Article
Immunology
Nikita R. Raje, Janelle R. Noel-MacDonnell, Katherine A. Shortt, Nicole M. Gigliotti, Marcia A. Chan, Daniel P. Heruth
Summary: The phenotypic variations of chromosome 22q11.2 deletion syndrome (22qDS) are not well explained. This study investigated gene expression in T cells of individuals with and without 22qDS, and found differentially expressed genes associated with T cell counts and markers. This suggests an important role of T cells in defective communication in 22qDS.
JOURNAL OF IMMUNOLOGY
(2022)
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
Genetics & Heredity
Marta Smyk, Maciej Geremek, Kamila Ziemkiewicz, Tomasz Gambin, Anna Kutkowska-Kazmierczak, Katarzyna Kowalczyk, Izabela Plaskota, Barbara Wisniowiecka-Kowalnik, Magdalena Bartnik-Glaska, Magdalena Niemiec, Dominika Grad, Malgorzata Piotrowicz, Dorota Gieruszczak-Bialek, Aleksandra Pietrzyk, T. Blaine Crowley, Victoria Giunta, Daniel E. McGinn, Elaine H. Zackai, Oanh Tran, Beverly S. Emanuel, Donna M. McDonald-McGinn, Beata A. Nowakowska
Summary: This study investigated the impact of additional genomic variants on the clinical presentation of patients with 22q11.2 deletion syndrome. Findings showed that 6.3% of patients had pathogenic or likely pathogenic copy number variants outside of the 22q11.2 region, indicating their contribution to the clinical phenotype. Furthermore, exome sequencing revealed pathogenic and likely pathogenic single nucleotide variants and small copy number variants in 3.49% and 5.81% of patients, respectively. These results highlight the importance of genome-wide approaches in identifying clinically relevant changes in individuals with 22q11 deletion syndrome.
Article
Biology
Sara Ciof, Gemma Flore, Stefania Martucciello, Marchesa Bilio, Maria Giuseppina Turturo, Elizabeth Illingworth
Summary: The loss of a single copy of TBX1 accounts for most of the clinical signs and symptoms of 22q11.2 deletion syndrome. The main function of TBX1 in the mouse brain is to suppress vessel branching morphogenesis through regulation of Vegfr3. Inactivating Vegfr3 enhances brain vessel branching and filopodia formation, while increasing Vegfr3 expression fully rescues these phenotypes.
LIFE SCIENCE ALLIANCE
(2022)
Article
Medicine, Research & Experimental
Pratibha Bhalla, Qiumei Du, Ashwani Kumar, Chao Xing, Angela Moses, Igor Dozmorov, Christian A. Wysocki, Ondine B. Cleaver, Timothy J. Pirolli, Mary Louise Markert, Maria Teresa de la Morena, Antonio Baldini, Nicolai S. C. van Ders
Summary: 22q11.2 deletion syndrome (22q11.2DS) is the most common human chromosomal microdeletion, causing thymic hypoplasia and T cell lymphopenia. This study identified that abnormal thymic mesenchymal cells were responsible for the small size of the embryonic thymuses in the 22q11.2DS mouse models, and this could be corrected by replacing them with normal mesenchyme.
JOURNAL OF CLINICAL INVESTIGATION
(2022)
Article
Neurosciences
Ilaria Favicchia, Gemma Flore, Sara Cioffi, Gabriella Lania, Antonio Baldini, Elizabeth Illingworth
Summary: This research identified two FDA-approved drugs, Tranylcypromine and Vitamin B12, which successfully rescued cortical abnormalities in Tbx1 mutant mice. The rescue was achieved through mechanisms independent of Tbx1 function, suggesting potential importance for targeting specific genes within the deleted 22q11.2 region for effective treatments.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2021)
Article
Cell Biology
Shan Li, Weiwei Xu, Bingying Xu, Shuchang Gao, Qian Zhang, Yingying Qin, Ting Guo
Summary: This study identified novel homozygous variations in the HSF2BP gene through WES and found that these variations impaired the function of HSF2BP, playing an essential role in the pathogenesis of sporadic POI.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Genetics & Heredity
Jill M. Arganbright, Meghan Tracy, Max Feldt, Srivats Narayanan, Ashna Mahadev, Janelle Noel-MacDonnell
Summary: This study reviewed the occurrence of postoperative hypocalcemia in children with 22q11DS following non-cardiac surgeries and evaluated the frequency of calcium monitoring. The results showed that postoperative hypocalcemia is common in children with 22q11DS, and it can affect patients with or without a prior history of hypocalcemia. Therefore, establishing a protocol for perioperative testing/management of hypocalcemia is important for these patients.
Article
Genetics & Heredity
Caiyun Zhu, Yang Yang, Bo Pan, Hui Wei, Jiahang Ju, Nuo Si, Qi Xu
Summary: This study identifies genetic variations in the 22q11.2 genomic region that may contribute to the coexistence of microtia and congenital heart defect. Specifically, the study identifies potential deleterious variations in genes related to ear and heart development, suggesting a combination of genetic variations plays a crucial role in these comorbidities.
Article
Biochemistry & Molecular Biology
Mohammad Reza Karimzadeh, Fatemeh Omidi, Afsaneh Sahebalzamani, Kolsoum Saeidi
Summary: Cohen syndrome is caused by homozygous mutations in the VPS13B gene, leading to intellectual disability, facial abnormalities, and eye disorders. Whole-exome sequencing identified a pathogenic variant in two unrelated families, expanding the mutation spectrum of the VPS13B gene and providing valuable information for genetic diagnosis and counseling in Cohen syndrome patients.
JOURNAL OF MOLECULAR NEUROSCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Jing Zhang, Yiqin Dai, Dan Wu, Yue Li, Jianjiang Xu
Summary: This study identified FAM149A as a potential causative gene for CHED and revealed its role in antioxidant signaling pathways, providing new insights for future investigations targeting CHED.
FREE RADICAL BIOLOGY AND MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Elizabeth M. Paronett, Corey A. Bryan, Megan E. Maynard, Julia A. Goroff, Daniel W. Meechan, Anthony-Samuel LaMantia, Thomas M. Maynard
Summary: Facial dysmorphology is a hallmark of 22q11.2 deletion syndrome. The gene Ranbp1, which mediates nucleocytoplasmic protein trafficking, is a key player in craniofacial development. Mutations in Ranbp1 lead to facial phenotypes, particularly in the midline facial skeleton.
HUMAN MOLECULAR GENETICS
(2023)
Article
Genetics & Heredity
Beilei Jiang, Hua Zhang, Yuling Kan, Xueping Gao, Zhaoli Du, Quan Liu
Summary: This study reports on a Chinese family with OCA and identifies two novel variants in the OCA2 gene. By expanding the mutation spectrum of the gene, this finding contributes to a better understanding of the genetic basis of OCA.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Lucia Pia Bruno, Gabriella Doddato, Floriana Valentino, Margherita Baldassarri, Rossella Tita, Chiara Fallerini, Mirella Bruttini, Caterina Lo Rizzo, Maria Antonietta Mencarelli, Francesca Mari, Anna Maria Pinto, Francesca Fava, Alessandra Fabbiani, Vittoria Lamacchia, Anna Carrer, Valentina Caputo, Stefania Granata, Elisa Benetti, Kristina Zguro, Simone Furini, Alessandra Renieri, Francesca Ariani
Summary: Intelectual disability (ID) and autism spectrum disorder (ASD) are often associated and characterized by impairments in cognitive processes and daily life tasks. Molecular diagnosis is crucial for improving prognosis and initiating treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Medicine, General & Internal
Huiyan Luan, Lei Zhang, Sijin Zhang, Meng Zhang
Summary: This case report presents a Chinese girl diagnosed with familial hemiplegic migraine type 1 through genetic and clinical assessment. Prophylactic therapy with flunarizine did not show improvement in the intensity of attacks in this patient.
Article
Genetics & Heredity
Koki Nagai, Tetsuya Niihori, Nobuhiko Okamoto, Akane Kondo, Kenichi Suga, Tomoko Ohhira, Yasunobu Hayabuchi, Yukako Homma, Ryuji Nakagawa, Toshinobu Ifuku, Taiki Abe, Takeshi Mizuguchi, Naomichi Matsumoto, Yoko Aoki
Summary: Costello syndrome is an autosomal dominant disorder characterized by distinctive facial features, hypertrophic cardiomyopathy, skeletal abnormalities, intellectual disability, and predisposition to cancers, with germline variants in HRAS being identified in patients. In this study, it was found that small in-frame duplications within the HRAS gene enhance the activation of the ERK pathway, resulting in developmental abnormalities in zebrafish embryos or patients with Costello syndrome.
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
Maki Fukami, Junya Shindo, Tsutomu Ogata, Ikuko Kageyama, Tsutomu Kamimaki
Summary: Haploinsufficiency of SHOX is a major genetic cause of nonsyndromic short stature. Recent research has identified a novel cis-acting enhancer in the far-downstream region of SHOX, whose deletion leads to varying degrees of short stature. Furthermore, SHOX-flanking regions exhibit genomic instability, resulting in diverse nonrecurrent copy number variations.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2022)
Article
Genetics & Heredity
Yu Aihara, Matsuyuki Shirota, Atsuo Kikuchi, Yu Katata, Yu Abe, Tetsuya Niihori, Ryo Funayama, Keiko Nakayama, Yoko Aoki, Shigeo Kure
Summary: This case report describes a two-year-old girl with developmental delay, tremor, and ataxic gait, but no obvious dystonia. Exome sequencing identified a novel variant in the ANO3 gene, which has been associated with intellectual disability. The study suggests that specific variants in the transmembrane 4 domain of ANO3 may be a cause of childhood-onset movement disorder with intellectual disability, even in the absence of dystonia.
JOURNAL OF HUMAN GENETICS
(2023)
Article
Oncology
Hidekazu Shirota, Keigo Komine, Masanobu Takahashi, Shin Takahashi, Eisaku Miyauchi, Hidetaka Niizuma, Hiroshi Tada, Muneaki Shimada, Tetsuya Niihori, Yoko Aoki, Ikuko Sugiyama, Maako Kawamura, Jun Yasuda, Shuhei Suzuki, Takeshi Iwaya, Motonobu Saito, Tsuyoshi Saito, Hiroyuki Shibata, Toru Furukawa, Chikashi Ishioka
Summary: There has been a paradigm shift in cancer chemotherapy towards personalized medicine with molecular-targeted drugs. The Molecular Tumor Board (MTB) serves as a platform that integrates clinical and molecular features for clinical decisions. This study retrospectively analyzed cases discussed at the MTB, summarizing genetic alterations and treatment recommendations. The results provide valuable insights for simplifying treatment recommendations and improving personalized medicine accuracy.
Letter
Genetics & Heredity
Kyoko Fukahori, Kaori Yamoto, Hirotomo Saitsu, Tsutomu Ogata, Keisuke Nagasaki
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2023)
Article
Hematology
Masahiro Irie, Tetsuya Niihori, Tomohiro Nakano, Tasuku Suzuki, Saori Katayama, Kunihiko Moriya, Hidetaka Niizuma, Nobu Suzuki, Yuka Saito-Nanjo, Masaei Onuma, Takeshi Rikiishi, Atsushi Sato, Mayumi Hangai, Mitsuteru Hiwatari, Junji Ikeda, Reo Tanoshima, Norio Shiba, Yuki Yuza, Nobuyuki Yamamoto, Yoshiko Hashii, Motohiro Kato, Junko Takita, Miho Maeda, Yoko Aoki, Masue Imaizumi, Yoji Sasahara
Summary: This study retrospectively assessed the efficacy and safety of allogeneic hematopoietic stem cell transplantation (HSCT) in infants with MECOM-associated syndrome. The results showed that HSCT with reduced-intensity conditioning (RIC) was effective and feasible, with all patients achieving stable engraftment and complete chimerization. There were no severe regimen-related toxicities, and only mild acute graft-versus-host disease was observed. Therefore, allogeneic HSCT with RIC is a promising treatment option for infants with MECOM-associated syndrome.
INTERNATIONAL JOURNAL OF HEMATOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Yuko Katoh-Fukui, Atsushi Hattori, Ruogu Zhang, Miho Terao, Shuji Takada, Kazuhiko Nakabayashi, Kenichiro Hata, Yutaka Yamada, Nobuo Matsuura, Maki Fukami
Summary: This study reports a case of pituitary gigantism in a Japanese woman who carried a heterozygous deletion at 20q11.23. The deletion resulted in overexpression of GHRH, leading to the extreme phenotype of excessive body growth.
HUMAN MOLECULAR GENETICS
(2023)
Article
Biochemistry & Molecular Biology
Noriyuki Azuma, Tadashi Yokoi, Taku Tanaka, Emiko Matsuzaka, Yuki Saida, Sachiko Nishina, Miho Terao, Shuji Takada, Maki Fukami, Kohji Okamura, Kayoko Maehara, Tokiwa Yamasaki, Jun Hirayama, Hiroshi Nishina, Hiroshi Handa, Yuki Yamaguchi
Summary: This study reports the molecular and genetic characterization of Integrator complex subunit 15 (INTS15). INTS15 is highly expressed in the eye and brain, and it interacts with the Integrator complex to support small nuclear RNA 3' end processing. Knockdown of INTS15 leads to missplicing of numerous genes and affects genes associated with eye and brain development.
HUMAN MOLECULAR 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
Maako Kawamura, Hidekazu Shirota, Tetsuya Niihori, Keigo Komine, Masanobu Takahashi, Shin Takahashi, Eisaku Miyauchi, Hidetaka Niizuma, Atsuo Kikuchi, Hiroshi Tada, Muneaki Shimada, Naoki Kawamorita, Masayuki Kanamori, Ikuko Sugiyama, Mari Tsubata, Hitotshi Ichikawa, Jun Yasuda, Toru Furukawa, Yoko Aoki, Chikashi Ishioka
Summary: Cancer treatment is shifting towards personalized medicine, using genetic sequencing to identify therapeutic targets. This study retrospectively analyzed comprehensive genomic profiling (CGP) tests conducted at a hospital, focusing on the identification of presumed germline pathogenic variants (PGPV). The study found that confirmatory testing was recommended for 64 patients, with 17 patients testing positive for pathogenic variants. The results provide valuable insights for the management of secondary findings in genomic analysis.
JOURNAL OF HUMAN GENETICS
(2023)
Review
Biochemistry & Molecular Biology
Atsushi Hattori, Maki Fukami
Summary: This review article discusses the relationship between pathogenic variants of three nuclear receptor genes (NR5A1, NR0B1, and NR2F2) and disorders of sex development (DSD). NR5A1 variants are associated with 46,XY DSD and 46,XX testicular/ovotesticular DSD. NR0B1 and NR2F2 mutations are also implicated in DSD, but their exact roles are still unclear. Understanding these nuclear receptors provides new insights into the molecular networks involved in human fetal gonadal development.
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)
Review
Obstetrics & Gynecology
Erina Suzuki, Mami Miyado, Yoko Kuroki, Maki Fukami
Summary: The human hypothalamic-pituitary-gonadal (HPG) axis regulates pubertal development and involves six G-protein coupled receptors (GPCRs). Rare variants of these GPCR genes have been identified in patients with pubertal disorders. Loss-of-function variants in KISS1R, TACR3, PROKR2, and GNRHR cause hypogonadotropic hypogonadism, while gain-of-function variants of KISS1R, PROKR2, and LHCGR are implicated in precocious puberty. More research is needed to fully understand the molecular network involving these GPCRs.
REPRODUCTIVE MEDICINE AND BIOLOGY
(2023)
Article
Endocrinology & Metabolism
Kazuhisa Akiba, Yukihiro Hasegawa, Yuko Katoh-Fukui, Miho Terao, Shuji Takada, Tomonobu Hasegawa, Maki Fukami, Satoshi Narumi
Summary: This study demonstrates that the c.143-83A>G variant leads to splicing disruption, resulting in morphological and functional abnormalities in the pituitary gland. The findings provide valuable insights into the role of POU1F1/Pou1f1 transcripts in pituitary development.