Article
Multidisciplinary Sciences
Lingyan Cheng, Yinong Zhang, Yuzhi Ding, Zhilan Yuan, Xiao Han
Summary: This study described the clinical and genetic findings of an Axenfeld-Rieger syndrome family with a new PITX2 splicing mutation. All patients in the family showed abnormalities in the anterior segment of both eyes. A novel PITX2 splicing mutation was identified in the family, expanding the genetic spectrum of ARS and confirming the role of PITX2 gene deficiency in the development of ARS.
Article
Medicine, General & Internal
Dan Xie, Jiangfen Wu, Wenyi Zhang, Tingting Jin, Peng Wu, Banquan An, Shengwen Huang
Summary: This study reports a case of genetic diagnosis in a patient with congenital nephrotic syndrome. The patient presented with massive proteinuria, hypoproteinemia, hyperlipidemia, and marked edema. Whole exome sequencing identified compound heterozygous mutations in the NPHS1 gene, confirming the diagnosis of congenital nephrotic syndrome. The patient received anti-infective and symptomatic treatment, but died 2 months later with an unclear cause. The identification of a novel mutation expands the gene-mutation spectrum of the NPHS1 gene and provides a potential approach for prenatal screening and early genetic counseling for kidney diseases.
Article
Cell Biology
Ken Saida, Tokiko Fukuda, Daryl A. Scott, Toru Sengoku, Kazuhiro Ogata, Annarita Nicosia, Andres Hernandez-Garcia, Seema R. Lalani, Mahshid S. Azamian, Haley Streff, Pengfei Liu, Hongzheng Dai, Takeshi Mizuguchi, Satoko Miyatake, Miki Asahina, Tsutomu Ogata, Noriko Miyake, Naomichi Matsumoto
Summary: X-linked intellectual disability (XLID) is a common disorder with over 100 mutated genes reported. This study identified pathogenic OTUD5 variants in two families with developmental delay, showing features of LINKage-specific-deubiquitylation-deficiency-induced embryonic defects (LINKED) syndrome. Unlike previous reports of early lethality, the patients in this study have survived with a milder phenotype.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Genetics & Heredity
Chunhui Huang, Yonghong Zheng, Wei Zhang, Zhigang Chen, Zhixin Huang, Yuan Fang
Summary: We reported the first case of familial hypertrophic cardiomyopathy caused by a novel FLNC splicing mutation in China. Duo exome sequencing revealed a heterozygous mutation in the FLNC gene as a potential cause of autosomal dominant HCM. Treatment with furosemide, spironolactone, and metoprolol improved the patient's heart function and alleviated symptoms.
FRONTIERS IN GENETICS
(2022)
Review
Genetics & Heredity
James Jiqi Wang, Bo Yu, Yang Sun, Xiuli Song, Dao Wen Wang, Zongzhe Li
Summary: We reported a novel splice-altering mutation in the FBN1 gene that leads to two abnormal transcripts simultaneously. By systematically summarizing previous transcriptional studies of splice-altering mutations, we gained further insights into the clinical and transcriptional consequences of these mutations.
Article
Clinical Neurology
Qin Zhou, Jingwei Wang, Li Xia, Rong Li, Qiumin Zhang, Songqing Pan
Summary: This study characterized a genetic mutation in the X-linked SYN1 gene causing toothbrushing epilepsy in a Chinese family, and identified a novel mutation that could contribute to understanding the mechanism of this form of epilepsy.
FRONTIERS IN NEUROLOGY
(2021)
Article
Endocrinology & Metabolism
Kheloud M. Alhamoudi, Balgees Alghamdi, Meshael Alswailem, Abdul Nasir, Abeer Aljomaiah, Hindi Al-Hindi, Ali S. Alzahrani
Summary: This study reports a novel synonymous PHEX variant that causes X-linked hypophosphatemia (XLH) through a unique mechanism.
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
(2022)
Article
Genetics & Heredity
Chen Li, Xingwang Wang, Fake Li, Hongke Ding, Ling Liu, Ying Xiong, Chaoxiang Yang, Yan Zhang, Jing Wu, Aihua Yin
Summary: A novel nonsense variant in the OFD1 gene was identified in a suspected JBS family, broadening the genetic variation spectrum of JBS10 caused by OFD1. RNA-seq and protein structure prediction revealed that this variant may lead to a change in the structure of the OFD1 protein.
FRONTIERS IN GENETICS
(2023)
Article
Genetics & Heredity
Fengchang Qiao, Cuiping Zhang, Yan Wang, Gang Liu, Binbin Shao, Ping Hu, Zhengfeng Xu
Summary: Cornelia de Lange syndrome is a genetically heterogeneous disorder with NIPBL gene variants accounting for a significant portion of cases. A new de novo synonymous variant in the NIPBL gene was identified through whole-exome sequencing, expanding the mutation spectrum and highlighting the crucial role of WES in identifying genetic variants. The study also underscores the importance of considering synonymous mutations as potential pathogenic variants in clinical diagnoses.
FRONTIERS IN GENETICS
(2021)
Article
Biochemistry & Molecular Biology
Yu-Wen Cheng, Chia-Tung Wu, Chi-Jen Chang, Yung-Hsin Yeh, Gwo-Jyh Chang, Hsin-Yi Tsai, Lung-An Hsu
Summary: Through whole-exome sequencing, we identified a novel AGCGACAC deletion (S981fs) in the hERG gene of an LQT2 patient. Functional expression of the mutant K channel was restored by lowering temperature and using potassium channel inhibitors or openers. Our study reveals the mechanisms underlying LQT2 and offers potential therapeutic avenues.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Zhenxing Liu, Kaikai Guo, Xuebin Hu, Xianqin Zhang
Summary: In this study, a novel heterozygous mutation (c.1159C>T, p.Q387X) in the KRIT1 gene was identified in a four-generation family with cerebral cavernous malformation (CCM). This mutation resulted in premature termination of the KRIT1 protein, providing further evidence that KRIT1 mutations are a cause of CCM. These findings are important for the treatment and genetic diagnosis of CCM.
FRONTIERS IN ONCOLOGY
(2023)
Article
Genetics & Heredity
Qian Zhang, Shuya Yang, Xin Chen, Hongdan Wang, Keyan Li, Chaonan Zhang, Shixiu Liao, Litao Qin, Qiaofang Hou
Summary: This study aimed to analyze the genotype of Meckel Syndrome (MKS) patients and investigate the correlation between genotype and phenotype. The researchers performed whole exome sequencing (WES) and Sanger sequencing in a family affected by MKS. They identified two novel splice site variants of the TMEM231 gene, and confirmed the carriers in the family. Their findings revealed the pathological etiology of primary cilia in humans and provided a basis for genetic counselling.
FRONTIERS IN GENETICS
(2023)
Article
Genetics & Heredity
Jiachen Lin, Lina Zhao, Sen Zhao, Shengjie Li, Zhengye Zhao, Zefu Chen, Zhifa Zheng, Jiashen Shao, Yuchen Niu, Xiaoxin Li, Jianguo Terry Zhang, Zhihong Wu, Nan Wu
Summary: Genetic perturbations in NADSYN1 may predispose individuals to VCRL syndrome, and the study found that variants in NADSYN1 could impact protein levels and enzymatic activity, contributing to the complex genetic etiology of congenital vertebral malformations.
Article
Genetics & Heredity
Na Ma, Zhenhua Zhu, Jing Liu, Ying Peng, Xiaomeng Zhao, Weiling Tang, Zhengjun Jia, Hui Xi, Bodi Gao, Hua Wang, Juan Du
Summary: The study identified a synonymous COL5A2 gene mutation that can cause skipping of exon 29 in the RNA transcript, resulting in the production of mutant alpha 2(V)-chains and clinical phenotype of cEDS. This highlights the importance of including splicing-altering synonymous mutations in the screening for cEDS.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2021)
Article
Cell Biology
Aixia Jin, Qingqing Zhao, Shuting Liu, Zi-bing Jin, Shuyan Li, Mengqing Xiang, Mingbing Zeng, Kangxin Jin
Summary: A new mutation in GJA8 causing congenital cataract was identified and its functional impact was revealed. This finding expands the pathogenic mutation spectrum of Cx50 underlying cataract, providing more support for clinical diagnosis and genetic counseling.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Genetics & Heredity
Jessica Omark, Yohei Masunaga, Mark Hannibal, Brandon Shaw, Maki Fukami, Fumiko Kato, Hirotomo Saitsu, Masayo Kagami, Tsutomu Ogata
Summary: This study reported a case of an African American female infant with Kagami-Ogata syndrome (KOS14) phenotype caused by a chromosomal translocation involving the 14q32.2 imprinted region. The analysis revealed disruption of MEG3 leading to excessive RTL1 expression as a potential mechanism for KOS14 development.
JOURNAL OF HUMAN GENETICS
(2021)
Article
Genetics & Heredity
Takuya Hiraide, Yohei Masunaga, Akira Honda, Fumiko Kato, Tokiko Fukuda, Maki Fukami, Mitsuko Nakashima, Hirotomo Saitsu, Tsutomu Ogata
Summary: This article describes X-linked dominant chondrodysplasia punctata (CDPX2), a rare congenital disorder, and identifies the presence of retrotransposition-induced insertion in the genes of two patients through whole genome sequencing.
JOURNAL OF HUMAN GENETICS
(2022)
Article
Genetics & Heredity
Takuya Hiraide, Kenji Shimizu, Sachiko Miyamoto, Kazushi Aoto, Mitsuko Nakashima, Tomomi Yamaguchi, Tomoki Kosho, Tsutomu Ogata, Hirotomo Saitsu
Summary: Exome sequencing and panel testing have improved the diagnostic yield in genetic analysis. This study utilized genome sequencing and RNA sequencing to explore the genetic basis of Marfan syndrome in a family. The findings suggest that urinary cells can be used as a clinically accessible tissue for RNA sequencing, especially when disease-causing genes are poorly expressed in the blood.
JOURNAL OF HUMAN GENETICS
(2022)
Article
Genetics & Heredity
Sachiko Miyamoto, Mitsuko Nakashima, Shinobu Fukumura, Satoko Kumada, Hirotomo Saitsu
Summary: This study reported an intronic variant in the GNAO1 gene, which was found to cause abnormal splicing and result in the insertion of 2 amino acids, leading to movement disorders. By conducting RNA testing and immunological methods, the researchers found that the cellular localization pattern of the mutant protein was different from the wild type.
Article
Genetics & Heredity
Yohei Masunaga, Yumiko Ohkubo, Gen Nishimura, Taizo Ueno, Yasuko Fujisawa, Maki Fukami, Hirotomo Saitsu, Tsutomu Ogata
Summary: This study reports a case of a Japanese girl with severe idiopathic short stature caused by biallelic loss-of-function variants in the ACAN gene. The findings provide new evidence for the association between ACAN gene mutations and idiopathic short stature.
JOURNAL OF HUMAN GENETICS
(2022)
Article
Genetics & Heredity
Kazuo Abe, Kumiko Ando, Mitsuhiro Kato, Hirotomo Saitsu, Mitsuko Nakashima, Shintaro Aoki, Takashi Kimura
Summary: This study reports a case of a 24-year-old male patient with intellectual disability and childhood-onset seizures. The patient was found to have newly identified biallelic variants in the LAMC3 gene, along with previously unreported cortical malformations. The findings suggest a unique role of LAMC3 in brain development.
NEUROLOGY-GENETICS
(2022)
Article
Genetics & Heredity
Kazuki Watanabe, Mitsuko Nakashima, Rie Wakatsuki, Tomoyasu Bunai, Yasuomi Ouchi, Tomohiko Nakamura, Hiroaki Miyajima, Hirotomo Saitsu
Summary: This study investigated the genetic basis and brain metabolism and blood flow of a Japanese family with spinocerebellar degeneration (SCD). Whole-exome sequencing (WES) and whole-genome sequencing (WGS) were performed, but no likely pathogenic variants were identified. ExpansionHunter Denovo detected repeat expansions in the RFC1 gene, leading to the diagnosis of RFC1-related disorders. The patients showed a variety of clinical features, including motor neuropathy and cognitive impairment. Imaging studies revealed cortical damage in some patients, while others showed no apparent cerebral damage.
NEUROLOGY-GENETICS
(2022)
Article
Genetics & Heredity
Takuya Hiraide, Tenpei Akita, Kenji Uematsu, Sachiko Miyamoto, Mitsuko Nakashima, Masayuki Sasaki, Atsuo Fukuda, Mitsuhiro Kato, Hirotomo Saitsu
Summary: This study reports a case of KCNB1 mutation that results in a milder phenotype compared to previously reported cases. The brain MRI of the patient showed characteristic abnormalities, and functional analysis revealed that the mutant variant reduces channel activation and inactivation at specific membrane voltages.
JOURNAL OF HUMAN GENETICS
(2023)
Article
Genetics & Heredity
Mitsuko Nakashima, Emanuela Argilli, Sayaka Nakano, Elliott H. Sherr, Mitsuhiro Kato, Hirotomo Saitsu
Summary: A recent study discovered that genetic variants in the CLCN3 gene can cause neurodevelopmental disorders and brain abnormalities. The study found that some variants had a gain-of-function effect on channel activity. Two patients with specific CLCN3 variants showed severe neurological symptoms and a range of brain abnormalities. These findings expand our understanding of CLCN3-related disorders.
JOURNAL OF HUMAN GENETICS
(2023)
Article
Genetics & Heredity
Takuya Hiraide, Kenji Shimizu, Yoshinori Okumura, Sachiko Miyamoto, Mitsuko Nakashima, Tsutomu Ogata, Hirotomo Saitsu
Summary: The recent use of genome sequencing in genetic analysis has led to the discovery of pathogenic variants located deep within introns. In this study, a Japanese boy with Joubert syndrome was found to have biallelic TCTN2 variants. Exome sequencing identified one variant, and subsequent genome sequencing found a deep intronic variant. Machine learning algorithms were unable to predict the effect of the intronic variant on splicing, but the tool SpliceRover was successful in detecting a cryptic exon. Further RNA sequencing confirmed the presence of the cryptic exon. The patient exhibited typical symptoms of TCTN2-related disorders along with some uncommon features. These findings highlight the usefulness of genome sequencing and RNA sequencing in molecular diagnosis and suggest the potential of SpliceRover in extracting candidate variants from intronic variants in genome sequencing.
JOURNAL OF HUMAN GENETICS
(2023)
Article
Genetics & Heredity
Hazuki Morikawa, Sachiko Nishina, Kaoruko Torii, Katsuhiro Hosono, Tadashi Yokoi, Chika Shigeyasu, Masakazu Yamada, Motomichi Kosuga, Maki Fukami, Hirotomo Saitsu, Noriyuki Azuma, Yuichi Hori, Yoshihiro Hotta
Summary: We present the case of a 1-year-old girl with congenital stromal corneal dystrophy confirmed by genetic analysis. The patient exhibited bilateral diffuse opacity over the corneal stroma. Genetic analysis using whole exome sequencing identified a novel de novo variant, NM_001920.5: c.953del, p.(Asn318Thrfs*10), in the DCN gene. This information is important for counseling the parents regarding the recurrence risk.
HUMAN GENOME VARIATION
(2023)
Article
Genetics & Heredity
Kazuki Watanabe, Kazuo Kubota, Mitsuko Nakashima, Hirotomo Saitsu
Summary: This study presents a unique case of a patient with typical NF1 findings and infantile spasms who had three potentially pathogenic de novo variants in NF1 and one variant in GABBR1. It contributes to our understanding of the impact of these variants on NF1 phenotypes and GABBR1-related neuropsychiatric disorders.
HUMAN GENOME VARIATION
(2023)
Article
Genetics & Heredity
Karin Kojima, Takahito Wada, Hiroko Shimbo, Takahiro Ikeda, Eriko F. Jimbo, Hirotomo Saitsu, Naomichi Matsumoto, Takanori Yamagata
Summary: The ATRX variant c.21-1G>A was detected in a patient with Cockayne syndrome without ATR-XS. This variant leads to abnormal splicing and results in a slightly shorter but functional ATRX protein.
HUMAN GENOME VARIATION
(2022)
Article
Genetics & Heredity
Marina Hashiguchi, Yukifumi Monden, Yasuyuki Nozaki, Kazuki Watanabe, Mitsuko Nakashima, Hirotomo Saitsu, Takanori Yamagata, Hitoshi Osaka
Summary: TUBB4A gene variants can cause dystonia type 4 and hypomyelination with atrophy of the basal ganglia and cerebellum. This case report highlights the vulnerability of the cerebellum in patients with TUBB4A pathogenic variants.
HUMAN GENOME VARIATION
(2022)
Article
Genetics & Heredity
Shogo Furukawa, Sachiko Miyamoto, Shinobu Fukumura, Kazuo Kubota, Toshiaki Taga, Mitsuko Nakashima, Hirotomo Saitsu
Summary: Variants in ATP1A3 play a significant role in neuropsychiatric disorders, particularly those characterized by movement disorders. Whole exome sequencing identified two novel ATP1A3 variants in two patients with movement disorders, including a missense variant and an indel variant.
HUMAN GENOME VARIATION
(2022)