6.36% (49/771), and 0.13% (1/771), respectively. For SMN2, the proportions with 0, 1, 2, 3, and 4 copies were 6.10% (47/771), 33.07% (255/771), 57.59% (444/771), 2.98% (23/771), and 0.26% (2/771), respectively. The carrier frequency of SMN1 deletions was 2.33% (18/771). Additionally, we analyzed four SMA patients using SMRT sequencing. The results demonstrate that this technology accurately detects SMN1 and SMN2 copy numbers, providing essential information for patient diagnosis and clinical management.</p><p><strong>Conclusion: </strong>With results fully concordant with qPCR, SMRT sequencing enables accurate detection of SMN1 and SMN2 copy numbers, providing robust technical support for population-based prevention, genetic counseling, and clinical management of SMA.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 10","pages":"e70314"},"PeriodicalIF":1.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112407","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":"Building Sustainable Patient Involvement in Rare Condition Research.","authors":"Dani Bancroft, Natasha Ratcliffe, Amy Hunter","doi":"10.1002/mgg3.70300","DOIUrl":"10.1002/mgg3.70300","url":null,"abstract":"<p><p>An overview of the structural and cultural barriers to patient and public involvement and engagement (PPIE) in academic research, which are amplified in rare condition research, with recommendations on how to address them and reflections from patient, researcher and funder perspectives.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 10","pages":"e70300"},"PeriodicalIF":1.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13639521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112340","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":"The First Case of Digenic MODY Diabetes Involving Compound Heterozygosity of Three Variants in the PDX1 and HNF1B Genes.","authors":"Magdalena Płonka-Stępień, Magdalena Szopa, Magdalena Zawada, Maciej T Malecki","doi":"10.1002/mgg3.70308","DOIUrl":"10.1002/mgg3.70308","url":null,"abstract":"<p><strong>Objectives: </strong>We report a rare case of digenic MODY. In 2016, at age 15, the patient was diagnosed with type 1 diabetes and began insulin therapy. After discrepancies in her glycaemic control were observed, an extensive differential diagnosis was conducted. In 2024, genetic testing confirmed monogenic diabetes, allowing for tailored treatment of the patient.</p><p><strong>Methods and results: </strong>The initial diagnosis was type 1 diabetes, later revised to MODY after Sanger screening. Genetic testing detected c.293C>T, p.Ala98Val in the HNF1A gene, which was initially misinterpreted as a variant causing Maturity Onset Diabetes of the Young (MODY), an autosomal dominant monogenic diabetes. Eventually, next-generation sequencing (NGS) revealed three heterozygous variants in the MODY genes: HNF1B and PDX1. The HNF1B and PDX1 genes are transcription factors responsible for pancreas development and insulin gene transcription. Two variants located very close to each other in the PDX1 gene were identified: c.694G>A, p.Gly232Ser and c.697G>T, p.Glu233Ter. The first causes an amino acid change, while the latter leads to an early termination codon. The third variant, c.827_828insT, p.Gly277ArgfsTer17, was found in the HNF1B gene, resulting in a premature STOP codon and a truncated nonsense protein product. This is the first report of a patient with a double MODY variant resulting in early protein termination. Overall, the available evidence suggests that all variants may be pathogenic. The variants' severity and likely digenic nature matched the proband's diabetes presentation, which didn't respond to oral agents and required insulin. Neither parent nor brother, each with a detected variant in a single gene, has developed diabetes. However, renal cysts were discovered in the mother and brother, and the father was diagnosed with prediabetes.</p><p><strong>Conclusions: </strong>This case highlights the severe presentation of likely digenic MODY, similar to type 1 diabetes. As NGS use increases, more patients like these are expected to be identified.</p>","PeriodicalId":18852,"journal":{"name":"Molecular Genetics & Genomic Medicine","volume":"14 10","pages":"e70308"},"PeriodicalIF":1.6,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13670014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183195","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}