Article
Genetics & Heredity
Xiaohong Li, Shasha Huang, Guojian Wang, Dongyang Kang, Mingyu Han, Xiedong Wu, Jinyuan Yang, Qiuchen Zheng, Chaoyue Zhao, Yongyi Yuan, Pu Dai
Summary: This study further investigates the occurrence of low-level parental mosaicism in 33 WS families with de novo variants and introduces a procedure for quantifying low-level mosaicism. Four families were validated to have low-level mosaic variants, including three SNVs and one CNV, all identified in SOX10. The rate of parental mosaicism was 25% in WS families with de novo SOX10 variants. The lowest allele ratio of a mosaic variant was 2.0% in parental saliva. These findings highlight the importance of systematically investigating low-level parental mosaicism for WS genetic counseling using personalized sensitive testing such as amplicon-based NGS and ddPCR.
Article
Multidisciplinary Sciences
Yoo-Jin Ha, Myung Joon Oh, Junhan Kim, Jisoo Kim, Seungseok Kang, John D. Minna, Hyun Seok Kim, Sangwoo Kim
Summary: This study provides a set of ultra-deep sequenced data for somatic mosaicism detection strategies based on cell line mixtures. By mimicking the cumulative nature of mosaic variant acquisition, the study reveals the inter-sample relationships and holds significance for optimizing detection strategies and developing algorithms.
Article
Hematology
Maria Jose Ramirez, Roser Pujol, Juan Pablo Trujillo-Quintero, Jordi Minguillon, Massimo Bogliolo, Paula Rio, Susana Navarro, Jose A. Casado, Isabel Badell, Estela Carrasco, Judith Balmana, Albert Catala, Julian Sevilla, Cristina Belendez, Bienvenida Argiles, Monica Lopez, Cristina Diaz de Heredia, Gayatri Rao, Eileen Nicoletti, Jonathan D. Schwartz, Juan A. Bueren, Jordi Surralles
Summary: Fanconi anemia is a genetic disorder characterized by chromosome fragility, bone marrow failure, and predisposition to cancer. A study in Spain found that mosaic FA patients had more favorable long-term clinical outcomes, with some showing multilineage mosaicism. This reverse mosaicism was associated with older age, lower percentage of aberrant cells, and more stable hematology in these patients.
AMERICAN JOURNAL OF HEMATOLOGY
(2021)
Article
Multidisciplinary Sciences
Ioan-Andrei Iliuta, Aung Zaw Win, Matthew B. Lanktree, Seung Heyck Lee, Marina Pourafkari, Fatemeh Nasri, Elsa Guiard, Amirreza Haghighi, Ning He, Alistair Ingram, Crystal Quist, David Hillier, Korosh Khalili, York Pei
Summary: The Mayo Clinic Imaging Classification provides a validated approach to assess the risk of chronic kidney disease progression in autosomal dominant polycystic kidney disease (ADPKD), but excludes patients with atypical imaging patterns. In this study, the prevalence, clinical and genetic characteristics of patients with atypical polycystic kidney disease were analyzed. Patients with atypical polycystic kidney disease were older, less likely to have a family history or detectable mutations, and had a lower risk of progression to chronic kidney disease.
SCIENTIFIC REPORTS
(2023)
Article
Oncology
Fresia Pareja, Ryan N. Ptashkin, David N. Brown, Fatemeh Derakhshan, Pier Selenica, Edaise M. da Silva, Andrea M. Gazzo, Arnaud Da Cruz Paula, Kelsey Breen, Ronglai Shen, Antonio Marra, Ahmet Zehir, Ryma Benayed, Michael F. Berger, Ozge Ceyhan-Birsoy, Sowmya Jairam, Margaret Sheehan, Utsav Patel, Yelena Kemel, Jacklyn Casanova-Murphy, Christopher J. Schwartz, Mahsa Vahdatinia, Elizabeth Comen, Laetitia Borsu, Xin Pei, Nadeem Riaz, David H. Abramson, Britta Weigelt, Michael F. Walsh, Anna-Katerina Hadjantonakis, Marc Ladanui, Kenneth Offit, Zsofia K. Stadler, Mark E. Robson, Jorge S. Reis-Filho, Diana Mandelker
Summary: This study demonstrates that mosaic variants in cancer susceptibility genes (CSGs) arising in early embryogenesis contribute to the development of apparently sporadic cancers. These variants can be systematically detected through the analysis of tumor/normal sequencing data, and their detection may impact therapeutic decisions and preventive measures for patients and their offspring.
Article
Genetics & Heredity
Abbe Lai, Aubrie Soucy, Christelle Moufawad El Achkar, Anthony J. Barkovich, Yang Cao, Marina DiStefano, Michael Evenson, Renzo Guerrini, Devon Knight, Yi-Shan Lee, Heather C. Mefford, David T. Miller, Ghayda Mirzaa, Ganesh Mochida, Lance H. Rodan, Mayher Patel, Lacey Smith, Sara Spencer, Christopher A. Walsh, Edward Yang, Christopher J. Yuskaitis, Timothy Yu, Annapurna Poduri
Summary: This study established a rigorous framework for interpreting somatic mosaic variants, addressing unique issues related to somatic variants that are applicable to many genes and conditions.
GENETICS IN MEDICINE
(2022)
Article
Neurosciences
Sahibjot Sran, Tracy A. Bedrosian
Summary: During cell division in development, errors in DNA replication and repair can cause somatic mosaicism, leading to unique constellations of genetic variants in different cell lineages. Recent studies have shown that somatic variants affecting the Ras pathway are strongly associated with focal epilepsy. The Ras pathway, known for its role in tumorigenesis, also plays a role in brain development and epileptogenesis, as evidenced by Ras pathway disruption in RASopathies. This review summarizes the involvement of the Ras pathway in epilepsy and neurodevelopmental disorders, focusing on the emerging evidence of Ras pathway mosaicism and its potential clinical implications.
NEUROBIOLOGY OF DISEASE
(2023)
Article
Clinical Neurology
Daniel C. Koboldt, Katherine E. Miller, Anthony R. Miller, Jocelyn M. Bush, Sean McGrath, Kristen Leraas, Erin Crist, Summer Fair, Wesley Schwind, Saranga Wijeratne, James Fitch, Jeffrey Leonard, Ammar Shaikhouni, Mark E. Hester, Vincent Magrini, Mai-Lan Ho, Christopher R. Pierson, Richard K. Wilson, Adam P. Ostendorf, Elaine R. Mardis, Tracy A. Bedrosian
Summary: This study reports two somatic variants of PTEN affecting a single patient with intractable epilepsy and hemimegalencephaly, varying in clinical severity throughout the left cerebral hemisphere. High-throughput sequencing analysis identified two somatic variants in PTEN, with one affecting multiple cell lineages throughout the hemisphere and associated with mild cerebral overgrowth, while the other restricted to posterior brain regions resulted in a segmental region of more severe malformation.
Article
Genetics & Heredity
Ying-Chen Claire Hou, Michael J. Evenson, Meagan M. Corliss, Lily Mahapatra, Ali Aldawood, David F. Carpentieri, Sarah L. Chamlin, Ann M. Kulungowski, Suneeta Madan-Khetarpal, Jessica Sebastian, Mitchell A. Pet, Carrie C. Coughlin, Marcia C. Willing, Gregory D. Pearson, Bhuvana A. Setty, Zaki El-Haffaf, Catherine E. Cottrell, Bijal A. Parikh, Kilannin Krysiak, Molly C. Schroeder, Jonathan W. Heusel, Julie A. Neidich, Yang Cao
Summary: This study investigates the mutational spectrum of RAS variants in nonmalignant conditions and explores their genotype-phenotype associations. Classic hotspots were found to have a high frequency in nonmalignant conditions and were associated with a broad phenotypic spectrum. In addition, the study identified insertion/deletion variants in the switch II domain of HRAS and KRAS that were associated with vascular malformations. This research provides insights into the genetic and clinical heterogeneity of mosaic RAS variants in nonmalignant conditions.
GENETICS IN MEDICINE
(2023)
Article
Genetics & Heredity
Esra Yildiz Bolukbasi, Justyna A. Karolak, Przemyslaw Szafranski, Tomasz Gambin, Nicholas Willard, Steven H. Abman, Csaba Galambos, John P. Kinsella, Pawel Stankiewic
Summary: This study aimed to investigate a family with a deceased neonate with ACDMPV. It was found that the pathogenic CNV deletion of the lung-specific FOXF1 enhancer in the proband was inherited from an unaffected mother who had high-level somatic mosaicism. PGT studies revealed a high proportion of embryos carrying the deletion, indicating a high level of germline mosaicism.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2022)
Article
Medicine, General & Internal
Haiyue Deng, Yanqin Zhang, Jie Ding, Fang Wang
Summary: This study focused on evaluating mosaicism in Chinese XLAS families with suspected parental mosaicism, in order to provide more appropriate genetic counseling. The results revealed germline and very low-level somatic mosaicism for a COL4A5 splicing variant in an asymptomatic female, highlighting the importance of excluding parental mosaicism when a COL4A5 de novo disease-causing variant is detected.
FRONTIERS IN MEDICINE
(2022)
Review
Biochemistry & Molecular Biology
Noemi Alvarez-Lindo, Teresa Suarez, Enrique J. de la Rosa
Summary: Genetic mosaicism is an intriguing feature of the mammalian brain, similar to the immune system, that generates diversity in genetic information and cellular function. However, its origin and physiological significance are still poorly understood. Our studies in the developing retina shed light on the relationship between DNA rearrangements, neurogenesis, and early neuronal cell death, providing new insights into the mechanisms of DNA rearrangements in the developing brain.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Cardiac & Cardiovascular Systems
Ying Wang, Soichi Sano, Hayato Ogawa, Keita Horitani, Megan A. Evans, Yoshimitsu Yura, Emiri Miura-Yura, Heather Doviak, Kenneth Walsh
Summary: Clonal haematopoiesis is a phenomenon where somatic mutations in haematopoietic stem cells can lead to an increased risk of cardiovascular disease and mortality, particularly in the elderly. Studies have shown mechanistic connections between clonal haematopoiesis and cardiovascular disease in murine models, and a deeper understanding of specific mutations may pave the way for personalized therapeutic strategies.
CARDIOVASCULAR RESEARCH
(2022)
Article
Immunology
Lies Van Horebeek, Nina Dedoncker, Benedicte Dubois, An Goris
Summary: This study investigated somatic mosaicism in T lymphocyte subsets and found that it is widespread in both control individuals and multiple sclerosis (MS) patients. Somatic variants were more common and abundant in CD8(+) T lymphocytes, but their presence and abundance did not differ between MS patients and controls.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Bartlomiej Swiatczak
Summary: Normal cells in the body may evolve through mutation and selection during the lifetime of the organism, challenging our traditional understanding of biological individuals and collectives.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Clinical Neurology
Yuka Murofushi, Itaru Hayakawa, Yuichi Abe, Tatsuyuki Ohto, Kei Murayama, Hisato Suzuki, Toshiki Takenouchi, Kenjiro Kosaki, Masaya Kubota
Summary: Mutations in KARS can lead to impaired protein synthesis, resulting in progressive leukodystrophies with mitochondrial dysfunction. Current therapy is limited to supportive care, but a ketogenic diet and vitamin supplementation may help alleviate symptoms and improve some functions in patients.
Article
Genetics & Heredity
Miyako Kanno, Mitsuyoshi Suzuki, Ken Tanikawa, Chikahiko Numakura, Shu-ichi Matsuzawa, Tetsuya Niihori, Yoko Aoki, Yoichi Matsubara, Satoshi Makino, Gen Tamiya, Satoshi Nakano, Ryo Funayama, Matsuyuki Shirota, Keiko Nakayama, Tetsuo Mitsui, Kiyoshi Hayasaka
Summary: PILBD is a heterogeneous disorder classified into syndromic and non-syndromic categories. In a family with dominantly inherited PILBD, a pathogenic variant CACYBP/SIP p.E177Q was found, leading to enhanced degradation of beta-catenin and delayed intrahepatic bile duct maturation. This discovery suggests that accurate regulation of beta-catenin concentration is crucial for bile duct development.
JOURNAL OF HUMAN GENETICS
(2022)
Article
Clinical Neurology
Mitsuhiro Kato, Akiko Kada, Hideaki Shiraishi, Jun Tohyama, Eiji Nakagawa, Yukitoshi Takahashi, Tomoyuki Akiyama, Akiyoshi Kakita, Noriko Miyake, Atsushi Fujita, Akiko M. Saito, Yushi Inoue
Summary: Sirolimus has a certain inhibitory effect on focal seizures in patients with FCD type II, however, the reduction level did not reach statistical significance.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(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
Pediatrics
Masaya Kubota, Nobuhiko Haga
Summary: COVID-19 outbreaks have had various effects on the physical and mental health of families and children with congenital insensitivity to pain with anhidrosis (CIPA). A questionnaire survey was conducted to identify the specific issues and needs of CIPA patients and their families during the pandemic. The survey found that families faced difficulties in predicting the future, household and work concerns, and fear of infection. Increased time together during the pandemic led to both stress and better understanding among families. Sleep disturbances and behavioral changes were observed in a significant number of CIPA patients. Each family had its own coping mechanisms, but the importance of peer support, connections with experts, and prompt responses for resolution were emphasized.
PEDIATRICS INTERNATIONAL
(2023)
Article
Clinical Neurology
Kaoru Yamamoto, Shimpei Baba, Takashi Saito, Eiji Nakagawa, Kenji Sugai, Masaki Iwasaki, Atsushi Fujita, Hiromi Fukuda, Takeshi Mizuguchi, Mitsuhiro Kato, Naomichi Matsumoto, Masayuki Sasaki
Summary: Suppression-burst (SB) is an EEG pattern observed in DEEs, which are associated with high mortality in early life. This study investigated the relation between SB-EEG and autonomic function in DEEs to explore the mechanism of early death. The results showed that patients with KCNT1-DEE exhibited synchronous HR fluctuations during SB-EEG, with a decrease in HR during suppression and an increase during burst. Patients with KCNT1-DEE had larger HR decreases and longer suppression durations compared to other patients. A strong negative correlation was found between suppression duration and HR reduction rates in one patient with KCNT1-DEE.
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)