Article
Clinical Neurology
Shehrazade Dahimene, Leonie von Elsner, Tess Holling, Lauren S. Mattas, Jess Pickard, Davor Lessel, Kjara S. Pilch, Ivan Kadurin, Wendy S. Pratt, Igor B. Zhulin, Hongzheng Dai, Maja Hempel, Maura R. Z. Ruzhnikov, Kerstin Kutsche, Annette C. Dolphin
Summary: This study reports biallelic variants in CACNA2D1 causing developmental and epileptic encephalopathy in two unrelated individuals. Patient 1 showed a frameshift variant leading to nonsense-mediated mRNA decay and absence of alpha(2)delta-1 protein. Patient 2 exhibited a compound heterozygous with a frameshift variant likely representing a null allele and a missense variant severely impairing the function of alpha(2)delta-1 as a calcium channel subunit.
Article
Cell Biology
Deepa S. Rajan, Sukhleen Kour, Tyler R. Fortuna, Margot A. Cousin, Sarah S. Barnett, Zhiyv Niu, Dusica Babovic-Vuksanovic, Eric W. Klee, Brian Kirmse, Micheil Innes, Siri Lynne Rydning, Kaja K. Selmer, Magnus Dehli Vigeland, Anne Kjersti Erichsen, Andrea H. Nemeth, Francisca Millan, Catherine DeVile, Katherine Fawcett, Adrien Legendre, David Sims, Ricardo Parolin Schnekenberg, Lydie Burglen, Sandra Mercier, Somayeh Bakhtiari, Encarnacion Martinez-Salas, Kristen Wigby, Jerica Lenberg, Jennifer R. Friedman, Michael C. Kruer, Udai Bhan Pandey
Summary: This study discovered biallelic variants in the GEMIN5 gene among nine affected individuals, leading to abnormal protein structure and reduced expression of snRNP complex proteins. The research expands on the phenotypic spectrum associated with GEMIN5-related disease, providing insights into patients with spastic ataxia, cerebellar atrophy, and motor predominant developmental delay.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Almundher Al-Maawali, Fathiya Al-Murshedi, Amna Al-Futaisi, Ahmed Mansy, Asila Al-Habsi, Katta M. Girisha
Summary: Biallelic loss of function variants in SV2A result in early onset intractable epilepsy, with affected children being normal at birth but developing recurrent seizures beginning in the second month of life and experiencing secondary failure of growth and development.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Clinical Neurology
Dana Marafi, Jawid M. Fatih, Rauan Kaiyrzhanov, Matteo P. Ferla, Charul Gijavanekar, Aljazi Al-Maraghi, Ning Liu, Emily Sites, Hessa S. Alsaif, Mohammad Al-Owain, Mohamed Zakkariah, Ehab El-Anany, Ulviyya Guliyeva, Sughra Guliyeva, Colette Gaba, Ateeq Haseeb, Amal M. Alhashem, Enam Danish, Vasiliki Karageorgou, Christian Beetz, Alaa A. Subhi, Sureni Mullegama, Erin Torti, Monisha Sebastin, Margo Sheck Breilyn, Susan Duberstein, Mohamed S. Abdel-Hamid, Tadahiro Mitani, Haowei Du, Jill A. Rosenfeld, Shalini N. Jhangiani, Zeynep Coban Akdemir, Richard A. Gibbs, Jenny C. Taylor, Khalid A. Fakhro, Jill Hunter, Davut Pehlivan, Maha S. Zaki, Joseph G. Gleeson, Reza Maroofian, Henry Houlden, Jennifer E. Posey, V. Reid Sutton, Fowzan S. Alkuraya, Sarah H. Elsea, James R. Lupski
Summary: SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy, and the likely pathophysiology of the disease is perturbations in glutamine homeostasis.
Article
Clinical Neurology
Marieke M. van der Knoop, Reza Maroofian, Yuko Fukata, Yvette van Ierland, Ehsan G. Karimiani, Anna Elina Lehesjoki, Mikko Muona, Anders Paetau, Yuri Miyazaki, Yoko Hirano, Laila Selim, Marina de Franca, Rodrigo Ambrosio Fock, Christian Beetz, Claudia A. L. Ruivenkamp, Alison J. Eaton, Francois D. Morneau-Jacob, Lena Sagi-Dain, Lilach Shemer-Meiri, Amir Peleg, Jumana Haddad-Halloun, Daan J. Kamphuis, Cacha M. P. C. D. Peeters-Scholte, Semra Hiz Kurul, Rita Horvath, Hanns Lochmueller, David Murphy, Stephan Waldmueller, Stephanie Spranger, David Overberg, Alison M. Muir, Aboulfazl Rad, Barbara Vona, Firdous Abdulwahad, Sateesh Maddirevula, Inna S. Povolotskaya, Victoria Y. Voinova, Vykuntaraju K. Gowda, Varunvenkat M. Srinivasan, Fowzan S. Alkuraya, Heather C. Mefford, Majid Alfadhel, Tobias B. Haack, Pasquale Striano, Mariasavina Severino, Masaki Fukata, Yvonne Hilhorst-Hofstee, Henry Houlden
Summary: The paper provides a detailed description of the clinical features of ADAM22 deficiency, including treatment-resistant epilepsy, global developmental delay, intellectual disability, and hypotonia. The deleteriousness of ADAM22 variants is confirmed through functional studies.
Article
Genetics & Heredity
Laura Licchetta, Lucia Di Giorgi, Margherita Santucci, Lisa Taruffi, Carlotta Stipa, Raffaella Minardi, Valerio Carelli, Francesca Bisulli
Summary: This study identifies PARS2 as a causative gene in DEE-SWAS, expanding the genetic heterogeneity of this syndrome. It highlights the importance of prolonged sleep EEG recording in recognizing SWAS as a possible electroclinical evolution of PARS2-related DEE.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2023)
Article
Genetics & Heredity
Vandana Shashi, Kelly Schoch, Rebecca Ganetzky, Peter G. Kranz, Neal Sondheimer, M. Louise Markert, Heidi Cope, Azita Sadeghpour, Philip Roehrs, Thomas Arbogast, Colleen Muraresku, Undiagnosed Diseases Undiagnosed Dis Network, Amanda V. Tyndall, Michael J. Esser, Kristine E. Woodward, Billie Ping-Yee Au, Jillian S. Parboosingh, Ryan E. Lamont, Francois P. Bernier, Nicola A. M. Wright, Susa M. Benseler, Simon J. Parsons, Mays El-Dairi, Edward C. Smith, Purnima Valdez, Michael Tennison, A. Micheil Innes, Erica E. Davias
Summary: This study provides evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive subtype of acute necrotizing encephalopathy (ANE2) in previously healthy children. The findings highlight the importance of RNH1 in the etiology of acute encephalopathies in this population.
GENETICS IN MEDICINE
(2023)
Article
Genetics & Heredity
Jihong Hu, Juan Liu, Chunguang Guo, Yaqin Duan, Chunlei Liu, Yaqiong Tan, Ying Pan
Summary: This study reports the occurrence of novel ST3GAL3 gene variants in a Chinese patient with DEE15. These variants should be considered when evaluating patients presenting with unexplained early-onset epileptic encephalopathy, severe developmental delay, and/or intellectual disability.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2023)
Article
Genetics & Heredity
Pan Gong, Xianru Jiao, Dan Yu, Zhixian Yang
Summary: KCNT2 gene mutations have been found to cause developmental and epileptic encephalopathies. This study presented detailed clinical features and genetic analysis of two unrelated patients with de novo variants in KCNT2, along with a review of eight previous cases. The most common phenotypes associated with KCNT2 mutations were infantile spasms and epilepsy of infancy with migrating focal seizures, suggesting potential overlap between gain- and loss-of-function mutations in epilepsy phenotype.
FRONTIERS IN GENETICS
(2021)
Review
Genetics & Heredity
Vivien M. Y. Wong-Spracklen, Anna Kolesnik, Josefine Eck, Saras Sabanathan, Olivera Spasic-Boskovic, Anna Maw, Kate Baker
Summary: This study reports a case of a child with drug-resistant epilepsy and developmental delay. Genetic sequencing revealed biallelic variants in the CACNA1A gene. The findings provide further evidence of the association between biallelic CACNA1A variants and severe epileptic and developmental encephalopathy with progressive cerebellar atrophy, and highlight complexities in genetic counseling in such cases.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2022)
Article
Biochemistry & Molecular Biology
A. Arteche-Lopez, MI. Alvarez-Mora, MT. Sanchez Calvin, JM. Lezana Rosales, C. Palma Milla, M. J. Gomez Rodriguez, I. Gomez Manjon, A. Blazquez, A. Juarez Rufian, P. Ramos Gomez, O. Sierra Tomillo, I. Hidalgo Mayoral, R. Perez de la Fuente, IJ. Posada Rodriguez, LI. Gonzalez Granado, Miguel A. Martin, JF. Quesada-Espinosa, M. Moreno-Garcia
Summary: This study identified families with co-dominant or recessive inheritance in genes previously associated with dominant inheritance, showing more severe or different phenotypes than their dominant counterparts. Patients harbored homozygous disease-related variants in three genes, resulting in a more severe clinical phenotype. It is suggested that geneticists should be aware of different forms of inheritance in genes to improve WES diagnostic capacity.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2021)
Article
Biochemistry & Molecular Biology
Arthur Macha, Filip Liebsch, Steffen Fricke, Florian Hetsch, Franziska Neuser, Lena Johannes, Vanessa Kress, Tania Djemie, Jose A. Santamaria-Araujo, Catheline Vilain, Alec Aeby, Patrick Van Bogaert, Borislav Dejanovic, Sarah Weckhuysen, Jochen C. Meier, Guenter Schwarz
Summary: Synaptic inhibition plays a crucial role in neuronal network dynamics, and abnormalities in inhibition are associated with epilepsy. Gephyrin, as the principal scaffolding protein at inhibitory synapses, is essential for the clustering of glycine and GABA type A receptors. Mutations in the gephyrin gene (GPHN) are linked to neurodevelopmental disorders and epilepsy. This study identifies bi-allelic variants in GPHN, including a missense mutation and a splice acceptor variant, in a patient with developmental and epileptic encephalopathy. The findings demonstrate that these variants lead to aberrant gephyrin structure and reduced inhibitory signal transmission in neurons.
HUMAN MOLECULAR GENETICS
(2022)
Article
Clinical Neurology
Christopher M. McGraw, Sonal Mahida, Parul Jayakar, Hyun Yong Koh, Alan Taylor, Trevor Resnick, Lance Rodan, Marc A. Schwartz, Ayesha Ejaz, Vijay G. Sankaran, Gerard Berry, Annapurna Poduri
Summary: Two siblings with intractable epilepsy, developmental regression, and progressive cerebellar atrophy due to biallelic variants in the gene CAD. Uridine treatment resulted in dramatic improvements for the affected girl, while her older brother had a more modest response. Treatment via uridine supplementation demonstrates precision diagnosis and treatment with clear outcome measures and biomarkers for monitoring efficacy.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(2021)
Article
Genetics & Heredity
Maria Lisa Dentici, Viola Alesi, Mathieu Quinodoz, Barbara Robens, Andrea Guerin, Sebastien Lebon, Annapurna Poduri, Lorena Travaglini, Federica Graziola, Alexandra Afenjar, Boris Keren, Valerio Licursi, Alessandro Capuano, Bruno Dallapiccola, Andrea Superti-Furga, Antonio Novelli
Summary: In this study, five patients with homozygous ZNF526 variants were identified, showing severe neurodevelopmental disorders primarily affecting the brain and eyes. The patients exhibited features such as severe microcephaly, simplified gyral pattern, epileptic encephalopathy, and bilateral cataracts. Experimental findings in mutant znf526 zebrafish larvae also demonstrated malformations resembling human holoprosencephaly spectrum.
JOURNAL OF MEDICAL GENETICS
(2022)
Article
Clinical Neurology
Sathiya N. Manivannan, Jolien Roovers, Noor Smal, Candace T. Myers, Dilsad Turkdogan, Filip Roelens, Oguz Kanca, Hyung-Lok Chung, Tasja Scholz, Katharina Hermann, Tatjana Bierhals, Hande S. Caglayan, Hannah Stamberger, Heather Mefford, Peter de Jonghe, Shinya Yamamoto, Sarah Weckhuysen, Hugo J. Bellen
Summary: This study identified new de novo missense variants in the FZR1 gene associated with developmental and epileptic encephalopathies. Functional studies in a Drosophila model supported the loss-of-function effect of the variants. The clinical phenotypes of patients were consistent with heterozygous loss-of-function of FZR1, including seizure, intellectual disability, and ataxia.
Review
Genetics & Heredity
Samantha M. Baxter, Jennifer E. Posey, Nicole J. Lake, Nara Sobreira, Jessica X. Chong, Steven Buyske, Elizabeth E. Blue, Lisa H. Chadwick, Zeynep H. Coban-Akdemir, Kimberly F. Doheny, Colleen P. Davis, Monkol Lek, Christopher Wellington, Shalini N. Jhangiani, Mark Gerstein, Richard A. Gibbs, Richard P. Lifton, Daniel G. MacArthur, Tara C. Matise, James R. Lupski, David Valle, Michael J. Bamshad, Ada Hamosh, Shrikant Mane, Deborah A. Nickerson, Heidi L. Rehm, Anne O'Donnell-Luria
Summary: This article discusses the transformation and development of Mendelian disease genomic research, highlighting the role of the National Institutes of Health-supported Centers for Mendelian Genomics (CMGs) and their impact on the research community. In addition to data sharing and candidate gene exchange, the CMGs provide resources, tools, and training to foster understanding of genes and genome variation.
GENETICS IN MEDICINE
(2022)
Article
Clinical Neurology
Felippe Borlot, Silvia Kozlik, Leanne Alfaro, Eric T. Payne, Alice W. Ho, Juan P. Appendino, Morris H. Scantlebury, Julia Jacobs
Summary: This study aimed to evaluate clinical and EEG variables that may influence the results of pediatric ambulatory-EEG (A-EEG) and develop a pathway for its utilization in children. The results showed that A-EEG is highly useful for evaluating electrical status epilepticus in slow-wave sleep and interictal/ictal burden, and it is often helpful for spell classification. Among all the variables analyzed, the test indication was the only independent predictor of obtaining a helpful A-EEG.
JOURNAL OF CLINICAL NEUROPHYSIOLOGY
(2023)
Article
Genetics & Heredity
Dana Marafi, Nina Kozar, Ruizhi Duan, Stephen Bradley, Kenji Yokochi, Fuad Al Mutairi, Nebal Waill Saadi, Sandra Whalen, Theresa Brunet, Urania Kotzaeridou, Daniela Choukair, Boris Keren, Caroline Nava, Mitsuhiro Kato, Hiroshi Arai, Tawfiq Froukh, Eissa Ali Faqeih, Ali M. AlAsmari, Mohammed M. Saleh, Filippo Pinto E. Vairo, Pavel N. Pichurin, Eric W. Klee, Christopher T. Schmitz, Christopher M. Grochowski, Tadahiro Mitani, Isabella Herman, Daniel G. Calame, Jawid M. Fatih, Haowei Du, Zeynep Coban-Akdemir, Davut Pehlivan, Shalini N. Jhangiani, Richard A. Gibbs, Satoko Miyatake, Naomichi Matsumoto, Laura J. Wagstaff, Jennifer E. Posey, James R. Lupski, Dies Meijer, Matias Wagner
Summary: The LGI family of genes, including LGI1-4, are highly expressed in the nervous systems of mammals. Variations in LGI1 and LGI4 are associated with neurological disorders, while no diseases have been reported to be associated with LGI2 or LGI3. This study identified individuals with deleterious variants in LGI3 and found that these variants cause a clinically recognizable PNHS trait characterized by developmental delay and intellectual disability.
AMERICAN JOURNAL OF HUMAN GENETICS
(2022)
Article
Clinical Neurology
Edibe Pembegul Yildiz, Mehmet Akif Kilic, Emek Uyur Yalcin, Fulya Kurekci, Ridvan Avci, Nilufer Eldes Hacifazlioglu, Serdar Ceylaner, Alper Gezdirici, Mine Caliskan
Summary: In this study, we retrospectively collected and analyzed clinical data from 18 patients with congenital myasthenic syndromes (CMS). The most common mutations identified in CMS patients were in the acetylcholine receptor (CHRNE) gene and choline acetyltransferase (ChAT) gene. Eyelid ptosis was the most commonly observed initial finding, and pyridostigmine was the most commonly used drug. However, caution should be exercised as pyridostigmine may worsen certain types of CMS.
ACTA NEUROLOGICA BELGICA
(2023)
Article
Multidisciplinary Sciences
Quentin Plumereau, Aya Ebdalla, Hugo Poulin, Juan Pablo Appendino, Morris H. Scantlebury, Ping Yee Billie Au, Mohamed Chahine
Summary: In this study, a functional test was conducted to assess the effects of a SCN1A gene mutation on epilepsy, and it was found that a specific mutation led to the inability of the Na(V)1.1 channel to produce functional Na+ currents, possibly due to a pore defect in the channel. This study highlights the importance of functional testing in understanding the pathophysiology and potential treatment decisions for epilepsy.
SCIENTIFIC REPORTS
(2022)
Article
Multidisciplinary Sciences
Xiaoqin Zhan, Chris Drummond-Main, Dylan Greening, Jinjing Yo, S. W. R. Chen, J. P. Appendino, P. Y. Billie Au, Ray W. Turner
Summary: The study reveals that cannabidiol has the ability to reduce the effects of a pathogenic KCNQ variant, which could be a potential therapeutic approach to reduce seizure activity and treat neurodevelopmental disorders.
Article
Genetics & Heredity
Moez Dawood, Gulsen Akay, Tadahiro Mitani, Dana Marafi, Jawid M. Fatih, Alper Gezdirici, Hossein Najmabadi, Kimia Kahrizi, Jaya Punetha, Christopher M. Grochowski, Haowei Du, Angad Jolly, He Li, Zeynep Coban-Akdemir, Fritz J. Sedlazeck, Jill Hunter, Shalini N. Jhangiani, Donna Muzny, Davut Pehlivan, Jennifer E. Posey, Claudia M. B. Carvalho, Richard A. Gibbs, James R. Lupski
Summary: Protein phosphatase 1 regulatory subunit 35 (PPP1R35) is required for recruiting microtubule-binding elongation machinery in centrosomes. A homozygous frameshifting indel in PPP1R35 was identified in a severely microcephalic proband from a consanguineous Turkish kindred. Comprehensive analysis and literature search revealed the recurrent nature of this variant allele, supporting its pathogenicity and suggesting potential secondary structure mutagenesis models for its origin.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2023)
Article
Genetics & Heredity
Hasnaa M. Elbendary, Dana Marafi, Ahmed K. Saad, Rasha Elhossini, Ruizhi Duan, Karima Rafat, Shalini N. Jhangiani, Richard A. Gibbs, Davut Pehlivan, Daniel G. Calame, Jennifer E. Posey, James R. Lupski, Maha S. Zaki
Summary: Pathogenic variants in LSS are associated with three rare Mendelian diseases. We performed exome sequencing on a family and identified novel compound heterozygous LSS variant alleles. Previously unreported features and a genotype-phenotype correlation were observed. Brain imaging is important in LSS-related conditions.
Article
Clinical Neurology
Judith A. Pijpers, Ping Yee Billie Au, Lauren C. Weeke, Alla A. Vein, Liesbeth S. Smit, Ana Vilan, Elke Jacobs, Linda S. de Vries, Sylke J. Steggerda, Maria Roberta Cilio, Evelina Carapancea, Marie-Coralie Cornet, Juan P. Appendino, Cacha M. P. C. D. Peeters-Scholte
Summary: This study aimed to describe the aEEG and cEEG findings in neonatal seizures caused by pathogenic variants in SCN2A and KCNQ3. The results showed that a characteristic pattern of rapid onset with a decrease, followed by a quick rise and postictal amplitude attenuation was observed in the aEEG of most patients. This pattern correlated with bilateral EEG onset attenuation, rhythmic discharges, and post-ictal amplitude suppression, and was not observed in the comparison groups.
SEIZURE-EUROPEAN JOURNAL OF EPILEPSY
(2023)
Review
Genetics & Heredity
Priya T. Bhola, Radha Mishra, Jennifer E. Posey, Leslie E. Hamilton, Gail E. Graham, Jaya Punetha, James R. Lupski, Kym M. Boycott, Damien D'Amours, Kristin D. Kernohan
Summary: Our understanding of rare diseases is expanding, particularly in regards to the genetic and phenotypic heterogeneity. In this study, we report on two patients with KIF21A variants, providing detailed phenotypic descriptions and novel neuroaxonal dystrophy findings. We also found evidence of impaired protein function in a yeast model, highlighting the pathogenicity of the identified variant. Further research is needed to fully define the phenotypic spectrum and explore the molecular etiology of these conditions.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2023)
Article
Endocrinology & Metabolism
Ruizhi Duan, Dana Marafi, Zhi-Jie Xia, Bobby G. Ng, Reza Maroofian, Farhana Taher Sumya, Ahmed K. Saad, Haowei Du, Jawid M. Fatih, Jill V. Hunter, Hasnaa M. Elbendary, Shahid M. Baig, Uzma Abdullah, Zafar Ali, Stephanie Efthymiou, David Murphy, Tadahiro Mitani, Marjorie A. Withers, Shalini N. Jhangiani, Zeynep Coban-Akdemir, Daniel G. Calame, Davut Pehlivan, Richard A. Gibbs, Jennifer E. Posey, Henry Houlden, Vladimir V. Lupashin, Maha S. Zaki, Hudson H. Freeze, James R. Lupski
Summary: In this study, we report two homozygous missense variants in the COG3 gene that co-segregate with COG3-CDG phenotype. The affected individuals exhibit clinical manifestations such as global developmental delay, severe intellectual disability, microcephaly, and facial dysmorphism.
JOURNAL OF INHERITED METABOLIC DISEASE
(2023)
Review
Genetics & Heredity
Alper Gezdirici, Ozlem Kalaycik Sengul, Mustafa Dogan, Banu Y. Ozguven, Ekrem Akbulut
Summary: This study identified a novel USP53 splice variant causing cholestasis phenotype through whole-exome sequencing and characterized its clinical findings and biological insights. Through family segregation analysis and in silico analyses, the impact of this variant on the protein structure was confirmed.
MOLECULAR SYNDROMOLOGY
(2023)
Article
Genetics & Heredity
Ruizhi Duan, Hadia Hijazi, Elif Yilmaz Gulec, Hatice Kocak Eker, Silvia R. Costa, Yavuz Sahin, Zeynep Ocak, Sedat Isikay, Ozge Ozalp, Sevcan Bozdogan, Huseyin Aslan, Nursel Elcioglu, Debora R. Bertola, Alper Gezdirici, Haowei Du, Jawid M. Fatih, Christopher M. Grochowski, Gulsen Akay, Shalini N. Jhangiani, Ender Karaca, Shen Gu, Zeynep Coban-Akdemir, Jennifer E. Posey, Yavuz Bayram, V. Reid Sutton, Claudia M. B. Carvalho, Davut Pehlivan, Richard A. Gibbs, James R. Lupski
Summary: In a study of 18 families with congenital limb malformations, variants associated with disease traits were identified through family-based genomics, highlighting the complexity of genetic pathogenesis underlying these anomalies. The findings suggest a novel contributory genetic mechanism in limb birth defects and provide insights into the interconnections among allelic series, clinical severity, and reduced penetrance.
HUMAN GENETICS AND GENOMICS ADVANCES
(2022)