Non-invasive prenatal testing (NIPT) enables the screening of fetal chromosomal abnormalities by analyzing cell-free DNA (cfDNA) in maternal blood. Recent technological advancements have expanded its applications to the detection of copy number variations (CNVs). However, the clinical utility of CNV detection remains unclear. We aimed to investigate the association between fetal CNVs detected by genome-wide NIPT and perinatal outcomes in a large cohort in Japan. This retrospective cohort study included 46,082 patients who underwent NIPT at certified facilities in Japan between January 2015 and September 2021. Genome-wide NIPT was performed using massively parallel sequencing to detect fetal CNVs exceeding 7 Mb. Despite their small size, well-characterized microdeletions, such as 22q11.2 were included. From 46,082 patients with NIPT results, 30,373 cases with known birth outcomes were extracted, and cases with fetal CNV were included in the analysis. Fetal CNVs were detected in 66 patients (0.2%). Adverse outcomes, including miscarriage, growth restriction, and structural abnormalities, were observed in 14 of the 66 cases (21.2%). Pathogenic CNVs were frequently detected even in the 52 cases (78.8%) with favorable outcomes. Genome-wide NIPT may assist in the diagnosis of cases with structural abnormalities when combined with confirmatory testing. Our findings demonstrate that pathogenic CNVs are also detected in a substantial number of structurally normal fetuses with favorable short-term outcomes. This discordance presents a significant challenge for prenatal counseling. The clinical significance of the findings should be clarified through confirmatory testing of CNV cases and the accumulation of data from long-term follow-up studies.
{"title":"Perinatal outcomes of fetal CNVs detected by genome-wide non-invasive prenatal testing in Japan","authors":"Yuka Yamashita, Nahoko Shirato, Tatsuko Ishii, Mikiko Izumi, Kiyotake Ichizuka, Makiko Tominaga, Reina Komatsu, Tetsuro Kondo, Seiji Wada, Haruhiko Sago, Yuki Ito, Osamu Samura, Nobuhiro Suzumori, Hideaki Sawai, Yukiko Katagiri, Yoshiki Maeda, Hiroko Morisaki, Akira Namba, Yoshimasa Kamei, Junko Yotsumoto, Yuri Hasegawa, Kiyonori Miura, Setsuko Nakayama, Satoshi Kawaguchi, Haruka Hamanoue, Kazuya Mimura, Yuko Matsubara, Yoko Okamoto, Arisa Fujiwara, Kazutoshi Maeda, Takafumi Watanabe, Akinori Ida, Hiromi Hayakawa, Koshichi Goto, Akihiko Sekizawa","doi":"10.1038/s10038-025-01409-y","DOIUrl":"10.1038/s10038-025-01409-y","url":null,"abstract":"Non-invasive prenatal testing (NIPT) enables the screening of fetal chromosomal abnormalities by analyzing cell-free DNA (cfDNA) in maternal blood. Recent technological advancements have expanded its applications to the detection of copy number variations (CNVs). However, the clinical utility of CNV detection remains unclear. We aimed to investigate the association between fetal CNVs detected by genome-wide NIPT and perinatal outcomes in a large cohort in Japan. This retrospective cohort study included 46,082 patients who underwent NIPT at certified facilities in Japan between January 2015 and September 2021. Genome-wide NIPT was performed using massively parallel sequencing to detect fetal CNVs exceeding 7 Mb. Despite their small size, well-characterized microdeletions, such as 22q11.2 were included. From 46,082 patients with NIPT results, 30,373 cases with known birth outcomes were extracted, and cases with fetal CNV were included in the analysis. Fetal CNVs were detected in 66 patients (0.2%). Adverse outcomes, including miscarriage, growth restriction, and structural abnormalities, were observed in 14 of the 66 cases (21.2%). Pathogenic CNVs were frequently detected even in the 52 cases (78.8%) with favorable outcomes. Genome-wide NIPT may assist in the diagnosis of cases with structural abnormalities when combined with confirmatory testing. Our findings demonstrate that pathogenic CNVs are also detected in a substantial number of structurally normal fetuses with favorable short-term outcomes. This discordance presents a significant challenge for prenatal counseling. The clinical significance of the findings should be clarified through confirmatory testing of CNV cases and the accumulation of data from long-term follow-up studies.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 2","pages":"81-89"},"PeriodicalIF":2.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149599","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 : 2025-09-26DOI: 10.1038/s10038-025-01379-1
Yoshiko Murakami
Glycosylphosphatidylinositol (GPI) anchoring is a widely conserved post-translational modification in eukaryotes, in which various proteins-such as receptors, cell adhesion molecules, and complement regulatory proteins-are modified with a GPI moiety and tethered to the cell membrane. GPI anchors are synthesized in the endoplasmic reticulum (ER), where they are attached to newly translated proteins. These GPI-anchored proteins (GPI-APs) then undergo structural remodeling and are transported to the cell surface. To date, approximately 30 gene products have been identified as essential for the GPI biosynthetic and remodeling pathways. In addition to paroxysmal nocturnal hemoglobinuria (PNH), a well-characterized acquired hematologic disorder caused by somatic mutations in GPI biosynthesis genes, an increasing number of inherited GPI deficiencies (IGDs) have recently been reported. These congenital disorders are typically caused by hypomorphic mutations in GPI biosynthetic genes and present with neurological abnormalities. In this review, we provide an overview of the biosynthetic pathway of GPI anchors in mammalian cells and the genetic disorders resulting from its dysfunction. We also discuss emerging therapeutic approaches currently under investigation, including gene therapy, which hold promise for improving clinical outcomes in patients with IGD.
{"title":"Biosynthesis of GPI anchored proteins, its deficiencies and treatment.","authors":"Yoshiko Murakami","doi":"10.1038/s10038-025-01379-1","DOIUrl":"https://doi.org/10.1038/s10038-025-01379-1","url":null,"abstract":"<p><p>Glycosylphosphatidylinositol (GPI) anchoring is a widely conserved post-translational modification in eukaryotes, in which various proteins-such as receptors, cell adhesion molecules, and complement regulatory proteins-are modified with a GPI moiety and tethered to the cell membrane. GPI anchors are synthesized in the endoplasmic reticulum (ER), where they are attached to newly translated proteins. These GPI-anchored proteins (GPI-APs) then undergo structural remodeling and are transported to the cell surface. To date, approximately 30 gene products have been identified as essential for the GPI biosynthetic and remodeling pathways. In addition to paroxysmal nocturnal hemoglobinuria (PNH), a well-characterized acquired hematologic disorder caused by somatic mutations in GPI biosynthesis genes, an increasing number of inherited GPI deficiencies (IGDs) have recently been reported. These congenital disorders are typically caused by hypomorphic mutations in GPI biosynthetic genes and present with neurological abnormalities. In this review, we provide an overview of the biosynthetic pathway of GPI anchors in mammalian cells and the genetic disorders resulting from its dysfunction. We also discuss emerging therapeutic approaches currently under investigation, including gene therapy, which hold promise for improving clinical outcomes in patients with IGD.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149631","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}
Chromosomal insertions are a type of structural abnormality. While individuals with balanced insertions are typically asymptomatic, their offspring may have unbalanced abnormalities. We report two families with recurrent microstructural chromosomal abnormalities. To investigate the mechanisms, we performed chromosomal microarray (CMA), fluorescence in situ hybridization (FISH), and long-read whole-genome sequencing. In Family A, a duplication of 13q31.2–q33.1 was found in a proband with developmental and epileptic encephalopathy. A reciprocal deletion was detected in a fetus during a subsequent pregnancy. FISH confirmed an interchromosomal insertion involving chromosome 10. Long-read sequencing in the carrier parent revealed two split fragments of the inserted segment, one in inverted orientation. In Family B, a recurrent 1p36 interstitial deletion was associated with intellectual disability. FISH showed no abnormalities in the parents, but long-read sequencing of a suspected carrier revealed an intrachromosomal insertion of the 1p36 segment in inverted orientation. Breakpoint analysis showed minimal deletions or fragment overlaps in both families, indicating chromoanasynthesis as the likely mechanism. Although not routinely required for diagnosis of insertions, long-read sequencing can reveal hidden structural changes and clarify insertion mechanisms, as demonstrated in this study.
{"title":"Balanced chromosomal insertions as the mechanism of recurrent familial microstructural abnormalities: detailed analyses using long-read whole-genome sequencing","authors":"Hironao Shirai, Keiko Shimojima Yamamoto, Hirokazu Arai, Yukio Sawaishi, Saori Fujita, Yoko Kuriyama, Masaki Miura, Jun Tohyama, Toshiyuki Yamamoto","doi":"10.1038/s10038-025-01408-z","DOIUrl":"10.1038/s10038-025-01408-z","url":null,"abstract":"Chromosomal insertions are a type of structural abnormality. While individuals with balanced insertions are typically asymptomatic, their offspring may have unbalanced abnormalities. We report two families with recurrent microstructural chromosomal abnormalities. To investigate the mechanisms, we performed chromosomal microarray (CMA), fluorescence in situ hybridization (FISH), and long-read whole-genome sequencing. In Family A, a duplication of 13q31.2–q33.1 was found in a proband with developmental and epileptic encephalopathy. A reciprocal deletion was detected in a fetus during a subsequent pregnancy. FISH confirmed an interchromosomal insertion involving chromosome 10. Long-read sequencing in the carrier parent revealed two split fragments of the inserted segment, one in inverted orientation. In Family B, a recurrent 1p36 interstitial deletion was associated with intellectual disability. FISH showed no abnormalities in the parents, but long-read sequencing of a suspected carrier revealed an intrachromosomal insertion of the 1p36 segment in inverted orientation. Breakpoint analysis showed minimal deletions or fragment overlaps in both families, indicating chromoanasynthesis as the likely mechanism. Although not routinely required for diagnosis of insertions, long-read sequencing can reveal hidden structural changes and clarify insertion mechanisms, as demonstrated in this study.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 2","pages":"73-79"},"PeriodicalIF":2.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137877","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 : 2025-09-24DOI: 10.1038/s10038-025-01410-5
Emilie C. Ung, Nicholas A. Borja
LEO1 encodes a core subunit of the evolutionarily conserved RNA polymerase associated factor 1 complex (PAF1C), a key regulator of eukaryotic gene expression. While burden analyses suggest an association between rare LEO1 variants and an increased risk for neurodevelopmental disorder, the paucity of reported cases has prevented a definitive characterization of the resulting phenotype. We describe a male child with a novel de novo frameshift variant in LEO1 c.446dup (p.Asp149Gluf s*2) and undertake a comprehensive phenotype delineation of all previously reported patients. Developmental delay and autism spectrum disorder were core features common across patients with truncating variants, though rarer manifestations were also observed. This analysis supports LEO1 haploinsufficiency as a mechanism for this neurodevelopmental disorder. Further research is needed to more completely ascertain its associated features and penetrance. We nevertheless encourage its recognition as a definitive disease gene and inclusion in multigene panels.
{"title":"LEO1 haploinsufficiency is associated with developmental delays and autism spectrum disorder","authors":"Emilie C. Ung, Nicholas A. Borja","doi":"10.1038/s10038-025-01410-5","DOIUrl":"10.1038/s10038-025-01410-5","url":null,"abstract":"LEO1 encodes a core subunit of the evolutionarily conserved RNA polymerase associated factor 1 complex (PAF1C), a key regulator of eukaryotic gene expression. While burden analyses suggest an association between rare LEO1 variants and an increased risk for neurodevelopmental disorder, the paucity of reported cases has prevented a definitive characterization of the resulting phenotype. We describe a male child with a novel de novo frameshift variant in LEO1 c.446dup (p.Asp149Gluf s*2) and undertake a comprehensive phenotype delineation of all previously reported patients. Developmental delay and autism spectrum disorder were core features common across patients with truncating variants, though rarer manifestations were also observed. This analysis supports LEO1 haploinsufficiency as a mechanism for this neurodevelopmental disorder. Further research is needed to more completely ascertain its associated features and penetrance. We nevertheless encourage its recognition as a definitive disease gene and inclusion in multigene panels.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 2","pages":"109-111"},"PeriodicalIF":2.5,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12765696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137868","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}
Pub Date : 2025-09-16DOI: 10.1038/s10038-025-01407-0
Dibyendu Dutta, Jennifer Black, Daniela Macaya, Bobbi McGivern, Ria Garg
Nizon-Isidor syndrome (NIZIDS) is a rare neurodevelopmental disorder caused by heterozygous MED12L variants, where previously pathogenic single-nucleotide variants (SNVs) were only reported as de novo events. Here, we report the first case of maternally inherited MED12L nonsense variant in NIZIDS. Clinical assessment and family history evaluation revealed global developmental delay, intellectual disability, autism spectrum disorder, and speech impairment. Exome sequencing (ES) of the proband and both parents confirmed the presence of a maternally inherited likely pathogenic MED12L nonsense variant in the proband. Additional pathogenic variants in GAMT (maternal) and TNFRSF13B (paternal) genes were also identified in the proband. The clinical history of the mother suggested variable expressivity of the MED12L variant. Our case report challenges the presumed de novo inheritance of MED12L SNVs and demonstrates variable expressivity, thereby highlighting the benefit of a complete phenotype-driven approach when analyzing exome and genome data.
{"title":"Evidence of maternal inheritance of Nizon-Isidor syndrome in an individual with GAMT and TNFRSF13B sequence variants","authors":"Dibyendu Dutta, Jennifer Black, Daniela Macaya, Bobbi McGivern, Ria Garg","doi":"10.1038/s10038-025-01407-0","DOIUrl":"10.1038/s10038-025-01407-0","url":null,"abstract":"Nizon-Isidor syndrome (NIZIDS) is a rare neurodevelopmental disorder caused by heterozygous MED12L variants, where previously pathogenic single-nucleotide variants (SNVs) were only reported as de novo events. Here, we report the first case of maternally inherited MED12L nonsense variant in NIZIDS. Clinical assessment and family history evaluation revealed global developmental delay, intellectual disability, autism spectrum disorder, and speech impairment. Exome sequencing (ES) of the proband and both parents confirmed the presence of a maternally inherited likely pathogenic MED12L nonsense variant in the proband. Additional pathogenic variants in GAMT (maternal) and TNFRSF13B (paternal) genes were also identified in the proband. The clinical history of the mother suggested variable expressivity of the MED12L variant. Our case report challenges the presumed de novo inheritance of MED12L SNVs and demonstrates variable expressivity, thereby highlighting the benefit of a complete phenotype-driven approach when analyzing exome and genome data.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 2","pages":"105-108"},"PeriodicalIF":2.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075459","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 : 2025-09-16DOI: 10.1038/s10038-025-01406-1
Vera G. Pshennikova, Fedor M. Teryutin, Tuyara V. Borisova, Georgii P. Romanov, Alexandra M. Cherdonova, Alena A. Nikanorova, Igor V. Morozov, Alexander A. Bondar, Aisen V. Solovyev, Sardana A. Fedorova, Nikolay A. Barashkov
Previously only two families were known with progressive autosomal recessive deafness 103 (DFNB103, OMIM616042) caused by pathogenic variants of the CLIC5 gene. In this study we present the novel truncating variant c.644 G > A p.(Trp215*) of this gene which was found in homozygous state among 22 patients with hearing loss (HL) from 16 unrelated families living in the Sakha Republic of Russia (Eastern Siberia). Genotype-phenotype analysis in patients with DFNB103 showed that HL was sensorineural, symmetrical and variable by severity (from moderate to profound). Audiograms mostly have a down curve configuration, with pronounced loss of high and mid frequencies. In most cases this form of HL was detected in the post-lingual period (mean age 7.9 ± 1.2 years) and has a significant severity progression with age. In average the patients with DFNB103 lost 7.4 ± 13.65 dB on the speech frequency range in pure tone averages (PTA0.5,1.0,2.0,4.0 kHz) per year until reaching profound deafness in the second or third decade of the life. The high frequency of c.644 G > A p.(Trp215*) was found among Siberian GJB2-negative patients (9.9%) and this variant was not detected in GJB2-negative patients of Caucasian descent (predominantly Russians). The haplotype analysis based on the 730,000 whole genome SNP-markers indicates common origin of all studied mutant chromosomes. We conclude that the high prevalence of DFNB103 in Eastern Siberia is the result of founder effect, which occurred ~2500 years ago (~78 generations). These findings expand our knowledge of causative role of pathogenic variants in CLIC5 gene to the etiology of the HL.
以前已知只有两个家族患有由CLIC5基因致病变异引起的进行性常染色体隐性耳聋103 （DFNB103, OMIM616042）。本研究在俄罗斯萨哈共和国（东西伯利亚）16个无亲缘关系家庭的22例听力损失（HL）患者中发现了该基因的新截断变体c.644 G . > A . p.（Trp215*）。DFNB103患者的基因型-表型分析显示，HL是感音神经性的、对称的、严重程度可变的（从中度到重度）。听力图大多呈下曲线结构，高频和中频明显丧失。在大多数病例中，这种形式的HL在语后时期（平均年龄7.9±1.2岁）被检测到，并且随着年龄的增长严重程度有显著的进展。DFNB103患者平均每年在纯音语音频率范围（PTA0.5,1.0,2.0,4.0 kHz）上下降7.4±13.65 dB，直至在生命的第二或第三个十年达到深度耳聋。在西伯利亚gjb2阴性患者中发现c.644 G . > A . p.（Trp215*）的高频率（9.9%），而在白种人（主要是俄罗斯人）gjb2阴性患者中未检测到该变异。基于73万个全基因组snp标记的单倍型分析表明，所有研究的突变染色体具有共同的起源。结果表明，DFNB103在东西伯利亚地区的高流行率是约2500年前（约78代）的奠基人效应的结果。这些发现扩大了我们对CLIC5基因致病性变异对HL病因学的致病作用的认识。
{"title":"The c.644 G > A p.(Trp215*) founder variant in the CLIC5 gene causes progressive autosomal recessive deafness 103 (DFNB103) in Eastern Siberia","authors":"Vera G. Pshennikova, Fedor M. Teryutin, Tuyara V. Borisova, Georgii P. Romanov, Alexandra M. Cherdonova, Alena A. Nikanorova, Igor V. Morozov, Alexander A. Bondar, Aisen V. Solovyev, Sardana A. Fedorova, Nikolay A. Barashkov","doi":"10.1038/s10038-025-01406-1","DOIUrl":"10.1038/s10038-025-01406-1","url":null,"abstract":"Previously only two families were known with progressive autosomal recessive deafness 103 (DFNB103, OMIM616042) caused by pathogenic variants of the CLIC5 gene. In this study we present the novel truncating variant c.644 G > A p.(Trp215*) of this gene which was found in homozygous state among 22 patients with hearing loss (HL) from 16 unrelated families living in the Sakha Republic of Russia (Eastern Siberia). Genotype-phenotype analysis in patients with DFNB103 showed that HL was sensorineural, symmetrical and variable by severity (from moderate to profound). Audiograms mostly have a down curve configuration, with pronounced loss of high and mid frequencies. In most cases this form of HL was detected in the post-lingual period (mean age 7.9 ± 1.2 years) and has a significant severity progression with age. In average the patients with DFNB103 lost 7.4 ± 13.65 dB on the speech frequency range in pure tone averages (PTA0.5,1.0,2.0,4.0 kHz) per year until reaching profound deafness in the second or third decade of the life. The high frequency of c.644 G > A p.(Trp215*) was found among Siberian GJB2-negative patients (9.9%) and this variant was not detected in GJB2-negative patients of Caucasian descent (predominantly Russians). The haplotype analysis based on the 730,000 whole genome SNP-markers indicates common origin of all studied mutant chromosomes. We conclude that the high prevalence of DFNB103 in Eastern Siberia is the result of founder effect, which occurred ~2500 years ago (~78 generations). These findings expand our knowledge of causative role of pathogenic variants in CLIC5 gene to the etiology of the HL.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 1","pages":"49-58"},"PeriodicalIF":2.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075446","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}
Cyclin-dependent kinase 9 (CDK9) phosphorylates the C-terminal domain of RNA polymerase II (RNAPII) to regulate transcription. Previously, we reported that an 8-year-old boy with the biallelic CDK9 variants p.A288T and p.R303C exhibited a CHARGE-like malformation syndrome in which retinal dystrophy was a distinguishing feature. This dystrophy was caused by the decreased CDK9 kinase activity associated with these variant alleles [wild-type (WT) > A288T > R303C]. In this study, we describe a female patient who also bears biallelic CDK9 variants but displays retinal dystrophy without a CHARGE-like malformation syndrome. Trio-based whole-exome sequencing identified a new variant CDK9 allele, p.P321S, that occurred de novo in the patient. As a result, this female patient displayed compound heterozygous variants composed of the p.A288T CDK9 variant of maternal origin plus the novel p.P321S variant. With respect to reduced kinase activity, the new variant could be ranked as WT > P321S > A288T. Thus, our study raises a possibility that retinal dystrophy can arise with or without a CHARGE-like malformation syndrome depending on the level of kinase activity associated with the combination of variant CDK9 alleles present.
{"title":"Novel biallelic CDK9 variants are associated with retinal dystrophy without CHARGE-like malformation syndrome","authors":"Sachiko Nishina, Kaoruko Torii, Shizuka Ishitani, Tomoyo Yoshida, Maki Fukami, Kenji Kurosawa, Kenjiro Kosaki, Hirotomo Saitsu, Tohru Ishitani, Yoshihiro Hotta","doi":"10.1038/s10038-025-01395-1","DOIUrl":"10.1038/s10038-025-01395-1","url":null,"abstract":"Cyclin-dependent kinase 9 (CDK9) phosphorylates the C-terminal domain of RNA polymerase II (RNAPII) to regulate transcription. Previously, we reported that an 8-year-old boy with the biallelic CDK9 variants p.A288T and p.R303C exhibited a CHARGE-like malformation syndrome in which retinal dystrophy was a distinguishing feature. This dystrophy was caused by the decreased CDK9 kinase activity associated with these variant alleles [wild-type (WT) > A288T > R303C]. In this study, we describe a female patient who also bears biallelic CDK9 variants but displays retinal dystrophy without a CHARGE-like malformation syndrome. Trio-based whole-exome sequencing identified a new variant CDK9 allele, p.P321S, that occurred de novo in the patient. As a result, this female patient displayed compound heterozygous variants composed of the p.A288T CDK9 variant of maternal origin plus the novel p.P321S variant. With respect to reduced kinase activity, the new variant could be ranked as WT > P321S > A288T. Thus, our study raises a possibility that retinal dystrophy can arise with or without a CHARGE-like malformation syndrome depending on the level of kinase activity associated with the combination of variant CDK9 alleles present.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 2","pages":"97-103"},"PeriodicalIF":2.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12765697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069709","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}
Pub Date : 2025-09-16DOI: 10.1038/s10038-025-01402-5
Shuo Zhang, Yaqiong He, Yao Lu, Yi Huang, Jiaan Huang, Yichao Niu, Yueping Zhang, Yanzhi Du, Yun Sun, Ting Zhang, Zhe Wei
Preimplantation genetic testing for structural rearrangements (PGT-SR) has already been applied in inversion carriers. However, it has not been well clarified which inversion carriers should be recommended for PGT-SR in clinical practice. In this study, we retrospectively analyzed the segregation patterns of inverted loops in 522 blastocysts derived from 145 PGT-SR cycles. Multivariate logistic regression models were applied to identify independent predictors of unbalanced gamete production, while correlation analysis assessed the relationship between the rate of unbalanced embryos and inverted segment length. Among all embryos analyzed, 73 unbalanced embryos (13.98%, 73/522) related to the chromosome inversions originating from 33 carriers (31.43%, 33/105) were identified. Multivariate logistic regression showed neither the carrier’s gender nor age affected the production of unbalanced embryos. In contrast, the probability in the pericentric inversion group was significantly higher than that in the paracentric inversion group (p < 0.001), and significant difference was also identified among different chromosomal groups, with groups A (Chr1-3) and C (Chr 6-12) showing higher rates than other groups (p = 0.034). Moreover, we found the haploid autosomal length (HAL) and the ratio of inverted segment size in carriers who produced unbalanced embryos were significantly higher than in those who did not (p < 0.001). Furthermore, our results indicated a positive correlation between Segment size% and the rate of unbalanced embryos (p = 0.042, r = 0.357). In conclusion, carriers of pericentric inversions involving chromosomes from groups A and C are more prone to producing unbalanced embryos. Furthermore, a larger inverted segment size is associated with a higher frequency of unbalanced embryos.
{"title":"Meiotic determinants of unbalanced gametogenesis in chromosomal inversion carriers","authors":"Shuo Zhang, Yaqiong He, Yao Lu, Yi Huang, Jiaan Huang, Yichao Niu, Yueping Zhang, Yanzhi Du, Yun Sun, Ting Zhang, Zhe Wei","doi":"10.1038/s10038-025-01402-5","DOIUrl":"10.1038/s10038-025-01402-5","url":null,"abstract":"Preimplantation genetic testing for structural rearrangements (PGT-SR) has already been applied in inversion carriers. However, it has not been well clarified which inversion carriers should be recommended for PGT-SR in clinical practice. In this study, we retrospectively analyzed the segregation patterns of inverted loops in 522 blastocysts derived from 145 PGT-SR cycles. Multivariate logistic regression models were applied to identify independent predictors of unbalanced gamete production, while correlation analysis assessed the relationship between the rate of unbalanced embryos and inverted segment length. Among all embryos analyzed, 73 unbalanced embryos (13.98%, 73/522) related to the chromosome inversions originating from 33 carriers (31.43%, 33/105) were identified. Multivariate logistic regression showed neither the carrier’s gender nor age affected the production of unbalanced embryos. In contrast, the probability in the pericentric inversion group was significantly higher than that in the paracentric inversion group (p < 0.001), and significant difference was also identified among different chromosomal groups, with groups A (Chr1-3) and C (Chr 6-12) showing higher rates than other groups (p = 0.034). Moreover, we found the haploid autosomal length (HAL) and the ratio of inverted segment size in carriers who produced unbalanced embryos were significantly higher than in those who did not (p < 0.001). Furthermore, our results indicated a positive correlation between Segment size% and the rate of unbalanced embryos (p = 0.042, r = 0.357). In conclusion, carriers of pericentric inversions involving chromosomes from groups A and C are more prone to producing unbalanced embryos. Furthermore, a larger inverted segment size is associated with a higher frequency of unbalanced embryos.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 1","pages":"41-48"},"PeriodicalIF":2.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075431","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}
Facioscapulohumeral muscular dystrophy (FSHD) is a rare genetic disease with an estimated prevalence of no more than 1 in 8000; however, it is among the most common myopathies affecting global populations. This condition is classically categorised into two genetic types, FSHD1 (MIM: 158900) and FSHD2 (MIM: 158901), which, although have different genetic causes, are phenotypically indistinguishable, manifesting as progressive muscle weakness primarily affecting the face and periscapular muscles, as well as other muscle groups in later stages. The intense efforts of clinical and basic studies to understand this disease have revealed the critical necessity for disease manifestation: ectopic activation of the embryogenic and germline gene DUX4 (double homeobox 4, MIM: 606009) in skeletal muscles and the genetic and epigenetic backgrounds allowing DUX4 expression. Thus, the potential target therapies of FSHD include silencing DUX4 transcription or blocking its translation. Although the central role of DUX4 in FSHD pathology has almost reached a consensus, the mechanism of its activation remains largely unclear. Notably, the clinical dissection of genotype-epigenotype-phenotype observations, including non-penetrant and asymptomatic carriers of permissive genetic backgrounds, highlights the yet unsolved clinical diversity with potential additional layers of DUX4 regulation or other disease-modifying factors. This review provides an overview of essential findings with potential implications for further understanding the mechanisms underlying diverse clinical cases of FSHD and endogenous DUX4 activation in FSHD pathology.
{"title":"Diversity challenges and reconciles genetics in facioscapulohumeral muscular dystrophy.","authors":"Mitsuru Sasaki-Honda, Takumi Kishimoto, Hidetoshi Sakurai","doi":"10.1038/s10038-025-01401-6","DOIUrl":"https://doi.org/10.1038/s10038-025-01401-6","url":null,"abstract":"<p><p>Facioscapulohumeral muscular dystrophy (FSHD) is a rare genetic disease with an estimated prevalence of no more than 1 in 8000; however, it is among the most common myopathies affecting global populations. This condition is classically categorised into two genetic types, FSHD1 (MIM: 158900) and FSHD2 (MIM: 158901), which, although have different genetic causes, are phenotypically indistinguishable, manifesting as progressive muscle weakness primarily affecting the face and periscapular muscles, as well as other muscle groups in later stages. The intense efforts of clinical and basic studies to understand this disease have revealed the critical necessity for disease manifestation: ectopic activation of the embryogenic and germline gene DUX4 (double homeobox 4, MIM: 606009) in skeletal muscles and the genetic and epigenetic backgrounds allowing DUX4 expression. Thus, the potential target therapies of FSHD include silencing DUX4 transcription or blocking its translation. Although the central role of DUX4 in FSHD pathology has almost reached a consensus, the mechanism of its activation remains largely unclear. Notably, the clinical dissection of genotype-epigenotype-phenotype observations, including non-penetrant and asymptomatic carriers of permissive genetic backgrounds, highlights the yet unsolved clinical diversity with potential additional layers of DUX4 regulation or other disease-modifying factors. This review provides an overview of essential findings with potential implications for further understanding the mechanisms underlying diverse clinical cases of FSHD and endogenous DUX4 activation in FSHD pathology.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075395","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}
Rad50-interacting protein (RINT1) interacts with the endoplasmic reticulum (ER) tethering and SNARE complex, playing a central role in membrane trafficking and lipid metabolism. Loss-of-function variants of RINT1 have been related to episodic severe transaminitis with skeletal dysplasia or spastic paraplegia. We report two unrelated patients with recurrent markedly elevated aminotransferase triggered by fever, accompanied by coagulopathy and hyperammonemia. Liver biopsy revealed liver steatosis and bridging fibrosis in one patient, while the other displayed mild hepatocyte enlargement. Trio-whole-exome sequencing identified biallelic pathogenic RINT1 variants in the two patients. A novel missense variant [c.662 A > C, p.(His221Pro)] and a recurrent splice-site variant (c.1333+1 G > A) were identified in the first case. In the second case, a recurrent pathogenic RINT1 homozygous missense variant [c.1102 G > A, p.(Ala368Thr)] was identified. We investigated the pathogenicity of these variants through immunoprecipitation. Recombinant proteins produced from the mutant RINT1 transcript (p.His221Pro or p.Ala368Thr) displayed disrupted ER tether and SNARE interactions. Since the inhibition of ER-Golgi transport is associated with ER-stress activation, unfolded protein response (UPR)-related gene expression was investigated by qPCR. TIP20, a RINT1 homolog in Saccharomyces cerevisiae, is needed for autophagosome formation; therefore, an LC3-II turnover assay was performed and revealed disrupted autophagic flux. In addition, we created a fat-body-specific Rint1 knockdown in Drosophila. In the mutant larva, tissue atrophy and decreased lipid droplets in the fat body were observed. These results indicated that a loss of RINT1 function activated the UPR, impairs autophagy, and led to lipid storage abnormalities, contributing to the pathogenesis of liver disease.
rad50相互作用蛋白（RINT1）与内质网（ER）系结和SNARE复合物相互作用，在膜运输和脂质代谢中起核心作用。RINT1的功能丧失变体与偶发性严重转氨炎伴骨骼发育不良或痉挛性截瘫有关。我们报告了两例不相关的患者，由发热引起的转氨酶复发性明显升高，并伴有凝血功能障碍和高氨血症。肝活检显示1例肝脂肪变性和桥性纤维化，另1例肝细胞轻度增大。三全外显子组测序鉴定了两名患者的双等位致病RINT1变异。一种新的错义变体[c]。在第一个病例中发现了662 A > C, p.(His221Pro)]和一个复发剪接位点变异（C .1333+ 1g > A）。在第二种情况下，复发致病性RINT1纯合错义变异[c]。1102 G > A, p.(Ala368Thr)]。我们通过免疫沉淀研究了这些变异的致病性。由RINT1突变体转录本（p.His221Pro或p.p ala368thr）产生的重组蛋白显示ER系链和SNARE相互作用被破坏。由于er -高尔基转运的抑制与er -应激激活有关，我们利用qPCR研究了未折叠蛋白反应（UPR）相关基因的表达。TIP20是酿酒酵母中RINT1的同源物，是自噬体形成所必需的；因此，LC3-II转换实验显示自噬通量被破坏。此外，我们在果蝇中创建了脂肪体特异性Rint1敲低。突变体幼虫组织萎缩，脂肪体脂滴减少。这些结果表明，RINT1功能的缺失激活了UPR，损害了自噬，导致脂质储存异常，参与了肝病的发病机制。
{"title":"Functional analysis of novel and recurrent RINT1 variants in patients with infantile liver dysfunction","authors":"Taiga Aoki, Ayano Inui, Yoshiyasu Ogata, Arisa Igarashi, Kumiko Yanagi, Masahiko Yamamori, Takaya Iida, Yoshihiro H. Inoue, Yoichi Matsubara, Tadashi Kaname","doi":"10.1038/s10038-025-01404-3","DOIUrl":"10.1038/s10038-025-01404-3","url":null,"abstract":"Rad50-interacting protein (RINT1) interacts with the endoplasmic reticulum (ER) tethering and SNARE complex, playing a central role in membrane trafficking and lipid metabolism. Loss-of-function variants of RINT1 have been related to episodic severe transaminitis with skeletal dysplasia or spastic paraplegia. We report two unrelated patients with recurrent markedly elevated aminotransferase triggered by fever, accompanied by coagulopathy and hyperammonemia. Liver biopsy revealed liver steatosis and bridging fibrosis in one patient, while the other displayed mild hepatocyte enlargement. Trio-whole-exome sequencing identified biallelic pathogenic RINT1 variants in the two patients. A novel missense variant [c.662 A > C, p.(His221Pro)] and a recurrent splice-site variant (c.1333+1 G > A) were identified in the first case. In the second case, a recurrent pathogenic RINT1 homozygous missense variant [c.1102 G > A, p.(Ala368Thr)] was identified. We investigated the pathogenicity of these variants through immunoprecipitation. Recombinant proteins produced from the mutant RINT1 transcript (p.His221Pro or p.Ala368Thr) displayed disrupted ER tether and SNARE interactions. Since the inhibition of ER-Golgi transport is associated with ER-stress activation, unfolded protein response (UPR)-related gene expression was investigated by qPCR. TIP20, a RINT1 homolog in Saccharomyces cerevisiae, is needed for autophagosome formation; therefore, an LC3-II turnover assay was performed and revealed disrupted autophagic flux. In addition, we created a fat-body-specific Rint1 knockdown in Drosophila. In the mutant larva, tissue atrophy and decreased lipid droplets in the fat body were observed. These results indicated that a loss of RINT1 function activated the UPR, impairs autophagy, and led to lipid storage abnormalities, contributing to the pathogenesis of liver disease.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"71 1","pages":"23-34"},"PeriodicalIF":2.5,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145054034","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}
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