Article
Genetics & Heredity
Stephen F. Pastore, Sangyoon Y. Ko, Paul W. Frankland, Paul A. Hamel, John B. Vincent
Summary: Studies on copy number variation and whole-genome sequencing in the past one and a half decades have revealed significant genetic heterogeneity underlying autism spectrum disorder (ASD) and intellectual disability (ID). This review focuses on the identification and neurobiological characterization of two key genes, PTCHD1 and PTCHD1-AS, located in Xp22.11. Animal models and patient-derived induced pluripotent stem cells have been used to study the role of these genes in ASD etiology, highlighting their importance in understanding the genetic and biological mechanisms of ASD and ID.
Article
Genetics & Heredity
Silvestre Cuinat, Mathilde Nizon, Bertrand Isidor, Alexander Stegmann, Richard H. van Jaarsveld, Koen L. van Gassen, Jasper J. van der Smagt, Catharina M. L. Volker-Touw, Sjoerd J. B. Holwerda, Paulien A. Terhal, Sarah Schuhmann, Georgia Vasileiou, Mohamed Khalifa, Alaa A. Nugud, Hemad Yasaei, Lilian Bomme Ousager, Charlotte Brasch-Andersen, Wallid Deb, Thomas Besnard, Marleen E. H. Simon, Karin Huijsdens-van Amsterdam, Nienke E. Verbeek, Dena Matalon, Natalie Dykzeul, Shana White, Elizabeth Spiteri, Koen Devriendt, Anneleen Boogaerts, Marjolein Willemsen, Han G. Brunner, Margje Sinnema, Bert B. A. De Vries, Erica H. Gerkes, Rolph Pfundt, Kosuke Izumi, Ian D. Krantz, Zhou L. Xu, Jill R. Murrell, Irene Valenzuela, Ivon Cusco, Eulalia Rovira-Moreno, Yaping Yang, Varoona Bizaoui, Olivier Patat, Laurence Faivre, Frederic Tran-Mau-Them, Antonio Vitobello, Anne-Sophie Denomme-Pichon, Christophe Philippe, Stephane Bezieau, Benjamin Cogne
Summary: This study reports an association between SRRM2 gene variants and a rare neurodevelopmental disorder. It includes 22 patients with loss-of-function variants and provides a description of the phenotype. The patients exhibited mild developmental delay, predominant speech delay, autistic or attention-deficit/hyperactivity disorder features, overfriendliness, generalized hypotonia, overweight, and dysmorphic facial features. The intellectual disability varied and was mild when present.
GENETICS IN MEDICINE
(2022)
Article
Biology
Ethiraj Ravindran, Nobuto Arashiki, Lena-Luise Becker, Kohtaro Takizawa, Jonathan Levy, Thomas Rambaud, Konstantin L. Makridis, Yoshio Goshima, Na Li, Maaike Vreeburg, Benedicte Demeer, Achim Dickmanns, Alexander P. A. Stegmann, Hao Hu, Fumio Nakamura, Angela M. Kaindl
Summary: Variants in the CRMP1 gene are discovered to be associated with neurodevelopmental disorders such as muscular hypotonia, intellectual disability, and/or autism spectrum disorder. These variants may affect the protein structure and function of CRMP1, leading to alterations in cellular processes and neurite outgrowth.
Article
Multidisciplinary Sciences
Jennifer Cable, Ryan H. Purcell, Elise Robinson, Jacob A. S. Vorstman, Wendy K. Chung, John N. Constantino, Stephan J. Sanders, Mustafa Sahin, Ricardo E. Dolmetsch, Bina Maniar Shah, Audrey Thurm, Christa L. Martin, Carrie E. Bearden, Jennifer G. Mulle
Summary: Research has shown that rare high-risk variants can help elucidate the biological mechanisms of more common idiopathic diseases, demonstrating genetic heterogeneity and variable expressivity. Experts highlighted the need for detailed natural history studies of rare disorders, challenges in cohort recruitment, and the importance of viewing phenotypes as quantitative traits impacted by rare variants.
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
(2021)
Article
Health Care Sciences & Services
Yu-Shu Huang, Ting-Hsuan Fang, Belle Kung, Chia-Hsiang Chen
Summary: In this study, the genetic deficits in two siblings affected with ID and ASD were investigated. A microdeletion at 22q13.3 resulting in the haploinsufficiency of SHANK3 and several nearby genes was found in the younger sister, leading to the diagnosis of Phelan-McDermid syndrome. Whole-genome sequencing analysis in the family identified several rare, likely pathogenic variants in seven genes implicated in neurodevelopmental disorders in the elder brother. These variants have only moderate clinical effects and were transmitted from unaffected parents. The results suggest that the combination of multiple genes with moderate effects is part of the genetic mechanism of neurodevelopmental disorders.
JOURNAL OF PERSONALIZED MEDICINE
(2022)
Article
Medical Laboratory Technology
Shimeng Chen, Xiaolu Deng, Juan Xiong, Fang He, Lifen Yang, Baiyu Chen, Chen Chen, Ciliu Zhang, Li Yang, Jing Peng, Fei Yin
Summary: This study explored the clinical and genetic characteristics of Chinese patients with de novo DEAF1 variants. The patients exhibited intellectual disability, language delay, and behavior problems. Interestingly, the DEAF1-related epilepsy in Eastern-Asian individuals was found to be completely treatable. The study expanded the knowledge of DEAF1-related neurodevelopmental disorder and the de novo variant database of DEAF1.
CLINICA CHIMICA ACTA
(2021)
Review
Zoology
Zhu Li, Yuan-Xiang Zhu, Li-Jun Gu, Ying Cheng
Summary: This article summarizes several animal models used in ASD research, discussing their applications and challenges.
ZOOLOGICAL RESEARCH
(2021)
Review
Biochemistry & Molecular Biology
Sarah Larrigan, Sujay Shah, Alex Fernandes, Pierre Mattar
Summary: During brain development, the genome is repeatedly reconfigured to aid neuronal and glial differentiation, with a range of chromatin remodeling complexes facilitating the process. The non-redundancy of these complexes suggests a need for a variety of remodelers with different specificities and activities in neurodevelopment. The nucleosome remodeling and deacetylase (NuRD) complex plays a key role in the biochemistry, genetics, and functions of neural progenitors and neurons.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Genetics & Heredity
Ciara Hanly, Harshil Shah, Ping Yee Billie Au, Kara Murias
Summary: Neurodevelopmental disorders encompass a range of conditions including intellectual disability, global developmental delay, autism spectrum disorder, and attention deficit hyperactivity disorder. Despite advancements in genetic diagnostic technology, there are variations in reports on cognitive and developmental outcomes in affected individuals. Future research should focus on barriers to assessment, the development of modified assessment tools suitable for long-term outcomes in genetic neurodevelopmental disorders, and the collection of longitudinal data.
Article
Immunology
Nikhitha Sreenivas, Michael Maes, Hansashree Padmanabha, Apoorva Dharmendra, Priyanka Chakkera, Saptamita Paul Choudhury, Fazal Abdul, Thrinath Mullapudi, Vykuntaraju K. Gowda, Michael Berk, John Vijay Sagar Kommu, Monojit Debnath
Summary: Neurodevelopmental disorders (NDDs) are a spectrum of conditions with both common and differing characteristics in terms of phenome, symptomatome, neuropathology, risk factors and underlying mechanisms. This study investigates the possibility of a shared immune etiology among three early-onset NDDs, namely Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD) and Intellectual Disability Disorder (IDD).
BRAIN BEHAVIOR AND IMMUNITY
(2024)
Editorial Material
Psychiatry
Andre Strydom, Elizabeth Corcoran, Anne-Sophie Rebillat
Summary: The article explores whether individuals with neurodevelopment disorders have been overlooked during the COVID-19 pandemic, and highlights issues that need to be addressed in response to future health crises and pandemics.
BRITISH JOURNAL OF PSYCHIATRY
(2021)
Article
Medical Laboratory Technology
Shimeng Chen, Juan Xiong, Baiyu Chen, Ciliu Zhang, Xiaolu Deng, Fang He, Lifen Yang, Chen Chen, Jing Peng, Fei Yin
Summary: This study retrospectively analyzed the clinical characteristics and genetic spectrum of 79 ASD-NDDs patients, and found that 51.3% of the patients received a genetic diagnosis. Most patients had comorbid intellectual disability or global developmental delay, as well as epilepsy. The study also identified novel candidate genes related to ASD.
CLINICA CHIMICA ACTA
(2022)
Article
Neurosciences
Sandra Martin Lorenzo, Maria del Mar Muniz Moreno, Helin Atas, Marion Pellen, Valerie Nalesso, Wolfgang Raffelsberger, Geraldine Prevost, Loic Lindner, Marie-Christine Birling, Severine Menoret, Laurent Tesson, Luc Negroni, Jean-Paul Concordet, Ignacio Anegon, Yann Herault
Summary: Copy number variations (CNVs) of the human 16p11.2 locus are associated with developmental/neurocognitive syndromes. Mouse and rat models with deletion and duplication of the 16p11.2 genetic interval showed social behavior defects. Major pathways affecting MAPK1 and CUL3 were altered in rat models, with sexual dimorphism observed.
FRONTIERS IN NEUROSCIENCE
(2023)
Article
Biochemistry & Molecular Biology
Lisa Pavinato, Ehsan Nematian-Ardestani, Andrea Zonta, Silvia De Rubeis, Joseph Buxbaum, Cecilia Mancini, Alessandro Bruselles, Marco Tartaglia, Mauro Pessia, Stephen J. Tucker, Maria Cristina D'Adamo, Alfredo Brusco
Summary: In this study, biallelic missense variants in the KCNK18 gene were identified in a family with three siblings affected by mild-to-moderate ID, ASD, and other neurodevelopment-related features. Functional characterization of the variants showed impaired channel activity, particularly with the alteration of the Ser252 site leading to additive downstream effects. These findings expand the clinical variability associated with altered TRESK function and provide further insight into the relationship between altered function of this ion channel and human disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Genetics & Heredity
Marije Meuwissen, Aline Verstraeten, Emmanuelle Ranza, Justyna Iwaszkiewicz, Maaike Bastiaansen, Ligia Mateiu, Merlijn Nemegeer, Josephina A. N. Meester, Alexandra Afenjar, Michelle Amaral, Diana Ballhausen, Sarah Barnett, Magalie Barth, Bob Asselbergh, Katrien Spaas, Bavo Heeman, Jennifer Bassetti, Patrick Blackburn, Marie Schaer, Xavier Blanc, Vincent Zoete, Kari Casas, Thomas Courtin, Diane Doummar, Frederic Guerry, Boris Keren, John Pappas, Rachel Rabin, Amber Begtrup, Marwan Shinawi, Anneke T. Vulto-van Silfhout, Tjitske Kleefstra, Matias Wagner, Alban Ziegler, Elise Schaefer, Benedicte Gerard, Charlotte De Bie, Sjoerd J. B. Holwerda, Mary Alice Abbot, Stylianos E. Antonarakis, Bart Loeys
Summary: This study describes a neurodevelopmental disorder caused by de novo variants in CTR9, primarily affecting PAF1C function. Clinical features of the patients include intellectual disability, hypotonia, joint hyperlaxity, speech delay, coordination problems, tremor, and autism spectrum disorder.
GENETICS IN MEDICINE
(2022)
Article
Cell Biology
Sofia B. Lizarraga, Li Ma, Abbie M. Maguire, Laura van Dyck, Qing Wu, Qing Ouyang, Brian C. Kavanaugh, Dipal Nagda, Liane L. Livi, Matthew F. Pescosolido, Michael Schmidt, Shanique Alabi, Mara H. Cowen, Paul Brito-Vargas, Diane Hoffman-Kim, Ece D. Gamsiz Uzun, Avner Schlessinger, Richard N. Jones, Eric M. Morrow
Summary: Christianson syndrome (CS) is an X-linked neurological disorder caused by mutations in the SLC9A6 gene. By establishing induced pluripotent stem cell (iPSC) lines, researchers found that pathogenic mutations lead to loss of protein function, resulting in reduced neurite growth and arborization in patient-derived neurons. Rescue strategies included gene transfer and exogenous trophic factors like BDNF or IGF-1.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Editorial Material
Neurosciences
Eric M. Morrow
BIOLOGICAL PSYCHIATRY
(2021)
Article
Biochemistry & Molecular Biology
Ozan Baytas, Shawn M. Davidson, Ralph J. DeBerardinis, Eric M. Morrow
Summary: Deficiency in the mitochondrial enzyme glutamate pyruvate transaminase 2 (GPT2) leads to impaired neuronal growth and survival, potentially causing selective vulnerability in motor neurons.
HUMAN MOLECULAR GENETICS
(2022)
Article
Neurosciences
Matthew F. Pescosolido, Qing Ouyang, Judy S. Liu, Eric M. Morrow
Summary: Loss-of-function mutations in NHE6 result in the X-linked neurologic disorder Christianson syndrome, affecting both neurodevelopmental and neurodegenerative abnormalities, mainly characterized by lysosomal dysfunction. Defective endosome trafficking in NHE6-null neurons leads to worsening lysosome function, despite overacidification of the endosome and lysosome lumen. Enhanced exosome release from NHE6-null neurons suggests defects in endosome maturation and trafficking, contributing to lysosome deficiency and potential neurodegenerative disease.
JOURNAL OF NEUROSCIENCE
(2021)
Article
Cell & Tissue Engineering
Li Ma, Michael Schmidt, Eric M. Morrow
Summary: Loss-of-function mutations in Na+/H + exchanger 6 (NHE6) cause Christianson syndrome, and induced pluripotent stem cell (iPSC) lines were developed from a patient with this mutation. Using CRISPR/Cas9 gene editing, isogenic control lines were generated with the mutation corrected, serving as a valuable resource for studies in CS.
STEM CELL RESEARCH
(2021)
Article
Behavioral Sciences
Danielle Sipsock, Hasmik Tokadjian, Giulia Righi, Eric M. Morrow, Stephen J. Sheinkopf
Summary: This study found a strong association between increased burden of first-degree family psychiatric history and higher autism symptom severity, as measured by the Social Responsiveness Scale, Second Edition (SRS-2), but not with ADOS-2 severity scores, IQ, or adaptive functioning.
Article
Behavioral Sciences
Brian C. Kavanaugh, Tess Gabert, Richard N. Jones, Stephen J. Sheinkopf, Eric M. Morrow
Summary: The study revealed that advanced parental age at birth is associated with the severity and presence of ASD in offspring, particularly with the severity of restricted/repetitive behaviors.
Article
Clinical Neurology
YouJin Lee, Morgan R. Miller, Marty A. Fernandez, Elizabeth L. Berg, Adriana M. Prada, Qing Ouyang, Michael Schmidt, Jill L. Silverman, Tracy L. Young-Pearse, Eric M. Morrow
Summary: Loss-of-function mutations in the X-linked NHE6 gene cause Christianson syndrome in males, leading to early cerebellar degeneration and later-onset cortical and subcortical neurodegeneration. Studies have shown modulation of amyloid-beta levels and defects in endosome maturation and trafficking in experimental models with NHE6 expression targeted. A new NHE6-null rat model of Christianson syndrome has been generated, demonstrating neurodegeneration with deposition of endogenously-expressed amyloid-beta and tau, providing insights into mechanisms of neurodegenerative disorders like Alzheimer's disease.
Article
Neurosciences
Ozan Baytas, Julie A. Kauer, Eric M. Morrow
Summary: This study reveals a novel mechanism of degeneration of locus coeruleus (LC) neurons caused by loss of the mitochondrial enzyme GPT2. The loss of LC neurons in Gpt2-null mice is found to be the earliest during development compared to other genetic animal models, providing important insights into the metabolic vulnerability of LC.
NEUROBIOLOGY OF DISEASE
(2022)
Article
Cell & Tissue Engineering
Marty A. Fernandez, Fatmata Bah, Li Ma, YouJin Lee, Michael Schmidt, Elizabeth Welch, Eric M. Morrow, Tracy L. Young-Pearse
Summary: This study reveals the association of disruption in endolysosomal and autophagy-lysosomal systems with neurodegeneration. Loss of function mutations in NHE6 gene leads to abnormal tau expression and dysfunction in lysosomal and autophagy processes. Treatment with trehalose or rapamycin partially rescues this abnormal phenotype.
Article
Cell Biology
Emily B. Warren, Juan A. Briano, Jacob Ellegood, Taylor DeYoung, Jason P. Lerch, Eric M. Morrow
Summary: 17q12Del syndrome is a disorder associated with neurodevelopmental disorders and renal cysts and diabetes syndrome. Researchers successfully generated a mouse model of this syndrome using CRISPR/Cas9 genome editing and found that the severity of the phenotypes varied depending on the genetic background and was more severe in male mice.
DISEASE MODELS & MECHANISMS
(2022)
Article
Biology
Qing Wu, Li Ma, Lena Joesch-Cohen, Michael Schmidt, Ece D. Gamsiz Uzun, Eric M. Morrow
Summary: Through RNA-seq analysis, we identified the transcriptome signatures of Christianson syndrome (CS) caused by loss-of-function mutations in the SLC9A6 gene. Further research revealed critical modules associated with neurodevelopment and lysosome function.
Article
Psychology, Developmental
Brian C. Kavanaugh, Christine A. Schremp, Richard N. Jones, Carrie R. Best, Stephen J. Sheinkopf, Eric M. Morrow
Summary: The objective of this study was to identify the clinical features that result in a later age at ASD diagnosis in females. The study found that females were diagnosed with ASD on average 14 months later than males in the sample. This delay in diagnosis was associated with mild or atypical presentation, limited repetitive behaviors, intact IQ and language skills, and later emergence of recognized symptoms. This highlights the need for improved screening methods for ASD in females.
JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS
(2023)