Human Genetics最新文献

{"title":"RPGRorf15 nanopore long-read sequencing improves retinitis pigmentosa molecular diagnosis for men and women.","authors":"Manon Fabard, Aurore Devos, Anaïs F Poncet, Jean-Pascal Meneboo, Martin Figeac, Céline Villenet, Isabelle Drumare, Sabine Defoort-Dhellemmes, Isabelle Meunier, Xavier Zanlonghi, Olivier Grunewald, Vincent Huin, Claire Lecigne, Vasily Smirnov, Claire-Marie Dhaenens","doi":"10.1007/s00439-025-02807-0","DOIUrl":"10.1007/s00439-025-02807-0","url":null,"abstract":"<p><p>RPGR (Retinitis Pigmentosa GTPase Regulator) is the main gene involved in X-linked retinitis pigmentosa (RP) and up to 28% of sporadic RP. Pathogenic variants are mostly located in its retina-specific transcript, RPGRorf15, especially in the terminal exon named open reading frame 15 (ORF15), which is a highly repeated region. Because of this complex sequence, first- and second-generation short-read sequencing are difficult, both for male patients and for affected and relative females, resulting in numerous unresolved cases. Long-read sequencing appears to be the most appropriate to counter this problem. Using Oxford Nanopore Technology sequencing, we analysed 194 patients with retinal dystrophy (RD) (142 men and 52 women) suspected to be either X-linked (n = 42) or autosomal (n = 152), and for whom first-line sequencing of 230 retinal dystrophy genes, including RP2 and RPGRex1-19, was negative. Pathogenic ORF15 variants were found in 27 patients (13.9%), 21 men and 6 women. Of the 42 XLRD patients, 15 were carriers (35.7%), nine men and six women, most of them had rod-cone dystrophy. Of the 152 patients with isolated RD, only 12 carried ORF15 variants (7.9%),all male patients, most of them had cone-rod dystrophy (41.7%). We demonstrate the efficacy of this technology to diagnose male cases with a family history of X-linked RD, as well as sporadic cases clinically not suggestive of ORF15. We also show how easy it is to analyse female carriers or affected women. We expect that more heterozygous women with severe disease and no family history will be identified by this technique in the future.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"20"},"PeriodicalIF":3.4,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12904915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146179313","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}

{"title":"Leveraging polygenic risk scores to infer causal directions in genotype-by-environment interactions between complex traits.","authors":"Zinabu Fentaw, Buu Truong, Dovini Jayasinghe, Chris Della Vedova, Gibran Hemani, Beben Benyamin, Elina Hyppönen, S Hong Lee","doi":"10.1007/s00439-025-02799-x","DOIUrl":"10.1007/s00439-025-02799-x","url":null,"abstract":"<p><p>Most existing genotype-by-environment interaction (G×E) methods assume a known causal direction as an assumption that often does not hold and can lead to biased estimates and spurious findings. To address this, we introduce the Genetic Causality Inference Model (GCIM), a novel approach designed to infer causal directions in G×E studies. GCIM integrates polygenic risk scores (PRS) for both the exposure and the outcome to strengthen causal inference and reduce spurious interaction signals. We evaluated GCIM using simulated data across varying genetic and residual correlation settings and compared its performance to existing PRS-by-environment (PRS×E) models under both null and alternative G×E scenarios. GCIM was also applied to real-world UK Biobank data in both causal directions. GCIM consistently outperformed existing methods by accurately identifying the absence of G×E variance and avoiding false positives, even in the presence of strong phenotypic heteroscedasticity due to residual heterogeneity. Other methods often generated spurious associations, especially under reverse causality. Applying GCIM to UK Biobank data, we investigated 11 circulating biomarkers (including liver enzymes, lipids, and inflammatory markers) and three anthropometric traits (BMI, body fat, and waist-to-hip ratio [WHR]). GCIM identified that bilirubin modulates genetic effects on BMI and WHR, while body fat modulates genetic effects on C-reactive protein, with associations remaining significant after multiple testing corrections. Overall, GCIM provides a more reliable framework for GxE analysis, particularly under challenging conditions such as residual heterogeneity and uncertain causal direction. However, further development is needed to improve its statistical power.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"19"},"PeriodicalIF":3.4,"publicationDate":"2026-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12882956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131615","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}

{"title":"Mosaic variants in the LIM homeobox 1 (LHX1) gene contribute to Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome.","authors":"Dina Kira, Soumia Brakta, Hyung Goo Kim, Jennifer Butler, Lynn P Chorich, John A Phillips, Lawrence C Layman","doi":"10.1007/s00439-026-02817-6","DOIUrl":"10.1007/s00439-026-02817-6","url":null,"abstract":"<p><p>Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome presents as the congenital absence of the uterus and vagina and affects approximately 1 in 4500 women. Affected individuals have normal breast development, primary amenorrhea, and a 46,XX karyotype. Müllerian aplasia may be isolated (type 1) or associated with renal, skeletal, cardiac, and auditory anomalies (type 2). The pathogenesis of MRKH largely remains unknown, but the LHX1 gene, which encodes a transcription factor, is an attractive candidate. LHX1 has been extensively studied in animals but less studied in humans. The Lhx1-null mouse model is embryonic lethal, but conditional knockout models found it important for urogenital system development. Although several possible deleterious variants have been reported in humans, LHX1 has not been established as a cause of MRKH in OMIM. In this study, we identified heterozygous intragenic LHX1 deletions by qPCR in 3/134 (2.2%) individuals with MRKH, which were confirmed by RT-PCR of lymphoblast RNA. This 166 bp frameshift deletion produces a premature stop codon (c.676_841del;p.V226Ifs*120) and is predicted to disrupt the DNA-binding domain essential for function. Mapping of the variant in genomic DNA revealed an 1864 bp deletion encompassing intron 3, exon 4, and intron 4, with allele frequencies of 3.4, 6.2, and 1%, respectively, in the three patients. Our findings provide supportive evidence that a low-level mosaic likely pathogenic variant in LHX1 could contribute to the pathogenesis of MRKH with or without nonreproductive anomalies.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"18"},"PeriodicalIF":3.4,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146113113","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":"Bi-allelic TPP1 variants in neuronal ceroid lipofuscinosis 2: clinical findings from an Iranian cohort of 20 patients, founder effect, and in silico analyses.","authors":"Sajjad Biglari, Halimeh Rezaei, Elnaz Asadollahzadeh, Pooneh Nikuei, Mohammad Ali Sahraian, Atefeh Sohanforooshan Moghaddam, Hassan Vahidnezhad, Leila Youssefian, Hamid Galehdari, Tahere Seifi, Niloofar Chamanrou, Sogand Heydaran, Sahere Parvas, Gholamreza Shariati, Alihossein Saberi, Mohammad Hamid, Taher Zareei, Shahrzad Tabasi, Sina Ranjbar, Gholamreza Khademi, Hasan Golmakani, Narges Hashemi, Hossein Akhavan, Maryam Naseri, Nahid Donyadideh, Ehsan Barkhordari, Mehran Beiraghi Toosi, Samaneh Arabi, Negar Heidari, Fatemeh Eghbal, Hasan Badpar, Amin Saeidinia, Shima Imannezhad, Sepideh Bagheri, Mojtaba Lotfi, Majid Mirsadraee, Tina Loghmani, Azadeh Darabi, Raheleh Derafshi, Maryam Behmadi, Abbas Boskabadi, Salehe Akhondian, Peyman Eshraghi, Mahya Hosseini, Ahmadshah Farhat, Fatemeh Ghane Sharbaf, Samaneh Norooziasl, Nosrat Ghaemi, Najmeh Ahangari, Masoud Etemadifar, Toktam Moosavian, Reza Shervin Badv, Henry Houlden, Payam Sarraf, Mahsa Haghighatzadeh, Morteza Heidari, Ehsan Ghayoor Karimiani","doi":"10.1007/s00439-025-02812-3","DOIUrl":"10.1007/s00439-025-02812-3","url":null,"abstract":"<p><p>Neuronal Ceroid Lipofuscinosis Type 2 (CLN2) is a rare neurodegenerative disorder. It exhibits an autosomal recessive inheritance pattern and is attributable to pathogenic variants in the TPP1 gene. This study sought to identify and characterize TPP1 variants in eighteen Iranian consanguineous families affected by CLN2 disease. A developmental history, brain imaging, and neurological evaluation were conducted. Exome sequencing (ES) was conducted on the probands' DNA. ACMG criteria were used to evaluate pathogenicity, as well as several in silico prediction techniques, protein stability algorithms, and homozygosity mapping. Three-dimensional protein modeling was used to assess structural effects. Shared haplotypes have been determined to assess possible founder alleles and the time to the most recent common ancestor (MRCA). We found twelve different TPP1 bi-allelic variants, six of which had never been reported before, two of which were only listed in ClinVar, and four of which were known to be pathogenic alleles. It contained four various types of variants: missense (33%), nonsense (25%), frameshift (25%), and splice-site (17%). The majority of the variants were found within the peptidase S53 domain. All new alleles were found in the \"rare-plus-high-CADD\" range, which is higher than the gene-specific mutation significance cutoff (MSC). The recurrence of c.729C > G (p.Phe243Leu) in several families, along with a common ~ 2.86 Mb homozygous haplotype and an estimated most recent common ancestor (MRCA) of ~ 16.7 generations (~ 450 years), strongly indicates a founder effect. Psychomotor regression was universal in clinical settings, seizures usually started between the ages of 3 and 5, and 40% of patients died before the age of 10. No affected patients received enzyme replacement therapy due to financial constraints. This study represents the most extensive Iranian series of CLN2 to date, broadens the TPP1 mutational spectrum with six novel alleles, and reveals a significant founder effect. The results improve genotype–phenotype correlations and show how important it is to do carrier screening that is specific to each population and to make enzyme replacement therapy available quickly in regions with limited funding. ES proved critical for accurate CLN2 diagnosis, precise genetic counseling, and revealing gaps in the availability of broad treatment for rare disorders.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"17"},"PeriodicalIF":3.4,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146105273","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":"Deviations from additivity in APOE4-mediated late-onset Alzheimer's disease risk across races and ethnicities.","authors":"Razaq O Durodoye, Timothy H Ciesielski, Penelope Benchek, Jacquelaine Bartlett, Xiaofeng Zhu, Shiying Liu, Adam Naj, Brian Kunkle, Gerard D Schellenberg, Richard Mayeux, Lindsay Farrer, Li-San Wang, Margaret A Pericak-Vance, Farid Rajabli, Giuseppe Tosto, Jonathan L Haines, William S Bush, Scott M Williams","doi":"10.1007/s00439-025-02810-5","DOIUrl":"10.1007/s00439-025-02810-5","url":null,"abstract":"<p><p>APOE’s ε4 haplotype (APOE4) is late onset Alzheimer’s disease’s (LOAD) strongest genetic risk factor. Therefore, accurately modeling APOE4’s effect is critical to understanding LOAD. This is especially important as APOE4 odds ratios (OR) vary across racial and ethnic (R/E) groups. We analyzed the APOE4-LOAD association in 3,196 East Asian, 31,105 non-Hispanic White (White), 1,646 Hispanic and Latino (Hispanic), and 6,068 non-Hispanic Black (Black) participants using three genetic models: additive, genotypic, and a reparametrized model accounting for deviations from additivity (DA). Each model adjusted for age, sex, and genetic ancestry. We first calculated additive APOE4 ORs in each R/E group, finding East Asian participants had the largest APOE4 ORs (ORAPOE4: 5.2, 95%CI: 4.4–6.0) and Black participants among the smallest (ORAPOE4: 2.8, 95%CI: 2.6–3.1). Next, we generated APOE4 ORs for heterozygote and homozygote ε4 carriers. These genotypic ORs were statistically the same as the additive APOE4 estimates for all models except homozygote East Asian participants. The measured homozygote East Asian estimate (ORAPOE4: 41.5, 95%CI: 22.1–88.8) was 57% higher than its predicted counterpart based on additivity, indicating significant non-additive contributions. Finally, we used a reparametrized model that adjusted for DA. Although equivalent to the genotypic model, this adjustment provided insight into DA while significantly improving model performance among Black participants. This report demonstrates that APOE4 estimates differ based on the genetic modeling strategy, introduces explicit DA adjustments in the APOE4-LOAD association, and cautions against blindly assuming additivity across R/E groups.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"16"},"PeriodicalIF":3.4,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12827419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146018322","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}

{"title":"Evaluating genetic-based disease prediction approaches through simulation.","authors":"Max Shpak, Eric Parfitt, Soroush Mahmoudiandehkordi, Mehdi Maadooliat, Steven J Schrodi","doi":"10.1007/s00439-025-02798-y","DOIUrl":"10.1007/s00439-025-02798-y","url":null,"abstract":"<p><p>Common diseases exhibit substantial heritability, and GWAS of these diseases have revealed hundreds of thousands of high-frequency disease susceptibility variants throughout the genome. These studies offer the prospect of using genomic data to improve disease prediction and diagnosis, however, the relative performance of different predictive modeling approaches is not well-characterized. To investigate this systematically, we constructed a Monte Carlo simulation generating model genomes with 500 SNPs carrying risk alleles that are parameterized by the strength of their effects and by different modes of inheritance—additive, dominant, recessive, and combinations thereof. After generating genotypes for cases and controls, several machine learning classifiers (logistic regression, naïve Bayes, random forests, and neural networks, with and without feature selection) were applied to predict disease phenotypes from genotypes. Each classifier’s error rates were evaluated and compared using AUC. We found that random forest models were the most accurate predictors of disease over the range of inheritance parameters, followed by logistic regression and naïve Bayes, while the feedforward multilayer neural network model had lower AUC. We also investigated the association of AUC with the difference in polygenic risk score (PRS) between disease and control samples by comparing AUC in the simulations to the values predicted from the PRS distributions, finding a monotonic, curvilinear relationship as predicted analytically from odds-risk and liability threshold models. Our results also show that with small risk effects, the odds-risk model provided an accurate estimate of the AUC-PRS association while a liability threshold model performed better when risk alleles had strong effects.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"14"},"PeriodicalIF":3.4,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12823641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146010248","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}

{"title":"Cockayne syndrome mutation in XPG activate the integrated stress response.","authors":"Danhui Zhang, Max Hartmann, Zhouli Cao, Gaojie Zhu, Gregoire Najjar, Cagatay Günes, Steffen Emmert, Karin Scharffetter-Kochanek, Sebastian Iben","doi":"10.1007/s00439-025-02804-3","DOIUrl":"10.1007/s00439-025-02804-3","url":null,"abstract":"<p><p>Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are diseases provoked by mutations in multifunctional proteins that are involved in DNA repair. DNA-repair deficiency explains the high cancer incidence of XP, whereas cancer-free CS, characterized by growth retardation, neurological degeneration, and premature aging does not present as a classical DNA-repair deficiency disorder. Here, we compared a severe combined XP/CS case provoked by XPG-mutation with an XP \"only\" patient cell line caused by mutation in the same XPG gene to carve out the pathogenic cellular disturbances that provoke CS. We identified RNA polymerase I transcription and rRNA maturation defects, a highly phosphorylated eukaryotic initiation factor 2 alpha (eIF2alpha), and a shift from cap- to internal ribosomal entry site (IRES) translation, indicating an activated integrated stress response in CS. Disturbances in ribosomal biogenesis and translational control might thus contribute to the development of CS.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"15"},"PeriodicalIF":3.6,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12823737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146010302","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}

{"title":"Genetic landscape of male infertility: chromosomal abnormalities and Y chromosome microdeletions in a Turkish cohort (1 314 Cases).","authors":"Tülay Tos, Tufan Çiçek, Aida Nurul Barokah, Arslan Bayram, Yaprak Üstün, Ramazan Erda Pay","doi":"10.1007/s00439-025-02803-4","DOIUrl":"10.1007/s00439-025-02803-4","url":null,"abstract":"<p><p>Male infertility affects a significant portion of the global population and can arise from genetic and physiological abnormalities. This study assessed the clinical and genetic characteristics of 1 314 infertile males. Parameters included family history, age, marital duration, presence of physical conditions, clinical diagnoses (oligospermia and azoospermia), cytogenetic and Y-chromosome microdeletion analysis, and other laboratory data. The mean age was 31.37 years, with an average marital duration of 4.6 years. Oligospermia was observed in 601 patients, while 713 had azoospermia. Chromosomal abnormalities were identified in 9.89% (130/1 314) of cases, while 90.11% (1 184/1 314) showed a normal constitutional karyotype. The most prevalent chromosome abnormality was 47,XXY and its variants (n = 78, 5.94%). Azoospermia factor (AZF) deletion on the Y chromosome long arm (Yq) was found in 3.73% (49/1 314) of participants, occurring in 6.17% (44/713) of azoospermic and 0.83% (5/601) of oligospermic individuals. The most frequent microdeletions were detected in the AZFc region, with 23 cases showing AZFc deletion only. This study provides valuable insights into the intricate relationships among the clinical, cytogenetic, and molecular presentations of male infertility. These findings emphasize the importance of a multifaceted approach to diagnose and manage male infertility, taking into consideration both genetic and clinical factors.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"13"},"PeriodicalIF":3.4,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959199","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":"Targeted analysis of whole exome sequencing in Thai patients with neonatal diabetes.","authors":"Nattachet Plengvidhya, Thanida Tangjarusritaratorn, Nipaporn Teerawattanapong, Tassanee Narkdontri, Saranya Innang, Suavaluk Songlilitchuwong, Sarocha Suthon, Watip Tangjittipokin","doi":"10.1007/s00439-025-02815-0","DOIUrl":"10.1007/s00439-025-02815-0","url":null,"abstract":"<p><p>Neonatal diabetes mellitus (NDM) typically presents within the first 6 months of life and generally lacks islet autoantibodies. Genetic elucidation of NDM is a prime example of precision medicine in diabetes. However, no published genetic data exist for NDM in Thailand. We aimed to assess the genetic etiology of Thai NDM using whole exome sequencing (WES). We enrolled 14 Thai patients with NDM and measured GAD65, IA-2, and ZnT8 autoantibodies. We then performed WES and analyzed 43 NDM-related genes to identify causative variants. All subjects tested negative for the three islet autoantibodies. Eight harbored variants in well-established NDM genes (KCNJ11 [n = 5], ABCC8 [n = 1], INS [n = 2 in identical twins]). Two patients with KCNJ11 variants (rs80356616: p.Val59Met and rs8035661: p.Arg50Gln) achieved excellent glycemic control on sulfonylureas, illustrating precision therapy. The remaining six carried pathogenic variants in genes associated with monogenic diabetes, including LRBA, EIF2AK3, DOCK8, WFS1, GATA6, CISD2/SLC9B1, and COQ2. This is the first report on the genetic etiology of NDM in Thailand. WES is an effective approach to identifying variants in this rare diabetes subtype. Larger cohort studies are needed to determine the true prevalence of NDM in Thailand.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"11"},"PeriodicalIF":3.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12779698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911335","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}

{"title":"Genetic diversity of Usher syndrome in Moroccan patients.","authors":"Kenza El Khair, Amale Bousfiha, Aymane Bouzidi, Ghita Amalou, Majida Charif, Hicham Charoute, Adil El Hamouchi, Amina Bakhchane, Khalid Snoussi, Amal Hajjij, Mustapha Detsouli, Houda Benrahma, Crystel Bonnet, Guy Lenaers, Christine Petit, Abdelhamid Barakat","doi":"10.1007/s00439-025-02814-1","DOIUrl":"10.1007/s00439-025-02814-1","url":null,"abstract":"<p><p>Usher syndrome (USH) is a rare genetic disorder accounting for almost 50% of all hereditary deaf-blindness cases. This heterogeneous, autosomal recessive condition is categorized into 3 main clinical subtypes (USH1, USH2 and USH3) and an atypical form of USH based on the severity and age of onset of the hearing loss, the absence or presence of vestibular dysfunction and the age of retinitis pigmentosa (RP) onset. This study aims to characterize the genetic spectrum of Usher syndrome in the Moroccan population. We used targeted-exome, whole exome and Sanger sequencing to identify variants in USH genes. We identified 25 variants among which 6 novel ones with 22 variants in USH1, 3 in USH2 while none were identified in USH3. Twenty-eight out of 33 families had USH1 and 5 out of 33 had USH2. MYO7A is the most prevalent gene mutated in this study with a recurrent splice acceptor site variant c.2283-1G > T found in 7 families. Our findings contribute to the understanding of the genetic diversity of USH in the Moroccan and North African populations, and emphasize the importance of genetic screening in identifying novel variants and providing an early clinical diagnosis to establish a medical follow-up and genetic counseling.</p>","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":"12"},"PeriodicalIF":3.4,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145911375","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}