CAPZA2 encodes the α2 subunit of CAPZA, which is vital for actin polymerization and depolymerization in humans. However, understanding of diseases associated with CAPZA2 remains limited. To date, only three cases have been documented with neurodevelopmental abnormalities such as delayed motor development, speech delay, intellectual disability, hypotonia, and a history of seizures. In this study, we document a patient who exhibited seizures, mild intellectual disability, and impaired motor development yet did not demonstrate speech delay or hypotonia. The patient also suffered from recurrent instances of respiratory infections, gastrointestinal and allergic diseases. A novel de novo splicing variant c.219+1 G > A was detected in the CAPZA2 gene through whole-exome sequencing. This variant led to exon 4 skipping in mRNA splicing, confirmed by RT-PCR and Sanger sequencing. To our knowledge, this is the third study on human CAPZA2 defects, documenting the fourth unambiguously diagnosed case. Furthermore, this splicing mutation type is reported here for the first time. Our research offers additional support for the existence of a CAPZA2-related non-syndromic neurodevelopmental disorder. Our findings augment our understanding of the phenotypic range associated with CAPZA2 deficiency and enrich the knowledge of the mutational spectrum of the CAPZA2 gene.
{"title":"Heterozygous CAPZA2 mutations cause global developmental delay, hypotonia with epilepsy: a case report and the literature review","authors":"Xiao-Man Zhang, Kai-Li Xu, Jing-Hui Kong, Geng Dong, Shi-Jie Dong, Zhi-Xiao Yang, Shu-Jing Xu, Li Wang, Shu-Ying Luo, Yao-Dong Zhang, Chong-Chen Zhou, Wei-Yue Gu, Shi-Yue Mei","doi":"10.1038/s10038-024-01230-z","DOIUrl":"10.1038/s10038-024-01230-z","url":null,"abstract":"CAPZA2 encodes the α2 subunit of CAPZA, which is vital for actin polymerization and depolymerization in humans. However, understanding of diseases associated with CAPZA2 remains limited. To date, only three cases have been documented with neurodevelopmental abnormalities such as delayed motor development, speech delay, intellectual disability, hypotonia, and a history of seizures. In this study, we document a patient who exhibited seizures, mild intellectual disability, and impaired motor development yet did not demonstrate speech delay or hypotonia. The patient also suffered from recurrent instances of respiratory infections, gastrointestinal and allergic diseases. A novel de novo splicing variant c.219+1 G > A was detected in the CAPZA2 gene through whole-exome sequencing. This variant led to exon 4 skipping in mRNA splicing, confirmed by RT-PCR and Sanger sequencing. To our knowledge, this is the third study on human CAPZA2 defects, documenting the fourth unambiguously diagnosed case. Furthermore, this splicing mutation type is reported here for the first time. Our research offers additional support for the existence of a CAPZA2-related non-syndromic neurodevelopmental disorder. Our findings augment our understanding of the phenotypic range associated with CAPZA2 deficiency and enrich the knowledge of the mutational spectrum of the CAPZA2 gene.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 5","pages":"197-203"},"PeriodicalIF":3.5,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139905803","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 : 2024-02-14DOI: 10.1038/s10038-024-01228-7
Francisco Javier Cotrina-Vinagre, María Elena Rodríguez-García, Lucía del Pozo-Filíu, Aurelio Hernández-Laín, Ana Arteche-López, Beatriz Morte, Marta Sevilla, Luis Alberto Pérez-Jurado, Pilar Quijada-Fraile, Ana Camacho, Francisco Martínez-Azorín
We report the cases of two Spanish pediatric patients with hypotonia, muscle weakness and feeding difficulties at birth. Whole-exome sequencing (WES) uncovered two new homozygous VAMP1 (Vesicle Associated Membrane Protein 1) splicing variants, NM_014231.5:c.129+5 G > A in the boy patient (P1) and c.341-24_341-16delinsAGAAAA in the girl patient (P2). This gene encodes the vesicle-associated membrane protein 1 (VAMP1) that is a component of a protein complex involved in the fusion of synaptic vesicles with the presynaptic membrane. VAMP1 has a highly variable C-terminus generated by alternative splicing that gives rise to three main isoforms (A, B and D), being VAMP1A the only isoform expressed in the nervous system. In order to assess the pathogenicity of these variants, expression experiments of RNA for VAMP1 were carried out. The c.129+5 G > A and c.341-24_341-16delinsAGAAAA variants induced aberrant splicing events resulting in the deletion of exon 2 (r.5_131del; p.Ser2TrpfsTer7) in the three isoforms in the first case, and the retention of the last 14 nucleotides of the 3′ of intron 4 (r.340_341ins341-14_341-1; p.Ile114AsnfsTer77) in the VAMP1A isoform in the second case. Pathogenic VAMP1 variants have been associated with autosomal dominant spastic ataxia 1 (SPAX1) and with autosomal recessive presynaptic congenital myasthenic syndrome (CMS). Our patients share the clinical manifestations of CMS patients with two important differences: they do not show the typical electrophysiological pattern that suggests pathology of pre-synaptic neuromuscular junction, and their muscular biopsies present hypertrophic fibers type 1. In conclusion, our data expand both genetic and phenotypic spectrum associated with VAMP1 variants.
{"title":"Expanding the genetic and phenotypic spectrum of congenital myasthenic syndrome: new homozygous VAMP1 splicing variants in 2 novel individuals","authors":"Francisco Javier Cotrina-Vinagre, María Elena Rodríguez-García, Lucía del Pozo-Filíu, Aurelio Hernández-Laín, Ana Arteche-López, Beatriz Morte, Marta Sevilla, Luis Alberto Pérez-Jurado, Pilar Quijada-Fraile, Ana Camacho, Francisco Martínez-Azorín","doi":"10.1038/s10038-024-01228-7","DOIUrl":"10.1038/s10038-024-01228-7","url":null,"abstract":"We report the cases of two Spanish pediatric patients with hypotonia, muscle weakness and feeding difficulties at birth. Whole-exome sequencing (WES) uncovered two new homozygous VAMP1 (Vesicle Associated Membrane Protein 1) splicing variants, NM_014231.5:c.129+5 G > A in the boy patient (P1) and c.341-24_341-16delinsAGAAAA in the girl patient (P2). This gene encodes the vesicle-associated membrane protein 1 (VAMP1) that is a component of a protein complex involved in the fusion of synaptic vesicles with the presynaptic membrane. VAMP1 has a highly variable C-terminus generated by alternative splicing that gives rise to three main isoforms (A, B and D), being VAMP1A the only isoform expressed in the nervous system. In order to assess the pathogenicity of these variants, expression experiments of RNA for VAMP1 were carried out. The c.129+5 G > A and c.341-24_341-16delinsAGAAAA variants induced aberrant splicing events resulting in the deletion of exon 2 (r.5_131del; p.Ser2TrpfsTer7) in the three isoforms in the first case, and the retention of the last 14 nucleotides of the 3′ of intron 4 (r.340_341ins341-14_341-1; p.Ile114AsnfsTer77) in the VAMP1A isoform in the second case. Pathogenic VAMP1 variants have been associated with autosomal dominant spastic ataxia 1 (SPAX1) and with autosomal recessive presynaptic congenital myasthenic syndrome (CMS). Our patients share the clinical manifestations of CMS patients with two important differences: they do not show the typical electrophysiological pattern that suggests pathology of pre-synaptic neuromuscular junction, and their muscular biopsies present hypertrophic fibers type 1. In conclusion, our data expand both genetic and phenotypic spectrum associated with VAMP1 variants.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 5","pages":"187-196"},"PeriodicalIF":3.5,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139735422","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}
Truncus Arteriosus (TA) is a congenital heart disease characterized by a single common blood vessel emerging from the right and left ventricles instead of the main pulmonary artery and aorta. TA accounts for 4% of all critical congenital heart diseases. The most common cause of TA is 22q11.2 deletion syndrome, accounting for 12–35% of all TA cases. However, no major causes of TA other than 22q11.2 deletion have been reported. We performed whole-genome sequencing of 11 Japanese patients having TA without 22q11.2 deletion. Among five patients, we identified pathogenic variants in TMEM260; the biallelic loss-of-function variants of which have recently been associated with structural heart defects and renal anomalies syndrome (SHDRA). In one patient, we identified a de novo pathogenic variant in GATA6, and in another patient, we identified a de novo probably pathogenic variant in NOTCH1. Notably, we identified a prevalent variant in TMEM260 (ENST00000261556.6), c.1617del (p.Trp539Cysfs*9), in 8/22 alleles among the 11 patients. The c.1617del variant was estimated to occur approximately 23 kiloyears ago. Based on the allele frequency of the c.1617del variant in the Japanese population (0.36%), approximately 26% of Japanese patients afflicted with TA could harbor homozygous c.1617del variants. This study highlights TMEM260, especially c.1617del, as a major genetic cause of TA in the Japanese population.
{"title":"Genetic etiology of truncus arteriosus excluding 22q11.2 deletion syndrome and identification of c.1617del, a prevalent variant in TMEM260, in the Japanese population","authors":"Hisao Yaoita, Eiichiro Kawai, Jun Takayama, Shinya Iwasawa, Naoya Saijo, Masayuki Abiko, Kouta Suzuki, Masato Kimura, Akira Ozawa, Gen Tamiya, Shigeo Kure, Atsuo Kikuchi","doi":"10.1038/s10038-024-01223-y","DOIUrl":"10.1038/s10038-024-01223-y","url":null,"abstract":"Truncus Arteriosus (TA) is a congenital heart disease characterized by a single common blood vessel emerging from the right and left ventricles instead of the main pulmonary artery and aorta. TA accounts for 4% of all critical congenital heart diseases. The most common cause of TA is 22q11.2 deletion syndrome, accounting for 12–35% of all TA cases. However, no major causes of TA other than 22q11.2 deletion have been reported. We performed whole-genome sequencing of 11 Japanese patients having TA without 22q11.2 deletion. Among five patients, we identified pathogenic variants in TMEM260; the biallelic loss-of-function variants of which have recently been associated with structural heart defects and renal anomalies syndrome (SHDRA). In one patient, we identified a de novo pathogenic variant in GATA6, and in another patient, we identified a de novo probably pathogenic variant in NOTCH1. Notably, we identified a prevalent variant in TMEM260 (ENST00000261556.6), c.1617del (p.Trp539Cysfs*9), in 8/22 alleles among the 11 patients. The c.1617del variant was estimated to occur approximately 23 kiloyears ago. Based on the allele frequency of the c.1617del variant in the Japanese population (0.36%), approximately 26% of Japanese patients afflicted with TA could harbor homozygous c.1617del variants. This study highlights TMEM260, especially c.1617del, as a major genetic cause of TA in the Japanese population.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 5","pages":"177-183"},"PeriodicalIF":3.5,"publicationDate":"2024-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01223-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139729733","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 : 2024-02-09DOI: 10.1038/s10038-024-01220-1
K. E. Ahlers-Dannen, J. Yang, M. M. Spicer, D. Fu, A. DeVore, R. A. Fisher
Intellectual disability (ID) is associated with an increased risk of developing psychiatric disorders, suggesting a common underlying genetic factor. Importantly, altered signaling and/or expression of regulator of G protein signaling 6 (RGS6) is associated with ID and numerous psychiatric disorders. RGS6 is highly conserved and undergoes complex alternative mRNA splicing producing ~36 protein isoforms with high sequence similarity historically necessitating a global approach in functional studies. However, our recent analysis in mice revealed RGS6 is most highly expressed in CNS with RGS6L(+GGL) isoforms predominating. A previously reported genetic variant in intron 17 of RGS6 (c.1369-1G>C), associated with ID, may provide further clues into RGS6L(+GGL) isoform functional delineation. This variant was predicted to alter a highly conserved canonical 3’ acceptor site creating an alternative branch point within exon 18 (included in a subset of RGS6L(+GGL) transcripts) and a frameshift forming an early stop codon. We previously identified this alternative splice site and demonstrated its use generates RGS6Lζ(+GGL) isoforms. Here, we show that the c.1369-1G>C variant disrupts the canonical, preferred (>90%) intron 17 splice site and leads to the exclusive use of the alternate exon 18 splice site, inducing disproportionate expression of a subset of isoforms, particularly RGS6Lζ(+GGL). Furthermore, RGS6 global knockout mice do not exhibit ID. Thus, ID caused by the c.1369-1G>C variant likely results from altered RGS6 isoform expression, rather than RGS6 isoform loss. In summary, these studies highlight the importance of proper RGS6 splicing and identify a previously unrecognized role of G protein signaling in ID.
{"title":"A splice acceptor variant in RGS6 associated with intellectual disability, microcephaly, and cataracts disproportionately promotes expression of a subset of RGS6 isoforms","authors":"K. E. Ahlers-Dannen, J. Yang, M. M. Spicer, D. Fu, A. DeVore, R. A. Fisher","doi":"10.1038/s10038-024-01220-1","DOIUrl":"10.1038/s10038-024-01220-1","url":null,"abstract":"Intellectual disability (ID) is associated with an increased risk of developing psychiatric disorders, suggesting a common underlying genetic factor. Importantly, altered signaling and/or expression of regulator of G protein signaling 6 (RGS6) is associated with ID and numerous psychiatric disorders. RGS6 is highly conserved and undergoes complex alternative mRNA splicing producing ~36 protein isoforms with high sequence similarity historically necessitating a global approach in functional studies. However, our recent analysis in mice revealed RGS6 is most highly expressed in CNS with RGS6L(+GGL) isoforms predominating. A previously reported genetic variant in intron 17 of RGS6 (c.1369-1G>C), associated with ID, may provide further clues into RGS6L(+GGL) isoform functional delineation. This variant was predicted to alter a highly conserved canonical 3’ acceptor site creating an alternative branch point within exon 18 (included in a subset of RGS6L(+GGL) transcripts) and a frameshift forming an early stop codon. We previously identified this alternative splice site and demonstrated its use generates RGS6Lζ(+GGL) isoforms. Here, we show that the c.1369-1G>C variant disrupts the canonical, preferred (>90%) intron 17 splice site and leads to the exclusive use of the alternate exon 18 splice site, inducing disproportionate expression of a subset of isoforms, particularly RGS6Lζ(+GGL). Furthermore, RGS6 global knockout mice do not exhibit ID. Thus, ID caused by the c.1369-1G>C variant likely results from altered RGS6 isoform expression, rather than RGS6 isoform loss. In summary, these studies highlight the importance of proper RGS6 splicing and identify a previously unrecognized role of G protein signaling in ID.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 3-4","pages":"145-152"},"PeriodicalIF":3.5,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139706915","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}
Non-syndromic orofacial cleft (NSOC) is one of the most common craniofacial malformations with complex etiology. This study aimed to explore the role of specific SNPs in ZFP36L2 and its functional relevance in zebrafish models. We analyzed genetic data of the Chinese Han population from two previous GWAS, comprising of 2512 cases and 2255 controls. Based on the Hardy-Weinberg Equilibrium (HWE) and minor allele frequency (MAF), SNPs in the ZFP36L2 were selected for association analysis. In addition, zebrafish models were used to clarify the in-situ expression pattern of zfp36l2 and the impact of its Morpholino-induced knockdown. Via association analysis, rs7933 in ZFP36L2 was significantly associated with various non-syndromic cleft lip-only subtypes, potentially conferring a protective effect. Zebrafish embryos showed elevated expression of zfp36l2 in the craniofacial region during critical stages of oral cavity formation. Furthermore, Morpholino-induced knockdown of zfp36l2 led to craniofacial abnormalities, including cleft lip, which was partially rescued by the addition of zfp36l2 mRNA. Our findings highlight the significance of ZFP36L2 in the etiology of NSOC, supported by both human genetic association data and functional studies in zebrafish. These results pave the way for further exploration of targeted interventions for craniofacial malformations.
{"title":"Genetic association and functional validation of ZFP36L2 in non-syndromic orofacial cleft subtypes","authors":"Jialin Sun, Mujia Li, Huaqin Sun, Ziyuan Lin, Bing Shi, Zhonglin Jia","doi":"10.1038/s10038-024-01222-z","DOIUrl":"10.1038/s10038-024-01222-z","url":null,"abstract":"Non-syndromic orofacial cleft (NSOC) is one of the most common craniofacial malformations with complex etiology. This study aimed to explore the role of specific SNPs in ZFP36L2 and its functional relevance in zebrafish models. We analyzed genetic data of the Chinese Han population from two previous GWAS, comprising of 2512 cases and 2255 controls. Based on the Hardy-Weinberg Equilibrium (HWE) and minor allele frequency (MAF), SNPs in the ZFP36L2 were selected for association analysis. In addition, zebrafish models were used to clarify the in-situ expression pattern of zfp36l2 and the impact of its Morpholino-induced knockdown. Via association analysis, rs7933 in ZFP36L2 was significantly associated with various non-syndromic cleft lip-only subtypes, potentially conferring a protective effect. Zebrafish embryos showed elevated expression of zfp36l2 in the craniofacial region during critical stages of oral cavity formation. Furthermore, Morpholino-induced knockdown of zfp36l2 led to craniofacial abnormalities, including cleft lip, which was partially rescued by the addition of zfp36l2 mRNA. Our findings highlight the significance of ZFP36L2 in the etiology of NSOC, supported by both human genetic association data and functional studies in zebrafish. These results pave the way for further exploration of targeted interventions for craniofacial malformations.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 3-4","pages":"139-144"},"PeriodicalIF":3.5,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139697582","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}
The ACTA2 gene encodes actin α2, a major smooth muscle protein in vascular smooth muscle cells. Missense variants in the ACTA2 gene can cause inherited thoracic aortic diseases with characteristic symptoms, such as dysfunction of smooth muscle cells in the lungs, brain vessels, intestines, pupils, bladder, or heart. We identified a heterozygous missense variant of Gly148Arg (G148R) in a patient with a thoracic aortic aneurysm, dissection, and left ventricular non-compaction. We used zebrafish as an in vivo model to investigate whether or not the variants might cause functional or histopathological abnormalities in the heart. Following the fertilization of one-cell stage embryos, we injected in vitro synthesized ACTA2 mRNA of wild-type, novel variant G148R, or the previously known pathogenic variant Arg179His (R179H). The embryos were maintained and raised for 72 h post-fertilization for a heart analysis. Shortening fractions of heart were significantly reduced in both pathogenic variants. A histopathological evaluation showed that the myocardial wall of ACTA2 pathogenic variants was thinner than that of the wild type, and the total cell number within the myocardium was markedly decreased in all zebrafish with pathogenic variants mRNAs. Proliferating cell numbers were also significantly decreased in the endothelial and myocardial regions of zebrafish with ACTA2 variants compared to the wild type. These results demonstrate the effects of ACTA2 G148R and R179H on the development of left ventricle non-compaction and cardiac morphological abnormalities. Our study highlights the previously unknown significance of the ACTA2 gene in several aspects of cardiovascular development.
{"title":"Cardiac manifestations of human ACTA2 variants recapitulated in a zebrafish model","authors":"Wulan Apridita Sebastian, Masanori Inoue, Nobuyuki Shimizu, Ryosuke Sato, Saori Oguri, Tomoyo Itonaga, Shintaro Kishimoto, Hiroshi Shiraishi, Toshikatsu Hanada, Kenji Ihara","doi":"10.1038/s10038-024-01221-0","DOIUrl":"10.1038/s10038-024-01221-0","url":null,"abstract":"The ACTA2 gene encodes actin α2, a major smooth muscle protein in vascular smooth muscle cells. Missense variants in the ACTA2 gene can cause inherited thoracic aortic diseases with characteristic symptoms, such as dysfunction of smooth muscle cells in the lungs, brain vessels, intestines, pupils, bladder, or heart. We identified a heterozygous missense variant of Gly148Arg (G148R) in a patient with a thoracic aortic aneurysm, dissection, and left ventricular non-compaction. We used zebrafish as an in vivo model to investigate whether or not the variants might cause functional or histopathological abnormalities in the heart. Following the fertilization of one-cell stage embryos, we injected in vitro synthesized ACTA2 mRNA of wild-type, novel variant G148R, or the previously known pathogenic variant Arg179His (R179H). The embryos were maintained and raised for 72 h post-fertilization for a heart analysis. Shortening fractions of heart were significantly reduced in both pathogenic variants. A histopathological evaluation showed that the myocardial wall of ACTA2 pathogenic variants was thinner than that of the wild type, and the total cell number within the myocardium was markedly decreased in all zebrafish with pathogenic variants mRNAs. Proliferating cell numbers were also significantly decreased in the endothelial and myocardial regions of zebrafish with ACTA2 variants compared to the wild type. These results demonstrate the effects of ACTA2 G148R and R179H on the development of left ventricle non-compaction and cardiac morphological abnormalities. Our study highlights the previously unknown significance of the ACTA2 gene in several aspects of cardiovascular development.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 3-4","pages":"133-138"},"PeriodicalIF":3.5,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-024-01221-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139692029","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 : 2024-01-17DOI: 10.1038/s10038-024-01219-8
Yuta Inoue, Naomi Tsuchida, Chong Ae Kim, Bruno de Oliveira Stephan, Matheus Augusto Araujo Castro, Rachel Sayuri Honjo, Debora Romeo Bertola, Yuri Uchiyama, Kohei Hamanaka, Atsushi Fujita, Eriko Koshimizu, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Naomichi Matsumoto
The gene for ATP binding cassette subfamily A member 2 (ABCA2) is located at chromosome 9q34.3. Biallelic ABCA2 variants lead to intellectual developmental disorder with poor growth and with or without seizures or ataxia (IDPOGSA). In this study, we identified novel compound heterozygous ABCA2 variants (NM_001606.5:c.[5300–17C>A];[6379C>T]) by whole exome sequencing in a 28-year-old Korean female patient with intellectual disability. These variants included intronic and nonsense variants of paternal and maternal origin, respectively, and are absent from gnomAD. SpliceAI predicted that the intron variant creates a cryptic acceptor site. Reverse transcription-PCR using RNA extracted from a lymphoblastoid cell line of the patient confirmed two aberrant transcripts. Her clinical features are compatible with those of IDPOGSA.
ATP 结合盒亚族 A 成员 2（ABCA2）的基因位于染色体 9q34.3。ABCA2双倍变体会导致智力发育障碍，表现为生长发育不良，伴有或不伴有癫痫发作或共济失调（IDPOGSA）。在本研究中，我们通过全外显子测序在一名 28 岁的韩国女性智力障碍患者中发现了新型复合杂合 ABCA2 变异（NM_001606.5:c. [5300-17C>A];[6379C>T]）。这些变异包括分别来自父源和母源的内含变异和无义变异，在 gnomAD 中并不存在。SpliceAI 预测内含子变异会产生一个隐性接受位点。利用从患者的淋巴母细胞系提取的 RNA 进行反转录-PCR，证实了两个异常转录本。她的临床特征与 IDPOGSA 患者相符。
{"title":"Novel compound heterozygous ABCA2 variants cause IDPOGSA, a variable phenotypic syndrome with intellectual disability","authors":"Yuta Inoue, Naomi Tsuchida, Chong Ae Kim, Bruno de Oliveira Stephan, Matheus Augusto Araujo Castro, Rachel Sayuri Honjo, Debora Romeo Bertola, Yuri Uchiyama, Kohei Hamanaka, Atsushi Fujita, Eriko Koshimizu, Kazuharu Misawa, Satoko Miyatake, Takeshi Mizuguchi, Naomichi Matsumoto","doi":"10.1038/s10038-024-01219-8","DOIUrl":"10.1038/s10038-024-01219-8","url":null,"abstract":"The gene for ATP binding cassette subfamily A member 2 (ABCA2) is located at chromosome 9q34.3. Biallelic ABCA2 variants lead to intellectual developmental disorder with poor growth and with or without seizures or ataxia (IDPOGSA). In this study, we identified novel compound heterozygous ABCA2 variants (NM_001606.5:c.[5300–17C>A];[6379C>T]) by whole exome sequencing in a 28-year-old Korean female patient with intellectual disability. These variants included intronic and nonsense variants of paternal and maternal origin, respectively, and are absent from gnomAD. SpliceAI predicted that the intron variant creates a cryptic acceptor site. Reverse transcription-PCR using RNA extracted from a lymphoblastoid cell line of the patient confirmed two aberrant transcripts. Her clinical features are compatible with those of IDPOGSA.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 3-4","pages":"163-167"},"PeriodicalIF":3.5,"publicationDate":"2024-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139478061","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 : 2024-01-17DOI: 10.1038/s10038-023-01216-3
Bing Wen, Runqi Tang, Shuyao Tang, Yuan Sun, Jingwen Xu, Dandan Zhao, Tan Wang, Chuanzhu Yan
Lipid storage myopathy (LSM) is a heterogeneous group of lipid metabolism disorders predominantly affecting skeletal muscle by triglyceride accumulation in muscle fibers. Riboflavin therapy has been shown to ameliorate symptoms in some LSM patients who are essentially concerned with multiple acyl-CoA dehydrogenation deficiency (MADD). It is proved that riboflavin responsive LSM caused by MADD is mainly due to ETFDH gene variant (ETFDH-RRMADD). We described here a case with riboflavin responsive LSM and MADD resulting from FLAD1 gene variants (c.1588 C > T p.Arg530Cys and c.1589 G > C p.Arg530Pro, FLAD1-RRMADD). And we compared our patient together with 9 FLAD1-RRMADD cases from literature to 106 ETFDH-RRMADD cases in our neuromuscular center on clinical history, laboratory investigations and pathological features. Furthermore, the transcriptomics study on FLAD1-RRMADD and ETFDH-RRMADD were carried out. On muscle pathology, both FLAD1-RRMADD and ETFDH-RRMADD were proved with lipid storage myopathy in which atypical ragged red fibers were more frequent in ETFDH-RRMADD, while fibers with faint COX staining were more common in FLAD1-RRMADD. Molecular study revealed that the expression of GDF15 gene in muscle and GDF15 protein in both serum and muscle was significantly increased in FLAD1-RRMADD and ETFDH-RRMADD groups. Our data revealed that FLAD1-RRMADD (p.Arg530) has similar clinical, biochemical, and fatty acid metabolism changes to ETFDH-RRMADD except for muscle pathological features.
脂质贮积性肌病（LSM）是一类异质性脂质代谢紊乱疾病，主要通过甘油三酯在肌纤维中的蓄积而影响骨骼肌。核黄素疗法已被证明可改善一些主要患有多酰基-CoA 脱氢缺乏症（MADD）的 LSM 患者的症状。经证实，核黄素反应性 LSM 由 MADD 引起，主要是由于 ETFDH 基因变异（ETFDH-RRMADD）。我们在此描述了一例因FLAD1基因变异（c.1588 C > T p.Arg530Cys和c.1589 G > C p.Arg530Pro，FLAD1-RRMADD）而导致核黄素反应性LSM和MADD的病例。我们将该患者与文献中的9例FLAD1-RRMADD病例以及本神经肌肉中心的106例ETFDH-RRMADD病例在临床病史、实验室检查和病理特征方面进行了比较。此外，还对FLAD1-RRMADD和ETFDH-RRMADD进行了转录组学研究。在肌肉病理学方面，FLAD1-RRMADD和ETFDH-RRMADD均被证实患有脂质贮积性肌病，其中ETFDH-RRMADD患者的非典型锯齿状红色纤维更为常见，而FLAD1-RRMADD患者的纤维则多伴有微弱的COX染色。分子研究发现，FLAD1-RRMADD组和ETFDH-RRMADD组肌肉中GDF15基因的表达以及血清和肌肉中GDF15蛋白的表达均显著增加。我们的数据显示，除肌肉病理特征外，FLAD1-RRMADD（p.Arg530）与ETFDH-RRMADD具有相似的临床、生化和脂肪酸代谢变化。
{"title":"A comparative study on riboflavin responsive multiple acyl-CoA dehydrogenation deficiency due to variants in FLAD1 and ETFDH gene","authors":"Bing Wen, Runqi Tang, Shuyao Tang, Yuan Sun, Jingwen Xu, Dandan Zhao, Tan Wang, Chuanzhu Yan","doi":"10.1038/s10038-023-01216-3","DOIUrl":"10.1038/s10038-023-01216-3","url":null,"abstract":"Lipid storage myopathy (LSM) is a heterogeneous group of lipid metabolism disorders predominantly affecting skeletal muscle by triglyceride accumulation in muscle fibers. Riboflavin therapy has been shown to ameliorate symptoms in some LSM patients who are essentially concerned with multiple acyl-CoA dehydrogenation deficiency (MADD). It is proved that riboflavin responsive LSM caused by MADD is mainly due to ETFDH gene variant (ETFDH-RRMADD). We described here a case with riboflavin responsive LSM and MADD resulting from FLAD1 gene variants (c.1588 C > T p.Arg530Cys and c.1589 G > C p.Arg530Pro, FLAD1-RRMADD). And we compared our patient together with 9 FLAD1-RRMADD cases from literature to 106 ETFDH-RRMADD cases in our neuromuscular center on clinical history, laboratory investigations and pathological features. Furthermore, the transcriptomics study on FLAD1-RRMADD and ETFDH-RRMADD were carried out. On muscle pathology, both FLAD1-RRMADD and ETFDH-RRMADD were proved with lipid storage myopathy in which atypical ragged red fibers were more frequent in ETFDH-RRMADD, while fibers with faint COX staining were more common in FLAD1-RRMADD. Molecular study revealed that the expression of GDF15 gene in muscle and GDF15 protein in both serum and muscle was significantly increased in FLAD1-RRMADD and ETFDH-RRMADD groups. Our data revealed that FLAD1-RRMADD (p.Arg530) has similar clinical, biochemical, and fatty acid metabolism changes to ETFDH-RRMADD except for muscle pathological features.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 3-4","pages":"125-131"},"PeriodicalIF":3.5,"publicationDate":"2024-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139478053","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 : 2024-01-15DOI: 10.1038/s10038-023-01213-6
Tatsuhiko Naito, Yukinori Okada
The imputation of unmeasured genotypes is essential in human genetic research, particularly in enhancing the power of genome-wide association studies and conducting subsequent fine-mapping. Recently, several deep learning-based genotype imputation methods for genome-wide variants with the capability of learning complex linkage disequilibrium patterns have been developed. Additionally, deep learning-based imputation has been applied to a distinct genomic region known as the major histocompatibility complex, referred to as HLA imputation. Despite their various advantages, the current deep learning-based genotype imputation methods do have certain limitations and have not yet become standard. These limitations include the modest accuracy improvement over statistical and conventional machine learning-based methods. However, their benefits include other aspects, such as their “reference-free” nature, which ensures complete privacy protection, and their higher computational efficiency. Furthermore, the continuing evolution of deep learning technologies is expected to contribute to further improvements in prediction accuracy and usability in the future.
{"title":"Genotype imputation methods for whole and complex genomic regions utilizing deep learning technology","authors":"Tatsuhiko Naito, Yukinori Okada","doi":"10.1038/s10038-023-01213-6","DOIUrl":"10.1038/s10038-023-01213-6","url":null,"abstract":"The imputation of unmeasured genotypes is essential in human genetic research, particularly in enhancing the power of genome-wide association studies and conducting subsequent fine-mapping. Recently, several deep learning-based genotype imputation methods for genome-wide variants with the capability of learning complex linkage disequilibrium patterns have been developed. Additionally, deep learning-based imputation has been applied to a distinct genomic region known as the major histocompatibility complex, referred to as HLA imputation. Despite their various advantages, the current deep learning-based genotype imputation methods do have certain limitations and have not yet become standard. These limitations include the modest accuracy improvement over statistical and conventional machine learning-based methods. However, their benefits include other aspects, such as their “reference-free” nature, which ensures complete privacy protection, and their higher computational efficiency. Furthermore, the continuing evolution of deep learning technologies is expected to contribute to further improvements in prediction accuracy and usability in the future.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"69 10","pages":"481-486"},"PeriodicalIF":2.6,"publicationDate":"2024-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s10038-023-01213-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139472265","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：