Human GeneticsPub Date : 2026-08-12DOI: 10.1007/s00439-026-02863-0
Dawid Skoczek, Jerzy Hohendorff, Maciej T Malecki, Alicia Roig-Merino, Rasmus O Bak, Neli Kachamakova-Trojanowska
{"title":"CRISPR/Cas9-based repair of a heterozygous HNF1A mutation in patient-derived hiPSCs.","authors":"Dawid Skoczek, Jerzy Hohendorff, Maciej T Malecki, Alicia Roig-Merino, Rasmus O Bak, Neli Kachamakova-Trojanowska","doi":"10.1007/s00439-026-02863-0","DOIUrl":"10.1007/s00439-026-02863-0","url":null,"abstract":"<p><p>Human induced pluripotent stem cells (hiPSCs) represent a powerful platform for disease modeling, especially in monogenic diseases as they preserve the donor's genetic background while enabling directed differentiation into disease-relevant cell types. This makes them highly suitable for studying disease mechanisms in a patient-specific and physiologically relevant context. Although CRISPR/Cas9 is widely applied for genome editing, precise correction of pathogenic variants in hiPSCs remains challenging due to the lack of standardized CRISPR component selection and experimental design. Here, we describe an optimized CRISPR-based strategy for correcting a heterozygous HNF1A frameshift mutation (c.235_236insG; p.Glu79Glyfs*16) in HNF1A-MODY patient-derived hiPSCs. Using electroporation, we efficiently delivered CRISPR components, including a ribonucleoprotein complex of Cas9 and single-guide RNA, along with a single-stranded oligodeoxynucleotide repair template. Corrected hiPSC lines were validated for pluripotency, absence of exogenous reprogramming factors, and off-target effects. Additionally, we discuss key technical challenges encountered during the editing process and provide practical recommendations that may improve the generation of mutation-corrected hiPSC lines. These guidelines could serve as a useful reference for researchers employing CRISPR-based strategies for generation of reliable disease modelling tools.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13469492/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148727774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human GeneticsPub Date : 2026-08-10DOI: 10.1007/s00439-026-02862-1
S Rehan Ahmad, Md Zeyaullah, Mohammad Suhail Khan, Abdelrhman A G Altijani, Ali Mohieldin, Khursheed Muzammil
{"title":"TTC14 dysfunction contributing to microcephaly and lissencephaly spectrum features through protein mislocalization and impaired RNA processing.","authors":"S Rehan Ahmad, Md Zeyaullah, Mohammad Suhail Khan, Abdelrhman A G Altijani, Ali Mohieldin, Khursheed Muzammil","doi":"10.1007/s00439-026-02862-1","DOIUrl":"10.1007/s00439-026-02862-1","url":null,"abstract":"<p><p>Congenital microcephaly and lissencephaly spectrum disorders are characterized by disrupted neuronal proliferation and migration, often driven by underlying genetic variants. Here, we identified and characterized of a novel gene (Tetratricopeptide Repeat Domain 14, TTC14) and its homozygous missense variant (c.89 A > G; p.His30Arg (p.H30R)) in a female proband presenting with microcephaly, epileptic spasms, global developmental delay, and neuroimaging features of simplified gyral pattern, focal pachygyria, and corpus callosum thinning. Trio-based whole exome sequencing revealed this variant to be rare and autosomal recessively inherited from both asymptomatic parents. Structural modeling demonstrated that H30 lies at the start of an α-helical region and is evolutionarily conserved. The p.His30Arg substitution caused significant steric clashes and disrupted local folding. Interaction network analysis and molecular dynamics simulations confirmed structural destabilization, increased conformational flexibility, and loss of stability in the mutant protein. While mRNA and protein levels remained unaltered, the TTC14-p.His30Arg protein mislocalized from the nucleus to the cytosol and formed aggregates. Functionally, proband fibroblasts exhibited increased cell death and altered cell cycle progression. TTC14 interacts with RNA splicing and mRNA processing proteins, and gene ontology analysis implicated it in RNA binding and spliceosomal complex assembly in key brain regions including the cerebral cortex, hippocampus, and white matter. These findings collectively suggest that TTC14 plays a crucial role in RNA metabolism during neurodevelopment, and that the p.His30Arg variant impairs its function, possibly leading to a neurodevelopmental disorder within the lissencephaly spectrum. This study identifies TTC14 as a likely pathogenic candidate gene in cortical malformation syndromes.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148701013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human GeneticsPub Date : 2026-08-08DOI: 10.1007/s00439-026-02865-y
Anna Kuchina, Darya Sherstyukova, Artem Borovikov, Margarita Soloshenko, Nikolay Zernov, Dmitrii Subbotin, Elena Dadali, Inna Sharkova, Galina Rudenskaya, Sergey Kutsev, Mikhail Skoblov, Aysylu Murtazina
{"title":"The Russian FSHD registry: a first look at the cohort.","authors":"Anna Kuchina, Darya Sherstyukova, Artem Borovikov, Margarita Soloshenko, Nikolay Zernov, Dmitrii Subbotin, Elena Dadali, Inna Sharkova, Galina Rudenskaya, Sergey Kutsev, Mikhail Skoblov, Aysylu Murtazina","doi":"10.1007/s00439-026-02865-y","DOIUrl":"10.1007/s00439-026-02865-y","url":null,"abstract":"<p><p>Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary neuromuscular disorder. The Russian FSHD Patient Registry was established in 2019 following the development of a PCR-based method for genetic confirmation of the diagnosis. The registry included 491 participants, of whom 51% were male. The mean age was 38.2 years (range 0-97 years), indicating a younger cohort compared to international data. Genetic confirmation of FSHD type 1 or type 2 was achieved for 76% of participants (n = 373). The remaining participants had not yet undergone genetic testing and were included based on clinical and anamnestic data. D4Z4 repeat units (RUs) ranged from 1 to 10, with equally predominant 3, 5, and 6 RUs, making our cohort more similar to Asian cohorts published earlier. Clinical assessment forms and patient-reported questionnaires were analyzed for 279 and 134 patients with genetically confirmed diagnoses, respectively. A moderate inverse correlation was found between RU number and clinical severity scales. Shoulder girdle weakness was the most common onset manifestation (45.2%), followed by facial weakness (34.4%). A delta-adjusted cluster analysis (n = 187) identified three distinct disease progression trajectories based on the temporal pattern of muscle involvement. The smallest cluster comprised patients with very slow progression, in whom facial muscle involvement occurred at late stages. The Russian FSHD registry provides a comprehensive characterization of a large national cohort, revealing a D4Z4 repeat unit distribution similar to Asian countries and a younger demographic profile than reported in international data. Cluster analysis identified three distinct disease progression trajectories, offering a valuable framework for improved patient stratification.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13582244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148697516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human GeneticsPub Date : 2026-08-07DOI: 10.1007/s00439-026-02859-w
Lin Yan, Yang Qiu, Zhiwen Mo, Mingli Li, Xueran Huang, Yongfen Gao, Boteng Yan, Qiantu Hu, Haiying Zhang, Zengnan Mo, Rui Lin
{"title":"Identification of novel loci regulating circulating melatonin and its causal relationship with hypertension.","authors":"Lin Yan, Yang Qiu, Zhiwen Mo, Mingli Li, Xueran Huang, Yongfen Gao, Boteng Yan, Qiantu Hu, Haiying Zhang, Zengnan Mo, Rui Lin","doi":"10.1007/s00439-026-02859-w","DOIUrl":"10.1007/s00439-026-02859-w","url":null,"abstract":"<p><p>Melatonin exerts pleiotropic physiological functions and diverse disease associations, but its genetic architecture remains largely uncharacterized. Using low-coverage whole-genome sequencing (lcWGS) in 3,605 Han Chinese adults, we identified four independent loci (P < 1 × 10⁻⁷) associated with circulating melatonin (pg/mL)-located within or near LINC01807, PTPRD, EDIL3/NBPF22P, and LMO1/STK33. Conditional analyses indicated that the STAARpipeline single-variant and sliding-window signals were largely driven by these genome-wide association study (GWAS) lead variants, whereas a gene-centric noncoding aggregation signal in the ZSWIM9 promoter region remained independent. These genes showed tissue-specific expression in neural, vascular, and adrenal tissues (GTEx ). The heritability of serum melatonin was estimated at 21.72% (SE = 11.2%, P = 0.029) using GCTA-GREML, with the four independent significant loci collectively explaining 3.40%. Genetic risk score and one-sample Mendelian randomization analyses suggested a protective effect of higher serum melatonin levels on hypertension risk (OR = 0.45, P = 0.015), as well as on systolic (β = - 4.14, P = 0.014) and diastolic blood pressure (β = - 3.10, P = 0.007). Summary-data-based Mendelian Randomization and colocalization analyses suggested that LMO1 and PTPRD may influence hypertension through tissue-specific expression and DNA methylation. These findings reveal novel genetic contributors to melatonin regulation and establish their putative causal relationship with hypertension.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human GeneticsPub Date : 2026-08-07DOI: 10.1007/s00439-026-02861-2
Wendi Dang, Xiaoming Wu, Jing Zhao, Song Lin, Xirui Wang, Xiaomin Yang, Jin Sun, Tielin Yang, Chuan-Chao Wang, Hu-Qin Zhang
{"title":"Genetic ancestry of the Mulam ethnic group: admixture from ancient Yellow River, southern native, and Austronesian populations.","authors":"Wendi Dang, Xiaoming Wu, Jing Zhao, Song Lin, Xirui Wang, Xiaomin Yang, Jin Sun, Tielin Yang, Chuan-Chao Wang, Hu-Qin Zhang","doi":"10.1007/s00439-026-02861-2","DOIUrl":"10.1007/s00439-026-02861-2","url":null,"abstract":"<p><p>The Mulam people, an ethnic minority group native to southern China, primarily inhabit the Guangxi region. Systematic whole-genome studies on the Mulam population remain limited. In this study, we analyzed genome-wide genotyping data comprising over 700,000 single-nucleotide polymorphisms (SNPs) derived from 107 saliva samples of Mulam individuals in Guangxi, to investigate their genetic origins and relationships with other southern East Asian populations. Based on ancestry inference and population genetic analysis, we identified three major ancestral components in the Mulam genome: ancient Yellow River farmers, indigenous southern East Asian populations, and Austronesian-related groups. These results support historical records indicating that the proto-Mulam were formed through the integration of ancient Yellow River migrants with indigenous southern East Asian communities. Furthermore, shared southern East Asian ancestry reveals a genetic link between the Mulam and Taiwanese indigenous peoples, likely resulting from prehistoric southward population movements. This study emphasizes the complex genetic makeup of the Mulam people and offers new perspectives on population history and dynamics in East Asia.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"α-Thalassemia in Oraons-indigenous tribal population from Jharkhand, India: insights to common deletions.","authors":"Shaikh Roshan, Nadkarni Anita, Kerketta Lily, Ghosh Kanjaksha, Gorakshakar Ajit","doi":"10.1007/s00439-026-02857-y","DOIUrl":"10.1007/s00439-026-02857-y","url":null,"abstract":"<p><p>Alpha thalassemia is a common inherited blood disorder worldwide, with varying prevalence among different populations. This study investigates the prevalence and spectrum of alpha thalassemia deletions in the Oraon tribe, one of the largest indigenous populations in central-eastern India. Two hundred and twenty-seven Oraon individuals were genotyped using multiplex PCR for seven common alpha-globin gene deletions and triplications. Hematological profiling was performed on automated cell counter. A high frequency of alpha globin gene deletions was observed in the Oraon population, with the -α<sup>3.7</sup> deletion being predominant. The homozygous -α<sup>3.7</sup>/-α<sup>3.7</sup> genotype was found in 32.6% of Oraons, significantly higher than in other tribes. Compound heterozygosity (-α<sup>3.7</sup>/-α<sup>4.2</sup>) was also common (15.4%). Hematological analysis revealed significant differences between genotypes, with -α<sup>4.2</sup>/-α<sup>4.2</sup> individuals displaying lower hemoglobin levels. One individual with HbH disease (--<sup>SA</sup>/-α³·⁷) was identified with characteristic hematological features. The high prevalence of alpha thalassemia deletions in Oraons may reflect historical malaria selective pressure. These findings have important implications for public health strategies and clinical management of hemoglobinopathies in this community. The study underscores the genetic complexity of alpha thalassemia in indigenous populations and highlights the need for comprehensive screening approaches. Further research including non-deletional mutations is needed to provide a complete spectrum of α-thalassemia in this population.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148619785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human GeneticsPub Date : 2026-07-20DOI: 10.1007/s00439-026-02846-1
Haley McConkey, Liselot van der Laan, Sourav Ghosh, Lotte Kleinendorst, Michael A Levy, Jessica Rzasa, Johanna M van Hagen, Quinten Waisfisz, Heidi L Schulz, Corina Heller, Kerstin Huhn, Carolin D Obermaier, Konrad Platzer, Rami Abou Jamra, Nikos Marinakis, Danai Veltra, Konstantina Kosma, Christalena Sofocleous, Peter Henneman, Bekim Sadikovic, Mieke M van Haelst
{"title":"Discovery of a DNA methylation episignature for Weiss-Kruszka syndrome.","authors":"Haley McConkey, Liselot van der Laan, Sourav Ghosh, Lotte Kleinendorst, Michael A Levy, Jessica Rzasa, Johanna M van Hagen, Quinten Waisfisz, Heidi L Schulz, Corina Heller, Kerstin Huhn, Carolin D Obermaier, Konrad Platzer, Rami Abou Jamra, Nikos Marinakis, Danai Veltra, Konstantina Kosma, Christalena Sofocleous, Peter Henneman, Bekim Sadikovic, Mieke M van Haelst","doi":"10.1007/s00439-026-02846-1","DOIUrl":"10.1007/s00439-026-02846-1","url":null,"abstract":"<p><p>Weiss-Kruszka syndrome (WSKA; OMIM 618619) is a rare autosomal dominant neurodevelopmental disorder caused by haploinsufficiency of ZNF462, a zinc-finger transcription factor involved in chromatin regulation and early embryonic development. WSKA is characterized by developmental delay, hypotonia, craniofacial dysmorphic features (around 8) and variable congenital anomalies. Genome-wide DNAm profiling was performed on peripheral blood DNA from 9 WSKA cases with (likely) pathogenic ZNF462 variants and matched controls to look for differential methylation. Analysis using the EpiSign™ pipeline identified a robust DNAm pattern, or episignature, specific to WSKA syndrome. Supervised machine-learning classification demonstrated high sensitivity and specificity, with reproducibility confirmed by leave-one-out cross-validation, as well as correctly classifying a validation case with a pathogenic ZNF462 variant. Comparative analysis revealed partial overlap of genome-wide DNA methylation changes between the WSKA episignature and other neurodevelopmental disorders involving chromatin regulators. Functional annotation of differentially methylated probes and regions demonstrated enrichment for pathways related to neurodevelopment, neuron function and cell adhesion. These findings define and validate a distinct DNAm episignature for WSKA, providing a valuable diagnostic biomarker to support variant classification and offering insight into the epigenomic consequences of ZNF462 haploinsufficiency.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13385256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human GeneticsPub Date : 2026-07-16DOI: 10.1007/s00439-026-02858-x
Jin-Young Koh, Corentin Affortit, Kazuaki Homma, Satoe Takahashi, Jonathan M Nizar, Paul T Ranum, Rose Gogal, Eun-Mi Kim, Minkyung Kang, Diana L Kolbe, Fengxiao Bu, Cody West, Donghong Wang, Amanda Odell, Amy Weaver, Jori Hendon, William D Walls, Michael J Schnieders, Richard J H Smith
{"title":"Identification of a novel isoform of Slc26a4 by single-cell RNA-sequencing of pendrin-expressing cells in the cochlea.","authors":"Jin-Young Koh, Corentin Affortit, Kazuaki Homma, Satoe Takahashi, Jonathan M Nizar, Paul T Ranum, Rose Gogal, Eun-Mi Kim, Minkyung Kang, Diana L Kolbe, Fengxiao Bu, Cody West, Donghong Wang, Amanda Odell, Amy Weaver, Jori Hendon, William D Walls, Michael J Schnieders, Richard J H Smith","doi":"10.1007/s00439-026-02858-x","DOIUrl":"10.1007/s00439-026-02858-x","url":null,"abstract":"<p><p>Pathogenic variation of SLC26A4 gene causes both Pendred syndrome (PDS) and non-syndromic enlarged vestibular aqueduct (NSEVA/DFNB4), two autosomal recessive disorders. The former accounts for approximately 6% of human genetic hearing loss, making it the second most common form of syndromic deafness after Usher syndrome, while the latter is the most common radiological malformation associated with childhood sensorineural hearing loss (SNHL). Here, we used short- and long-read single-cell RNA sequencing (scRNA-seq) of pendrin-expressing cells in the murine cochlea to identify a novel short isoform of Slc26a4. We demonstrate that the short Slc26a4 isoform is expressed in both the inner ear and kidney and investigate its interactions and functions. We also characterize the genotype-phenotype association for SLC26A4-related hearing loss in the context of these two isoforms. These results provide a new reference for molecular profiling of pendrin and offer novel insights into cell-type-specific splicing events and SLC26A4-related hearing loss.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13375699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148470412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human GeneticsPub Date : 2026-07-08DOI: 10.1007/s00439-026-02843-4
Simona Cardaropoli, Lisa Pavinato, Slavica Trajkova, Diana Carli, Verdiana Pullano, Flavia Palermo, Alessandro Mussa, Elisa Biamino, Vincenzo Antona, Andrea Zonta, Paola Dimartino, Mariia Zadorozhna, Alessandro Bruselles, Roberto Keller, Barbara Pasini, Enrico Grosso, Giorgia Mandrile, Joseph D Buxbaum, Silvia De Rubeis, Tommaso Pippucci, Marco Tartaglia, Elisa Giorgio, Alfredo Brusco, Giovanni Battista Ferrero
{"title":"The NeuroWES project: lessons learned from comprehensive phenotyping and genetic analysis of neurodevelopmental disorders over a decade.","authors":"Simona Cardaropoli, Lisa Pavinato, Slavica Trajkova, Diana Carli, Verdiana Pullano, Flavia Palermo, Alessandro Mussa, Elisa Biamino, Vincenzo Antona, Andrea Zonta, Paola Dimartino, Mariia Zadorozhna, Alessandro Bruselles, Roberto Keller, Barbara Pasini, Enrico Grosso, Giorgia Mandrile, Joseph D Buxbaum, Silvia De Rubeis, Tommaso Pippucci, Marco Tartaglia, Elisa Giorgio, Alfredo Brusco, Giovanni Battista Ferrero","doi":"10.1007/s00439-026-02843-4","DOIUrl":"10.1007/s00439-026-02843-4","url":null,"abstract":"<p><p>Exome sequencing (ES) has become a primary tool for diagnosing neurodevelopmental disorders (NDDs), yet the interpretation of genetic variants in large, heterogeneous cohorts presents significant challenges that automated pipelines often fail to resolve. This study showcases the complexities and novel findings derived from a decade-long analysis of 419 Italian NDD patient-parent trios. While ES established a molecular diagnosis in 36.5% of cases (53.8% in syndromic presentations), our investigation moves beyond diagnostic yield to highlight the critical value of manual curation integrated with deep phenotyping. We demonstrate how this rigorous approach uncovers complex disease mechanisms, revealing that variants initially misclassified as missense or stop-gain are, in fact, pathogenic splicing defects confirmed by functional analysis. Furthermore, we resolve the paradox of pathogenic truncating PPM1D variants in control databases by demonstrating their somatic mosaic nature, a crucial insight for population data interpretation. Our work also refines gene-disease correlations by challenging the established role of MID2 in NDDs, providing further evidence for DSCAM as a high-confidence risk gene, and expanding the known phenotypic spectrum of disorders, such as a novel GNAI2-related syndrome lacking expected immune dysfunction. This study underscores that navigating the complexities of large NDD cohorts requires a detailed, expert-driven approach to not only enhance diagnostic yield but also to advance our fundamental understanding of rare disease genetics.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13346230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148411551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Human GeneticsPub Date : 2026-07-08DOI: 10.1007/s00439-026-02849-y
Yasas D Kolambage, Claudia Gonzaga-Jauregui, Guillermo Lay-Son, Rupesh Mishra, Njabulo Christian Mabaso, Sok-Kun Tae, Kristin A Maloney, Carolina I Galaz-Montoya, Dineshani Hettiarachchi, Bronwyn Dillon, Nilam Thakur, Ludivine de Menten, Cecilia Mellado, Carol L Greene, Toni I Pollin, Amanda Krause, Meow-Keong Thong, Alan R Shuldiner, Vajira H W Dissanayake
{"title":"Implementation of exome sequencing for rare undiagnosed diseases in LMICs: the G2MC rare diseases exome sequencing pilot project.","authors":"Yasas D Kolambage, Claudia Gonzaga-Jauregui, Guillermo Lay-Son, Rupesh Mishra, Njabulo Christian Mabaso, Sok-Kun Tae, Kristin A Maloney, Carolina I Galaz-Montoya, Dineshani Hettiarachchi, Bronwyn Dillon, Nilam Thakur, Ludivine de Menten, Cecilia Mellado, Carol L Greene, Toni I Pollin, Amanda Krause, Meow-Keong Thong, Alan R Shuldiner, Vajira H W Dissanayake","doi":"10.1007/s00439-026-02849-y","DOIUrl":"10.1007/s00439-026-02849-y","url":null,"abstract":"<p><p>Rare undiagnosed diseases impose a substantial burden on patients, families, and health systems. Collectively they affect an estimated 300-350 million people worldwide. Of these, approximately 250 million live in low- and middle-income countries (LMICs). Many rare diseases have a genetic basis and can be diagnosed using molecular testing. However, patients in LMICs often lack access to advanced diagnostics and specialist care, leading to prolonged diagnostic odysseys and significant distress. To address this gap, the Global Genomic Medicine Collaborative (G2MC) implemented a Rare Disease Pilot Project to enable clinical genomic testing at six LMIC sites (Chile, Malaysia, Mexico, Nepal, South Africa, Sri Lanka). Using trio exome sequencing for 18 selected families, supplemented by chromosomal microarray as indicated, definitive molecular diagnoses were established in 5 families (pathogenic/likely pathogenic variants explaining the phenotype). An additional 8 families had suspected molecular diagnoses with strong phenotype correlation that require functional validation, while 5 families remained undiagnosed at the end of the pilot. The integration of genomic data into clinical decision-making enabled definitive diagnoses, precise management, and genetic counseling for these patients. The pilot also strengthened local capacity building by conducting cross-site case conferences and enabling local reanalysis of sequence data at sites with bioinformatics capabilities. This study demonstrates the feasibility, effectiveness, and adaptability of implementing exome sequencing in resource-limited settings and highlights its potential to transform rare disease diagnosis and care in LMICs.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148411623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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