Pub Date : 2025-08-26DOI: 10.1038/s10038-025-01391-5
Yoshihiko Saito, Ichizo Nishino
In recent years, whole-exome and whole-genome sequencing have been increasingly applied for the genetic diagnosis of muscle diseases. However, standard short-read sequencing often fails to detect pathogenic variants in some inherited muscle diseases, such as Duchenne/Becker muscular dystrophy (DMD/BMD), facioscapulohumeral muscular dystrophy (FSHD), oculopharyngeal muscular dystrophy (OPMD), and oculopharyngodistal myopathy (OPDM). This review outlines the genetic diagnostic approaches for these conditions, with a particular focus on novel analytical approaches for genetic diagnosis.
{"title":"Disease-specific genetic diagnostic strategies for muscle diseases unresolved by short-read sequencing.","authors":"Yoshihiko Saito, Ichizo Nishino","doi":"10.1038/s10038-025-01391-5","DOIUrl":"https://doi.org/10.1038/s10038-025-01391-5","url":null,"abstract":"<p><p>In recent years, whole-exome and whole-genome sequencing have been increasingly applied for the genetic diagnosis of muscle diseases. However, standard short-read sequencing often fails to detect pathogenic variants in some inherited muscle diseases, such as Duchenne/Becker muscular dystrophy (DMD/BMD), facioscapulohumeral muscular dystrophy (FSHD), oculopharyngeal muscular dystrophy (OPMD), and oculopharyngodistal myopathy (OPDM). This review outlines the genetic diagnostic approaches for these conditions, with a particular focus on novel analytical approaches for genetic diagnosis.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
UBQLN2 is located on Xp11.21 and encodes the ubiquilin 2 protein involved in protein homeostasis. Heterozygous or hemizygous missense variants in UBQLN2 cause amyotrophic lateral sclerosis (ALS). In addition, rare cases of primary lateral sclerosis (PLS) and spastic paraplegia (SPG) associated with UBQLN2 variants have also been reported. Here, we report four male patients in a family with SPG carrying a hemizygous missense UBQLN2 variant (NM_013444.4:c.1442G>T, p.(Gly481Val)). These patients showed childhood-onset lower limb spasticity, progressing to gait disturbance. The mean onset age (11 years) was earlier than that of previous ALS (49.6 years), SPG (29 years) and PLS (25.5 years) cases, and their progression was slower than in ALS or PLS. Literature review reveals Pro506 missense variants are associated with various motor neuron disease phenotypes, with some SPG patients progressing to ALS. Therefore, we consider that careful follow-up is warranted for UBQLN2-related SPG patients.
UBQLN2位于Xp11.21上，编码参与蛋白稳态的泛素2蛋白。UBQLN2的杂合子或半合子错义变异导致肌萎缩性侧索硬化症（ALS）。此外，罕见的原发性侧索硬化症（PLS）和痉挛性截瘫（SPG）与UBQLN2变异相关的病例也有报道。在这里，我们报告了四名患有SPG家族的男性患者携带半合子错义UBQLN2变异（NM_013444.4:c）。1442 g > T, p。(Gly481Val))。这些患者表现为儿童期开始的下肢痉挛，进展为步态障碍。平均发病年龄（11岁）早于既往ALS（49.6岁）、SPG（29岁）和PLS（25.5岁）病例，进展速度慢于ALS或PLS。文献回顾显示Pro506错义变异与多种运动神经元疾病表型相关，部分SPG患者进展为ALS。因此，我们认为对ubqln2相关的SPG患者进行仔细的随访是必要的。
{"title":"A Japanese familial spastic paraplegia associated with a missense UBQLN2 variant","authors":"Kazuki Watanabe, Tatsuya Ema, Kenji Shimizu, Kosuke Yamada, Mitsuko Nakashima, Hirotomo Saitsu","doi":"10.1038/s10038-025-01392-4","DOIUrl":"10.1038/s10038-025-01392-4","url":null,"abstract":"UBQLN2 is located on Xp11.21 and encodes the ubiquilin 2 protein involved in protein homeostasis. Heterozygous or hemizygous missense variants in UBQLN2 cause amyotrophic lateral sclerosis (ALS). In addition, rare cases of primary lateral sclerosis (PLS) and spastic paraplegia (SPG) associated with UBQLN2 variants have also been reported. Here, we report four male patients in a family with SPG carrying a hemizygous missense UBQLN2 variant (NM_013444.4:c.1442G>T, p.(Gly481Val)). These patients showed childhood-onset lower limb spasticity, progressing to gait disturbance. The mean onset age (11 years) was earlier than that of previous ALS (49.6 years), SPG (29 years) and PLS (25.5 years) cases, and their progression was slower than in ALS or PLS. Literature review reveals Pro506 missense variants are associated with various motor neuron disease phenotypes, with some SPG patients progressing to ALS. Therefore, we consider that careful follow-up is warranted for UBQLN2-related SPG patients.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 12","pages":"645-648"},"PeriodicalIF":2.5,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gestational diabetes mellitus (GDM) is a prevalent pregnancy complication influenced by pre-pregnancy overweight or obese and high gestational weight gain (GWG). This study investigated the impact of body mass index (BMI)-related genetic variants on GWG and GDM risk among Taiwanese women. A case-control study of 3875 pregnant women included 3162 with GDM based on oral glucose tolerance tests and 2483 with GWG data. A genome-wide association study of 71,848 women identified BMI related genetic variants, and a polygenic risk score for BMI (PRS_BMI) was calculated. PRS_BMI was positively associated with GWG (R² = 0.010, P < 0.001). The odds ratio (ORs) for high GWG and GDM per standard deviation increase in PRS_BMI were 2.28 (95% CI = 2.03–2.55, P < 0.001) and 1.34 (95% CI = 1.24–1.45, P < 0.001), respectively. Stratified analyses indicated stronger associations in women with BMI < 25 kg/m², while weaker associations were observed in those with BMI ≥ 25 kg/m². These findings suggest PRS_BMI could be used to identify women at higher risk for excessive GWG and GDM, aiding in early monitoring and targeted risk-reduction strategies.
{"title":"Polygenic risk score as a tool to predict gestational weight gain and gestational diabetes among pregnant women in Taiwan","authors":"Wen-Ling Liao, Hao-I Hsieh, Ting-Yuan Liu, Hsing-Fang Lu, Yu-Chuen Huang, Ya-Wen Chang, Fuu-Jen Tsai","doi":"10.1038/s10038-025-01360-y","DOIUrl":"10.1038/s10038-025-01360-y","url":null,"abstract":"Gestational diabetes mellitus (GDM) is a prevalent pregnancy complication influenced by pre-pregnancy overweight or obese and high gestational weight gain (GWG). This study investigated the impact of body mass index (BMI)-related genetic variants on GWG and GDM risk among Taiwanese women. A case-control study of 3875 pregnant women included 3162 with GDM based on oral glucose tolerance tests and 2483 with GWG data. A genome-wide association study of 71,848 women identified BMI related genetic variants, and a polygenic risk score for BMI (PRS_BMI) was calculated. PRS_BMI was positively associated with GWG (R² = 0.010, P < 0.001). The odds ratio (ORs) for high GWG and GDM per standard deviation increase in PRS_BMI were 2.28 (95% CI = 2.03–2.55, P < 0.001) and 1.34 (95% CI = 1.24–1.45, P < 0.001), respectively. Stratified analyses indicated stronger associations in women with BMI < 25 kg/m², while weaker associations were observed in those with BMI ≥ 25 kg/m². These findings suggest PRS_BMI could be used to identify women at higher risk for excessive GWG and GDM, aiding in early monitoring and targeted risk-reduction strategies.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 11","pages":"597-602"},"PeriodicalIF":2.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We aimed to study the diagnostic yield and clinical impact of trio exome sequencing (tES) in children with autism spectrum disorder (ASD). Participants (n = 137) between 2 and 18 years with syndromic and non-syndromic ASD underwent tES, after excluding karyotype-detectable cytogenetic abnormalities and fragile X syndrome. The diagnostic yield was 22/137 (16.1%) when considering only pathogenic (P) and likely-pathogenic (LP) variants in known disease-causing genes. We reported 23 significant (P, LP) variants in 22 individuals, with one participant (AGS041) harbouring a dual genetic diagnosis. Nearly half of these (12/23, 52.2%) were novel, while 21/23 (91.3%) occurred de novo. 20/23 (86.9%) of the variants were single nucleotide variants, while 3/23 (13.1%) were copy number variants. The diagnostic yield in syndromic ASD (14/40, 35%) was significantly higher than the non-syndromic group (8/97, 8.2%, p = 0.000258). Variants of uncertain significance in two participants were considered to be likely causative for the phenotype, given the strong clinical correlation (likely-causative variant of uncertain significance, LcVUS). On considering these two participants and an additional 28 participants with significant variants in autism candidate genes (vACG), the net diagnostic yield increased to 37.9%. The clinical benefits among those receiving a definite genetic diagnosis (P/LP variants only) included better prognostication (100%), availing reproductive counselling (100%), disease-specific surveillance (86.4%), and therapeutic implications (27.3%). Thus, in conclusion, in our cohort of 137 children with ASD, tES provided a definite genetic diagnosis in 16.1% of the participants, the yield being higher in syndromic ASD. A confirmed genetic diagnosis aided in holistic clinical care, extending beyond reproductive counselling.
{"title":"Prospective study to analyze the yield and clinical impact of trio exome sequencing in 137 Indian children with autism spectrum disorder","authors":"Shruti Bajaj, Shreya Gandhi, Thenral S. Geetha, Malini Venkata, Anita Chitre, Nazema Sagi, Nisha Agrawal, Suhani Shah, Ruta Deo, Sudharshana Pai, Kripa Saira Jacob, Sakthivel Murugan, Ramesh Menon, Ravi Gupta, Jeevana Praharsha Athota, Vishakha Mali, Nagaraja M. Phani, Koyeli Sengupta, Puja Mehta, Vrajesh Udani, Akshi Bassi, Sandeep Charugulla, Pradnya Gadgil, Ramprasad Vedam, Anaita Udwadia Hegde","doi":"10.1038/s10038-025-01368-4","DOIUrl":"10.1038/s10038-025-01368-4","url":null,"abstract":"We aimed to study the diagnostic yield and clinical impact of trio exome sequencing (tES) in children with autism spectrum disorder (ASD). Participants (n = 137) between 2 and 18 years with syndromic and non-syndromic ASD underwent tES, after excluding karyotype-detectable cytogenetic abnormalities and fragile X syndrome. The diagnostic yield was 22/137 (16.1%) when considering only pathogenic (P) and likely-pathogenic (LP) variants in known disease-causing genes. We reported 23 significant (P, LP) variants in 22 individuals, with one participant (AGS041) harbouring a dual genetic diagnosis. Nearly half of these (12/23, 52.2%) were novel, while 21/23 (91.3%) occurred de novo. 20/23 (86.9%) of the variants were single nucleotide variants, while 3/23 (13.1%) were copy number variants. The diagnostic yield in syndromic ASD (14/40, 35%) was significantly higher than the non-syndromic group (8/97, 8.2%, p = 0.000258). Variants of uncertain significance in two participants were considered to be likely causative for the phenotype, given the strong clinical correlation (likely-causative variant of uncertain significance, LcVUS). On considering these two participants and an additional 28 participants with significant variants in autism candidate genes (vACG), the net diagnostic yield increased to 37.9%. The clinical benefits among those receiving a definite genetic diagnosis (P/LP variants only) included better prognostication (100%), availing reproductive counselling (100%), disease-specific surveillance (86.4%), and therapeutic implications (27.3%). Thus, in conclusion, in our cohort of 137 children with ASD, tES provided a definite genetic diagnosis in 16.1% of the participants, the yield being higher in syndromic ASD. A confirmed genetic diagnosis aided in holistic clinical care, extending beyond reproductive counselling.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 12","pages":"611-624"},"PeriodicalIF":2.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-21DOI: 10.1038/s10038-025-01388-0
Janaki M. Nair, Analabha Basu, Nikhil Tandon, Dwaipayan Bharadwaj
Elucidating the genetic basis of lipid metabolism in children is essential for early intervention in dyslipidemia and cardiovascular diseases. We performed a two-staged genome-wide association study (GWAS; N = 5412) and an independent exome-wide association study (ExWAS; N = 4750) on lipid parameters—HDL, LDL, Triglycerides (TG), Total Cholesterol (TC) in Indian school-going children - the largest single-cohort paediatric lipid study till date. GWAS identified robust associations at established loci, including CETP for HDL; CELSR2, and PSRC1 for LDL and TC, and GCKR, ZNF259, and TBL2 for TG. We also validated known associations at sub-GWAS significance in FADS2, GATAD2A, PRKCA, and QKI. Exome-based analyses further refined functional variants within these loci and revealed additional known loci in ALDH1A2 for HDL; APOE, APOC1, TM6SF2, CILP2, TOMM40, for LDL and TC; and APOA5, BUD13 for TG and novel loci in ATP8B3, MYH7B, GYS2, and RNF8 for TG. Conditional analysis revealed multiple independent signals at key loci. Gene-based GWAS pinpointed CETP and APOC1 as significant for HDL and LDL, respectively. Rare variant analysis identified significant contribution of loss-of-function missense variants in CETP, TM6SF2, and APOE, in regulating lipid profiles. Associations replicated with consistent directionality in European datasets and Indian adults, reinforcing conserved biology across ancestries and age groups. Functional enrichment analyses emphasized lipid-related pathways and differential expression in liver. These findings lay the foundation for ancestry-informed genetic risk prediction models to identify children at early risk for cardiovascular diseases.
阐明儿童脂质代谢的遗传基础对血脂异常和心血管疾病的早期干预至关重要。我们进行了一项两阶段全基因组关联研究（GWAS, N = 5412）和一项独立的全外显子组关联研究（ExWAS, N = 4750），研究对象是印度学龄儿童的脂质参数——hdl、LDL、甘油三酯（TG）、总胆固醇（TC）——这是迄今为止最大的单队列儿科脂质研究。GWAS在已建立的位点上发现了强大的关联，包括CETP与HDL的关联；CELSR2和PSRC1检测LDL和TC， GCKR， ZNF259和TBL2检测TG。我们还验证了FADS2、GATAD2A、PRKCA和QKI在亚gwas意义上的已知关联。基于外显子组的分析进一步细化了这些基因座内的功能变异，并揭示了ALDH1A2中HDL的其他已知基因座；APOE, APOC1, TM6SF2, CILP2, TOMM40，用于LDL和TC；APOA5、BUD13和ATP8B3、MYH7B、GYS2和RNF8中新的基因位点用于TG。条件分析显示在关键位点有多个独立的信号。基于基因的GWAS确定CETP和APOC1分别对HDL和LDL具有重要意义。罕见变异分析发现，CETP、TM6SF2和APOE中功能缺失的错义变异在调节脂质谱方面有重要贡献。在欧洲数据集和印度成人数据集中，这些关联以一致的方向性复制，加强了跨祖先和年龄组的保守生物学。功能富集分析强调脂质相关途径和肝脏中的差异表达。这些发现为建立基于血统的遗传风险预测模型奠定了基础，该模型可用于识别处于心血管疾病早期风险的儿童。
{"title":"Early lipid genetics: identification of common and rare genetic variants for lipid traits in Indian adolescents","authors":"Janaki M. Nair, Analabha Basu, Nikhil Tandon, Dwaipayan Bharadwaj","doi":"10.1038/s10038-025-01388-0","DOIUrl":"10.1038/s10038-025-01388-0","url":null,"abstract":"Elucidating the genetic basis of lipid metabolism in children is essential for early intervention in dyslipidemia and cardiovascular diseases. We performed a two-staged genome-wide association study (GWAS; N = 5412) and an independent exome-wide association study (ExWAS; N = 4750) on lipid parameters—HDL, LDL, Triglycerides (TG), Total Cholesterol (TC) in Indian school-going children - the largest single-cohort paediatric lipid study till date. GWAS identified robust associations at established loci, including CETP for HDL; CELSR2, and PSRC1 for LDL and TC, and GCKR, ZNF259, and TBL2 for TG. We also validated known associations at sub-GWAS significance in FADS2, GATAD2A, PRKCA, and QKI. Exome-based analyses further refined functional variants within these loci and revealed additional known loci in ALDH1A2 for HDL; APOE, APOC1, TM6SF2, CILP2, TOMM40, for LDL and TC; and APOA5, BUD13 for TG and novel loci in ATP8B3, MYH7B, GYS2, and RNF8 for TG. Conditional analysis revealed multiple independent signals at key loci. Gene-based GWAS pinpointed CETP and APOC1 as significant for HDL and LDL, respectively. Rare variant analysis identified significant contribution of loss-of-function missense variants in CETP, TM6SF2, and APOE, in regulating lipid profiles. Associations replicated with consistent directionality in European datasets and Indian adults, reinforcing conserved biology across ancestries and age groups. Functional enrichment analyses emphasized lipid-related pathways and differential expression in liver. These findings lay the foundation for ancestry-informed genetic risk prediction models to identify children at early risk for cardiovascular diseases.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 12","pages":"625-633"},"PeriodicalIF":2.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Spinocerebellar ataxia (SCA27B), due to an intronic GAA repeat expansion in the FGF14 gene, has been described recently. We screened DNA samples for expanded FGF14 GAA repeats in individuals with movement disorder (N = 526) in our laboratory at NIMHANS, Bengaluru, India. Clinically pathogenic repeat expansions of FGF14 (GAA) were detected in 14 of 526 patients (2.6%); seven with (GAA)>300 repeats and seven with (GAA)250-300 repeats. The classical downbeat nystagmus was seen in three patients. Four of the fourteen positive patients were symptomatic in early adulthood. A search for additional causative variants revealed two mutations. One patient with very early onset ataxia had a homozygous mutation (p.Arg199LeufsTer15) in the APTX ataxia gene, which is known to be involved in single-strand break repair. Another young patient who had developed symptoms at 11 years of age was heterozygous for a loss-of-function (p.Arg706*) allele in FAN1, a DNA modifier gene. Adaptive long-read sequencing of genomic DNA showed absence of a stabilising 17 bp sequence motif in expanded GAA alleles. Among healthy controls, 82% of alleles carried less than 25 GAA repeats, with (GAA)9 being the most frequent allele. We also found intermediate-sized GAA expansions in 8.2% of ataxia patients. The clinical presentation in SCA27B patients is heterogeneous and may be modified by alleles at other loci. While the disease biology of each triplet repeat expansion disorder differs based on the gene product affected, there are many commonalities that might be important for treatment.
{"title":"Unstable FGF14 GAA repeat expansions in Indian ataxia patients: a broader phenotype and involvement of modifier loci?","authors":"Pannaga Prasad G, Aleksandra Makarova, Kandasamy Kathirvel, Suleyman Gulsuner, Tomas Walsh, Shreevidya Parthaje, Chinu Patra, Bhagyalakshmi Shankarappa, Shridhar Utagi, Vaishnavi Desai, Vikram Holla, Nitish Kamble, Ravi Yadav, Atchayaram Nalini, Biju Viswanath, Marie-Claire King, Sanjeev Jain, Pramod Kumar Pal, Meera Purushottam","doi":"10.1038/s10038-025-01390-6","DOIUrl":"10.1038/s10038-025-01390-6","url":null,"abstract":"Spinocerebellar ataxia (SCA27B), due to an intronic GAA repeat expansion in the FGF14 gene, has been described recently. We screened DNA samples for expanded FGF14 GAA repeats in individuals with movement disorder (N = 526) in our laboratory at NIMHANS, Bengaluru, India. Clinically pathogenic repeat expansions of FGF14 (GAA) were detected in 14 of 526 patients (2.6%); seven with (GAA)>300 repeats and seven with (GAA)250-300 repeats. The classical downbeat nystagmus was seen in three patients. Four of the fourteen positive patients were symptomatic in early adulthood. A search for additional causative variants revealed two mutations. One patient with very early onset ataxia had a homozygous mutation (p.Arg199LeufsTer15) in the APTX ataxia gene, which is known to be involved in single-strand break repair. Another young patient who had developed symptoms at 11 years of age was heterozygous for a loss-of-function (p.Arg706*) allele in FAN1, a DNA modifier gene. Adaptive long-read sequencing of genomic DNA showed absence of a stabilising 17 bp sequence motif in expanded GAA alleles. Among healthy controls, 82% of alleles carried less than 25 GAA repeats, with (GAA)9 being the most frequent allele. We also found intermediate-sized GAA expansions in 8.2% of ataxia patients. The clinical presentation in SCA27B patients is heterogeneous and may be modified by alleles at other loci. While the disease biology of each triplet repeat expansion disorder differs based on the gene product affected, there are many commonalities that might be important for treatment.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 11","pages":"589-595"},"PeriodicalIF":2.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-20DOI: 10.1038/s10038-025-01387-1
Hiroshi Manya, Motoi Kanagawa
{"title":"Defective O-mannosyl glycan synthesis in dystroglycanopathies: pathogenesis and therapeutic frontiers.","authors":"Hiroshi Manya, Motoi Kanagawa","doi":"10.1038/s10038-025-01387-1","DOIUrl":"https://doi.org/10.1038/s10038-025-01387-1","url":null,"abstract":"","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-18DOI: 10.1038/s10038-025-01382-6
Muhammad Dawood, Xinran Ji, Irfan U. Shah, Niamat Khan, Shifeng Xue, Shamim Saleha
Anophthalmia/microphthalmia (A/M) are rare congenital ocular malformations involving the absence or underdevelopment of the eyes, and they display considerable clinical and genetic heterogeneity. Establishing a genetic diagnosis for A/M is critical because it facilitates early intervention, informed genetic counseling, and the prevention of disease transmission in high-risk families. This study explored the genotypic and phenotypic landscape of A/M in 10 Pakistani families meeting specific criteria: confirmed A/M phenotype, residence in Khyber Pakhtunkhwa, no prior genetic testing, and informed consent. Whole-exome sequencing (WES) and segregation analysis in families identified a novel missense variant in SMOC1 (c.406T>G, p.Cys136Gly) in a family with Waardenburg anophthalmia syndrome (WAS). Additionally, causative variants in VSX2 (c.598C>T, p.Arg200Ter) and ALDH1A3 (c.172dup, p.Glu58GlyfsTer5) were detected, potentially representing founder variants in the Pashtun ethnic group. Moreover, a likely pathogenic variant in FOXE3 (c.145G>T, p.Gly49Ter) and a variant of uncertain significance in STRA6 (c.1399C>T, p.Arg467Cys), which exhibited incomplete penetrance, were also identified. In addition, segregation analysis of the causal genetic variants in the 5 families revealed a carrier frequency of 60.86% among the phenotypically unaffected family members. Notably, the average size of autozygous regions among probands was substantial (282.62 Mb), indicating a high degree of consanguinity and familial relatedness due to endogamous practices. However, no causative variants were identified in five families, each with a single affected member, with unilateral A/M in the majority of cases. These findings support the value of genetic diagnostics in reproductive counseling and highlight the utility of broader genomic approaches to improve diagnostic outcomes in unresolved cases.
{"title":"Genotypic and phenotypic spectrum of anophthalmia/microphthalmia in families from Khyber Pakhtunkhwa, Pakistan","authors":"Muhammad Dawood, Xinran Ji, Irfan U. Shah, Niamat Khan, Shifeng Xue, Shamim Saleha","doi":"10.1038/s10038-025-01382-6","DOIUrl":"10.1038/s10038-025-01382-6","url":null,"abstract":"Anophthalmia/microphthalmia (A/M) are rare congenital ocular malformations involving the absence or underdevelopment of the eyes, and they display considerable clinical and genetic heterogeneity. Establishing a genetic diagnosis for A/M is critical because it facilitates early intervention, informed genetic counseling, and the prevention of disease transmission in high-risk families. This study explored the genotypic and phenotypic landscape of A/M in 10 Pakistani families meeting specific criteria: confirmed A/M phenotype, residence in Khyber Pakhtunkhwa, no prior genetic testing, and informed consent. Whole-exome sequencing (WES) and segregation analysis in families identified a novel missense variant in SMOC1 (c.406T>G, p.Cys136Gly) in a family with Waardenburg anophthalmia syndrome (WAS). Additionally, causative variants in VSX2 (c.598C>T, p.Arg200Ter) and ALDH1A3 (c.172dup, p.Glu58GlyfsTer5) were detected, potentially representing founder variants in the Pashtun ethnic group. Moreover, a likely pathogenic variant in FOXE3 (c.145G>T, p.Gly49Ter) and a variant of uncertain significance in STRA6 (c.1399C>T, p.Arg467Cys), which exhibited incomplete penetrance, were also identified. In addition, segregation analysis of the causal genetic variants in the 5 families revealed a carrier frequency of 60.86% among the phenotypically unaffected family members. Notably, the average size of autozygous regions among probands was substantial (282.62 Mb), indicating a high degree of consanguinity and familial relatedness due to endogamous practices. However, no causative variants were identified in five families, each with a single affected member, with unilateral A/M in the majority of cases. These findings support the value of genetic diagnostics in reproductive counseling and highlight the utility of broader genomic approaches to improve diagnostic outcomes in unresolved cases.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 11","pages":"565-575"},"PeriodicalIF":2.5,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-18DOI: 10.1038/s10038-025-01386-2
S Rehan Ahmad, Md. Zeyaullah, Yousef Zahrani, Abdelrhman A. G. Altijani, Adam Dawria, Ahmed Salih
Leukodystrophies are inherited disorders characterized by progressive degeneration of white matter in the central nervous system. Here, we investigate a previously uncharacterized autosomal recessive leukodystrophy which is associated with the homozygous missense variant in ZNF319 (c.800T>C; p.Phe267Ser) in an 18-year-old male presenting with spasticity, ataxia, cognitive decline, and white matter abnormalities on MRI. The variant was absent in population databases (gnomAD, ClinVar) and predicted to be pathogenic by multiple in silico tools. Molecular dynamics simulations revealed that F267 is a stabilizing residue within a β-strand of the zinc finger domain, forming π-stacking and hydrophobic interactions that are lost upon substitution with serine, leading to structural instability, increased flexibility, and protein unfolding. Despite normal transcript and protein expression, ZNF319-F267S mislocalized to the cytoplasm due to disruption of its bipartite nuclear localization signal (NLS), resulting in impaired interaction with importin α1 (KPNA1). Functional analysis confirmed that the mutation disrupts nuclear transport and prevents transcriptional activation of genes involved in myelination. Protein interaction network and gene ontology analysis highlighted ZNF319’s role in transcriptional regulation and its localization in the CHOP-C/EBP transcriptional complex. Expression profiling demonstrated ZNF319 enrichment in oligodendrocytes and white matter regions, correlating with the observed leukoencephalopathy. Our study identifies ZNF319 as a novel gene implicated in human leukodystrophy and highlights how a single-point mutation can compromise nuclear import and transcriptional function, leading to white matter degeneration. These findings expand the genetic landscape of leukodystrophies and provide mechanistic insights into transcriptional regulation in myelin maintenance.
{"title":"Pathogenic ZNF319 variant disrupts nuclear localization and transcriptional regulation to cause a novel form of autosomal recessive leukodystrophy","authors":"S Rehan Ahmad, Md. Zeyaullah, Yousef Zahrani, Abdelrhman A. G. Altijani, Adam Dawria, Ahmed Salih","doi":"10.1038/s10038-025-01386-2","DOIUrl":"10.1038/s10038-025-01386-2","url":null,"abstract":"Leukodystrophies are inherited disorders characterized by progressive degeneration of white matter in the central nervous system. Here, we investigate a previously uncharacterized autosomal recessive leukodystrophy which is associated with the homozygous missense variant in ZNF319 (c.800T>C; p.Phe267Ser) in an 18-year-old male presenting with spasticity, ataxia, cognitive decline, and white matter abnormalities on MRI. The variant was absent in population databases (gnomAD, ClinVar) and predicted to be pathogenic by multiple in silico tools. Molecular dynamics simulations revealed that F267 is a stabilizing residue within a β-strand of the zinc finger domain, forming π-stacking and hydrophobic interactions that are lost upon substitution with serine, leading to structural instability, increased flexibility, and protein unfolding. Despite normal transcript and protein expression, ZNF319-F267S mislocalized to the cytoplasm due to disruption of its bipartite nuclear localization signal (NLS), resulting in impaired interaction with importin α1 (KPNA1). Functional analysis confirmed that the mutation disrupts nuclear transport and prevents transcriptional activation of genes involved in myelination. Protein interaction network and gene ontology analysis highlighted ZNF319’s role in transcriptional regulation and its localization in the CHOP-C/EBP transcriptional complex. Expression profiling demonstrated ZNF319 enrichment in oligodendrocytes and white matter regions, correlating with the observed leukoencephalopathy. Our study identifies ZNF319 as a novel gene implicated in human leukodystrophy and highlights how a single-point mutation can compromise nuclear import and transcriptional function, leading to white matter degeneration. These findings expand the genetic landscape of leukodystrophies and provide mechanistic insights into transcriptional regulation in myelin maintenance.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 11","pages":"577-587"},"PeriodicalIF":2.5,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144873542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-15DOI: 10.1038/s10038-025-01385-3
David Curtis
A recently described method to predict pathogenicity of DNA variants uses a DNA language model and can be applied to both coding and non-coding variants. For coding variants the performance of this method, termed GPN-MSA (genomic pretrained network with multiple-sequence alignment), was reported to be superior to CADD. We compare the performance of this method against 45 other predictors applied to rare coding variants in 18 gene-phenotype pairs. We find that while GPN-MSA produces stronger evidence for association than CADD it is not the best-performing method for any gene and on average other prediction methods are superior. While GPN-MSA may be useful for predicting the pathogenicity of non-coding variants, it would seem sensible for clinicians and researchers to utilise other methods when dealing with coding variants. This research has been conducted using the UK Biobank Resource.
{"title":"Assessment of ability of a DNA language model to predict pathogenicity of rare coding variants","authors":"David Curtis","doi":"10.1038/s10038-025-01385-3","DOIUrl":"10.1038/s10038-025-01385-3","url":null,"abstract":"A recently described method to predict pathogenicity of DNA variants uses a DNA language model and can be applied to both coding and non-coding variants. For coding variants the performance of this method, termed GPN-MSA (genomic pretrained network with multiple-sequence alignment), was reported to be superior to CADD. We compare the performance of this method against 45 other predictors applied to rare coding variants in 18 gene-phenotype pairs. We find that while GPN-MSA produces stronger evidence for association than CADD it is not the best-performing method for any gene and on average other prediction methods are superior. While GPN-MSA may be useful for predicting the pathogenicity of non-coding variants, it would seem sensible for clinicians and researchers to utilise other methods when dealing with coding variants. This research has been conducted using the UK Biobank Resource.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 11","pages":"603-607"},"PeriodicalIF":2.5,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s10038-025-01385-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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