Article
Genetics & Heredity
Guangyu Wang, Wenjing Wu, Xiaoqing Lv, Chuanzhu Yan, Pengfei Lin
Summary: Mutations in the TTN gene can cause a range of neuromuscular disorders, and our study identified two novel intronic mutations in two individuals with TTN-related autosomal recessive neuromuscular disorders. These mutations resulted in aberrant mRNA splicing, expanding the spectrum of splicing mutations in the TTN gene associated with neuromuscular disorders.
JOURNAL OF HUMAN GENETICS
(2023)
Article
Clinical Neurology
Martin Rees, Roksana Nikoopour, Atsushi Fukuzawa, Ay Lin Kho, Miguel A. Fernandez-Garcia, Elizabeth Wraige, Istvan Bodi, Charu Deshpande, Oezkan Oezdemir, Hulya-Sevcan Daimagueler, Mark Pfuhl, Mark Holt, Birgit Brandmeier, Sarah Grover, Joel Fluss, Cheryl Longman, Maria Elena Farrugia, Emma Matthews, Michael Hanna, Francesco Muntoni, Anna Sarkozy, Rahul Phadke, Ros Quinlivan, Emily C. Oates, Rolf Schroeder, Christian Thiel, Jens Reimann, Nicol Voermans, Corrie Erasmus, Erik-Jan Kamsteeg, Chaminda Konersman, Carla Grosmann, Shane McKee, Sandya Tirupathi, Steven A. Moore, Ekkehard Wilichowski, Elke Hobbiebrunken, Gabriele Dekomien, Isabelle Richard, Peter Van den Bergh, Cristina Dominguez-Gonzalez, Sebahattin Cirak, Ana Ferreiro, Heinz Jungbluth, Mathias Gautel
Summary: The diagnosis of TTN-related myopathies can be complicated due to overlap with other myopathies and TTN variants in control populations. This study identified key clinical and pathological features that can suggest TTN-related myopathies, and demonstrated the destabilizing nature of missense mutations associated with CMs. These findings suggest a potential therapeutic target for recessive titinopathies.
ACTA NEUROPATHOLOGICA
(2021)
Article
Biochemistry & Molecular Biology
Lucas Bayones, Maria Jose Guerra-Fernandez, Fernando Hinostroza, Ximena Baez-Matus, Jacqueline Vasquez-Navarrete, Luciana Gallo, Sergio Parra, Agustin D. Martinez, Arlek Gonzalez-Jamett, Fernando D. Marengo, Ana M. Cardenas
Summary: Gain-of-function mutations of dynamin-2 result in centronuclear myopathy by impairing exocytosis, disrupting actin filament formation and impacting the plasmalemma expression of functional proteins in skeletal muscle cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biology
Jan Eckhardt, Alexis Ruiz, Stephane Koenig, Maud Frieden, Herve Meier, Alexander Schmidt, Susan Treves, Francesco Zorzato
Summary: Skeletal muscles are responsible for movement and metabolic regulation. Congenital myopathies, caused by mutations in genes such as RYR1, lead to weak muscles. This study found that RYR1 mutations decrease RyR1 protein content and alter the expression of proteins involved in calcium signaling, metabolism, and ER protein quality control. It also identified potential targets for treating RyR1-related congenital myopathies.
Article
Multidisciplinary Sciences
Alexandre Prola, Jordan Blondelle, Aymeline Vandestienne, Jerome Piquereau, Raphael G. P. Denis, Stephane Guyot, Hadrien Chauvin, Arnaud Mourier, Marie Maurer, Celine Henry, Nahed Khadhraoui, Cindy Gallerne, Thibaut Molinie, Guillaume Courtin, Laurent Guillaud, Melanie Gressette, Audrey Solgadi, Florent Dumont, Julien Castel, Julien Ternacle, Jean Demarquoy, Alexandra Malgoyre, Nathalie Koulmann, Genevieve Derumeaux, Marie-France Giraud, Frederic Joubert, Vladimir Veksler, Serge Luquet, Frederic Relaix, Laurent Tiret, Fanny Pilot-Storck
Summary: Mice deficient for a muscle-specific enzyme of very-long-chain fatty acid synthesis displayed increased basal energy expenditure and protection against high-fat diet-induced obesity. Muscle-specific modulation of the very-long-chain fatty acid pathway was associated with a reduced content of inner mitochondrial membrane phospholipid cardiolipin and a blunted coupling efficiency between the respiratory chain and ATP synthase, which was restored by cardiolipin enrichment. Selective increase of lipid oxidative capacities in skeletal muscle, through the cardiolipin-dependent lowering of mitochondrial ATP production, provides an effective option against obesity at the whole-body level.
Article
Biochemistry & Molecular Biology
Andrew H. Chiang, Jonathan Chang, Jiayao Wang, Dennis Vitkup
Summary: ASD patients with likely gene-disrupting de novo mutations affecting the same gene often exhibit different phenotypes, while truncating mutations affecting the same exon in unrelated individuals tend to result in similar intellectual phenotypes. Exons, rather than genes, are found to be the unit of effective phenotypic impact for truncating mutations in autism. Additionally, the preference of exon expression towards prenatal or postnatal periods is closely linked to the lower or higher IQ phenotypes in ASD cases.
MOLECULAR PSYCHIATRY
(2021)
Editorial Material
Clinical Neurology
Shen-yi Kuang, Yao Li, Shi-Lin Yang, Xiang Han
Summary: Aicardi-Goutieres syndrome (AGS) is a rare single-gene disorder characterized by neurological and skin involvement, with increased levels of interferon-alpha (IFN-alpha) in the cerebrospinal fluid (CSF). This case report describes a young patient with recurrent ischemic stroke, who was found to have chilblains, white matter abnormalities, cerebral atrophy, and raised IFN-alpha in the CSF. Compound heterozygous variants of the TREX1 gene were found, confirming a diagnosis of AGS.
Article
Multidisciplinary Sciences
Lauren G. Mascibroda, Mohammad Shboul, Nathan D. Elrod, Laurence Colleaux, Hanan Hamamy, Kai-Lieh Huang, Natoya Peart, Moirangthem Kiran Singh, Hane Lee, Barry Merriman, Jeanne N. Jodoin, Poojitha Sitaram, Laura A. Lee, Raja Fathalla, Baeth Al-Rawashdeh, Osama Ababneh, Mohammad El-Khateeb, Nathalie Escande-Beillard, Stanley F. Nelson, Yixuan Wu, Liang Tong, Linda J. Kenney, Sudipto Roy, William K. Russell, Jeanne Amiel, Bruno Reversade, Eric J. Wagner
Summary: Oral-facial-digital (OFD) syndromes are a group of congenital disorders characterized by face and oral cavity malformations, and digit anomalies. Mutations in the INTS13 gene have been found to cause OFD type 2, disrupting ciliogenesis and gene expression.
NATURE COMMUNICATIONS
(2022)
Article
Clinical Neurology
Danielle K. Franken, Karlijn Bouman, Stacha F. I. Reumers, Frederik Braun, Jennifer Spillane, Maartje Pennings, Saskia L. S. Houwen, Corrie E. Erasmus, Ulrike Schara-Schmidt, Erik-Jan Kamsteeg, Heinz Jungbluth, Nicol C. Voermans
Summary: This study investigated the clinical spectrum of neuromuscular features in X-linked myotubular myopathy (XL-MTM) carriers. The results showed that 52% of carriers exhibited muscle weakness, with some cases previously being misclassified. These findings are important for understanding the neuromuscular manifestations of XL-MTM carrier state and for future clinical trials.
Review
Medicine, General & Internal
Bogdan Doroftei, Radu Maftei, Ovidiu-Dumitru Ilie, Theodora Armeanu, Maria Puiu, Iuliu Ivanov, Loredana Nemtanu
Summary: Severe congenital myopathy with fatal cardiomyopathy (EOMFC) is a rare genetic disorder, and a successful pregnancy was achieved through IVF and PGT by a Romanian couple who were carriers. The first baby of the couple passed away due to complications, with both parents confirmed as carriers. Following IVF, a healthy baby girl was born without mutations.
Article
Biochemistry & Molecular Biology
Mine Koprulu, Muhammad Naeem, Gokhan Nalbant, Rana M. Kamran Shabbir, Tariq Mahmood, Zele Huma, Sajid Malik, Aslihan Tolun
Summary: This report describes the first case of pachyonychia congenita to involve all ectodermal derivatives and the first recessive KRT17-related PC, identified in seven members of two consanguineous Pakistani families. The atypical PC presents with a unique combination of symptoms including pachyonychia, plantar keratoderma, alopecia, sparse eyebrows, dental anomalies, acanthosis nigricans of neck, dry skin, palmoplantar hyperhidrosis, recurrent blisters, rough sparse hair, and keratosis pilaris. Exome sequencing revealed a homozygous KRT17 mutation in affected individuals, pointing to a recessive inheritance pattern. Additionally, heterozygous variants in KRT17 have been associated with a different phenotype, PC2, suggesting a need for caution in genetic testing and analysis.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2022)
Article
Clinical Neurology
Guangyu Wang, Xiaoqing Lv, Ling Xu, Rui Zhang, Chuanzhu Yan, Pengfei Lin
Summary: The authors report a case of LGMD2J in a Han Chinese family, identifying novel compound heterozygous mutations in the TTN gene through muscle biopsy and genetic analysis. This is the first time an elongation mutation in the TTN gene has been reported, expanding the genetic mutation spectrum of LGMD2J.
NEUROLOGICAL SCIENCES
(2022)
Article
Genetics & Heredity
Fabiana de Campos Gomes, Eric Renato Lima Figueiredo, Ediane Nunes De Araujo, Edila Monteiro De Andrade, Carlos Diego Lisboa Carneiro, Gabriel Macola De Almeida, Helana Augusta Andrade Leal Dias, Lucelia Inoue Bispo Teixeira, Manuela Trindade Almeida, Mariusa Fernandes De Farias, Natalia Albim Linhares, Natasha Lima Da Fonseca, Yago Dos Santos Pereira, Joao Simao de Melo-Neto
Summary: This study investigated the relationship between social, genetic, and histopathologic factors in women with ovarian serous cystadenocarcinoma and TTN mutations, as well as the predictive value and impact on mortality and survival. The TTN mutation frequency was found to be related to certain genetic variables and metabolic factors in ovarian cystadenocarcinoma.
Editorial Material
Oncology
Paolo Peterlongo, Gisella Figlioli, Andrew J. Deans, Fergus J. Couch
Summary: FANCM protein truncating variants (PTVs) are emerging as risk factors for ER-negative and triple negative breast cancer. The greatest risk is associated with PTVs that extensively truncate the FANCM protein, while risks associated with less-truncating PTVs may be amplified by additional gene variants acting as modifiers. Further studies are needed to explore these aspects.
Review
Biochemistry & Molecular Biology
Shiyu Luo, Samantha M. Rosen, Qifei Li, Pankaj B. Agrawal
Summary: Mutations in SPEG gene are associated with centronuclear myopathy, cardiomyopathy, or a combination of both, playing critical roles in skeletal and cardiac muscle development, maintenance, and function. Understanding the basic mechanisms of SPEG in regulating muscle development will provide insights into therapeutic targets for SPEG-related disorders.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Correction
Immunology
Hani Harb, Emmanuel Stephen-Victor, Elena Crestani, Mehdi Benamar, Amir Massoud, Ye Cui, Louis-Marie Charbonnier, Sena Arbag, Safa Baris, Amparito Cunnigham, Juan Manuel Leyva-Castillo, Raif S. Geha, Amirhosein J. Mousavi, Boris Guennewig, Klaus Schmitz-Abe, Constantinos Sioutas, Wanda Phipatanakul, Talal A. Chatila
Summary: The paper has been amended and the updated version can be accessed via a link at the top of the paper.
Article
Allergy
Burcu Kolukisa, Dilek Baser, Bengu Akcam, Jeffrey Danielson, Sevgi Bilgic Eltan, Yesim Haliloglu, Asena Pinar Sefer, Royale Babayeva, Gamze Akgun, Louis-Marie Charbonnier, Klaus Schmitz-Abe, Yasemin Kendir Demirkol, Yu Zhang, Claudia Gonzaga-Jauregui, Raul Jimenez Heredia, Nurhan Kasap, Ayca Kiykim, Esra Ozek Yucel, Veysel Gok, Ekrem Unal, Aysenur Pac Kisaarslan, Serdar Nepesov, Gokhan Baysoy, Zerrin Onal, Gozde Yesil, Tulin Tiraje Celkan, Haluk Cokugras, Yildiz Camcioglu, Ahmet Eken, Kaan Boztug, Bernice Lo, Elif Karakoc-Aydiner, Helen C. Su, Ahmet Ozen, Talal A. Chatila, Safa Baris
Summary: Biallelic loss-of-function mutations in CARMIL2 cause combined immunodeficiency associated with dermatitis, inflammatory bowel disease (IBD), and EBV-related smooth muscle tumors. Clinical and immunological features of CARMIL2 deficiency were characterized, with IBD being the most severe manifestation. Long-term follow-up showed all patients were alive, with various treatment responses.
Article
Genetics & Heredity
Talia S. Schwartz, Kurt D. Christensen, Melissa K. Uveges, Susan E. Waisbren, Amy L. McGuire, Stacey Pereira, Jill O. Robinson, Alan H. Beggs, Robert C. Green, Gloria A. Bachmann, Arnold B. Rabson, Ingrid A. Holm
Summary: Research has shown a strong correlation between parental depressive symptoms and their child's participation in genomic studies, however, these symptoms are typically transient and most parents attribute their symptomatology to life stressors rather than participation in the trial.
JOURNAL OF GENETIC COUNSELING
(2022)
Article
Hematology
Raffaele Renella, Katelyn Gagne, Ellen Beauchamp, Jonathan Fogel, Aleksej Perlov, Mireia Sola, Thorsten Schlaeger, Inga Hofmann, Akiko Shimamura, Benjamin L. Ebert, Klaus Schmitz-Abe, Kyriacos Markianos, Kristi Murphy, Liang Sun, Shira Rockowitz, Piotr Sliz, Dean R. Campagna, Timothy A. Springer, Christopher Bahl, Suneet Agarwal, Mark D. Fleming, David A. Williams
Summary: This study identified a novel germline stop-loss mutation in the X-linked gene SEPT6, leading to reduced SEPT6 staining in bone marrow granulocyte precursors and megakaryocytes in the patient. CRISPR/Cas9 knock-in experiments showed the critical role of SEPT6 in chromosomal segregation in myeloid progenitors. The in silico analysis predicted that the mutated protein hinders SEPT6 coiled-coil dimerization, affecting filament formation.
AMERICAN JOURNAL OF HEMATOLOGY
(2022)
Article
Oncology
P. Terraf, F. Pareja, D. N. Brown, O. Ceyhan-Birsoy, M. Misyura, S. Rana, E. O'Reilly, M. Carlo, C. Aghajanian, Y. Liu, F. Derakhshan, G. Jayakumaran, B. Weigelt, M. Walsh, Z. Stadler, K. Offit, M. Ladanyi, M. Robson, A. Zehir, J. S. Reis-Filho, D. Mandelker
Summary: Tumor-only sequencing is suitable for the detection of clinically actionable germline variants, particularly for single-nucleotide variants (SNVs) and small indels. However, for alterations affecting HRD, DDR, and MMR genes, the detection may not be optimal. Clinical genetic testing should be considered for high-risk patients with negative tumor-only sequencing results.
ANNALS OF ONCOLOGY
(2022)
Article
Immunology
Ye Cui, Mehdi Benamar, Klaus Schmitz-Abe, Varsha Poondi-Krishnan, Qian Chen, Bat-Erdene Jugder, Benoit Fatou, Jason Fong, Yuelin Zhong, Stuti Mehta, Altantsetseg Buyanbat, Beray Selver Eklioglu, Esra Karabiber, Safa Baris, Ayca Kiykim, Sevgi Keles, Emmanuel Stephen-Victor, Claudia Angelini, Louis-Marie Charbonnier, Talal A. Chatila
Summary: This study identifies Stk4 as a crucial regulator in regulatory T cells, which promotes immune tolerance by regulating the transcriptional programs of Foxp3 and p65 through complex formation.
SCIENCE IMMUNOLOGY
(2022)
Article
Genetics & Heredity
Leslie Hotchkiss Hayes, Morgane Perdomini, Asli Aykanat, Casie A. Genetti, Heather L. Paterson, Belinda S. Cowling, Christian Freitag, Alan H. Beggs
Summary: This study provides a detailed characterization of DNM2-related CNM, a rare neuromuscular disease, revealing its predominantly early-onset myopathy resulting in difficulty with ambulation and occasionally bulbar and respiratory dysfunction. The findings from this study are important for clinical trial readiness in future disease-modifying therapies.
NEUROLOGY-GENETICS
(2022)
Article
Biochemistry & Molecular Biology
Qifei Li, Rohan Agrawal, Klaus Schmitz-Abe, Casie A. Genetti, Melissa A. Fernandes, Noah L. Fryou, Jill A. Madden, Catherine A. Brownstein, Edward C. Smith, Farrah Rajabi, Alan H. Beggs, Pankaj B. Agrawal
Summary: Clinical exome/genome sequencing is commonly used to diagnose genetic conditions, but many cases remain undiagnosed. This study reports two cases where only one heterozygous variant was initially identified, but on reanalysis, a second variant was found. The importance of reanalyzing data in undiagnosed cases with a single disease-associated variant is highlighted.
EUROPEAN JOURNAL OF HUMAN GENETICS
(2023)
Article
Biochemistry & Molecular Biology
Nikhil Shri Sahajpal, Alex R. R. Hastie, Maximilian Schieck, Ashis K. K. Mondal, Marc Felde, Caspar I. I. van der Made, Janet S. S. Chou, Adrienne G. G. Randolph, Thomas Illig, Michael C. C. Zody, Catherine A. A. Brownstein, Alan H. H. Beggs, Alexander Hoischen, Alka Chaubey, Ravindra Kolhe
Summary: Several studies have found genetic variants associated with severe COVID-19, but none have reported genetic determinants for neurological complications. This report identifies rare/unique structural variants implicated in neurological functions in two individuals with neurological manifestations of COVID-19. It highlights the potential genetic link to neurological symptoms and calls for collective efforts to study these cohorts for possible genetic factors.
Article
Allergy
Safa Baris, Mehdi Benamar, Qian Chen, Mehmet Cihangir Catak, Monica Martinez-Blanco, Muyun Wang, Jason Fong, Michel J. Massaad, Asena Pinar Sefer, Altan Kara, Royala Babayeva, Sevgi Bilgic Eltan, Ayse Deniz Yucelten, Emine Bozkurtlar, Leyla Cinel, Elif Karakoc-Aydiner, Yumei Zheng, Hao Wu, Ahmet Ozen, Klaus Schmitz-Abe, Talal A. Chatila
Summary: This study reports a child with a novel gain-of-function STAT6 mutation, leading to severe allergic manifestations. The patient had enhanced TH2 responses and suppressed TH1 and TH17 responses. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib improved the patient's condition by reversing STAT6 hyperresponsiveness.
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
(2023)
Article
Genetics & Heredity
Robert J. Graham, Basil T. Darras, Tmirah Haselkorn, Dan Fisher, Casie A. Genetti, Weston Miller, Alan H. Beggs
Summary: This study analyzed healthcare resource utilization in XLMTM patients within a US medical claims database. The results showed a significant increase in healthcare resource use among XLMTM patients over the past five years. Most patients required respiratory and feeding support and had multiple hospitalizations throughout childhood and beyond.
ORPHANET JOURNAL OF RARE DISEASES
(2023)
Article
Genetics & Heredity
Margaret A. A. Hojlo, Merhawi Ghebrelul, Casie A. A. Genetti, Richard Smith, Shira Rockowitz, Emma Deaso, Alan H. H. Beggs, Pankaj B. B. Agrawal, David C. C. Glahn, Joseph Gonzalez-Heydrich, Catherine A. A. Brownstein
Summary: Children and adolescents with early-onset psychosis have more rare genetic variants, and this study found an increased burden of rare variants in the GRIN2A gene in individuals with early-onset psychosis compared to controls. GRIN2A variants have been associated with various neuropsychiatric disorders, highlighting its role in early-onset psychosis.
Article
Genetics & Heredity
Frances O. O. Flanagan, Alexander M. M. Holtz, Sara O. O. Vargas, Casie A. A. Genetti, Klaus Schmitz-Abe, Alicia Casey, John C. C. Kennedy, Benjamin A. A. Raby, Mary P. P. Mullen, Martha P. P. Fishman, Pankaj B. B. Agrawal
Summary: A male infant presented with neonatal respiratory failure and pulmonary hypertension. At 15 months of age, he re-presented with interstitial lung disease and progressive pulmonary hypertension. Genetic testing revealed an intronic TBX4 gene variant that was also carried by his father and deceased sister. This study highlights the variability in cardiopulmonary phenotypes caused by TBX4 mutation and the importance of genetic diagnostics in accurately identifying and classifying subtly affected family members.
NPJ GENOMIC MEDICINE
(2023)
Article
Chemistry, Medicinal
Emma Rybalka, Stephanie Kourakis, Charles A. Bonsett, Behzad Moghadaszadeh, Alan H. Beggs, Cara A. Timpani
Article
Medicine, Research & Experimental
Mehdi Benamar, Qian Chen, Janet Chou, Amelie M. Jule, Rafik Boudra, Paola Contini, Elena Crestani, Peggy S. Lai, Muyun Wang, Jason Fong, Shira Rockwitz, Pui Lee, Tsz Man Fion Chan, Ekin Zeynep Altun, Eda Kepenekli, Elif Karakoc-Aydiner, Ahmet Ozen, Perran Boran, Fatih Aygun, Pinar Onal, Ayse Ayzit Kilinc Sakalli, Haluk Cokugras, Metin Yusuf Gelmez, Fatma Betul Oktelik, Esin Aktas Cetin, Yuelin Zhong, Maria Lucia Taylor, Katherine Irby, Natasha B. Halasa, Elizabeth H. Mack, Sara Signa, Ignazia Prigione, Marco Gattorno, Nicola Cotugno, Donato Amodio, Raif S. Geha, Mary Beth Son, Jane Newburger, Pankaj B. Agrawal, Stefano Volpi, Paolo Palma, Ayca Kiykim, Adrienne G. Randolph, Gunnur Deniz, Safa Baris, Raffaele De Palma, Klaus Schmitz-Abe, Louis-Marie Charbonnier, Lauren A. Henderson, Talal A. Chatila, David A. Williams, Lucinda Williams, Myriam Armont, Leah Cheng
Summary: Multisystem inflammatory syndrome in children (MIS-C) is a disease that develops in some pediatric patients following acute infection with SARS-CoV-2 through unknown mechanisms. Tregs in MIS-C are destabilized through a Notch1-dependent mechanism. Genetic analysis revealed enrichment of rare deleterious variants affecting inflammation and autoimmunity pathways in MIS-C patients, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Tregs induces CD22, disrupting their stability in an mTORC1-dependent manner and promoting systemic inflammation. These findings highlight the Notch1/CD22 signaling axis as a crucial factor in Treg dysfunction in MIS-C and suggest distinct immune checkpoints controlled by individual Treg Notch receptors that influence the inflammatory outcome in SARS-CoV-2 infection.
JOURNAL OF CLINICAL INVESTIGATION
(2023)