Review
Genetics & Heredity
Rebecca Kingdom, Caroline F. Wright
Summary: The same genetic variant can cause a range of phenotypes, displaying incomplete penetrance or variable expressivity, influenced by various factors. Investigating the penetrance and expressivity of genetic variants is important for clinical classification and genetic counseling. Population cohort data can help redefine the understanding of these variants. Researching the causes of incomplete penetrance and variable expressivity in rare diseases is critical for our understanding.
FRONTIERS IN GENETICS
(2022)
Article
Immunology
Carmen Oleaga-Quintas, Edgar Borges de Oliveira-Junior, Jeremie Rosain, Franck Rapaport, Caroline Deswarte, Antoine Guerin, Sairaj Munavar Sajjath, Yu Jerry Zhou, Stephane Marot, Claire Lozano, Lidia Branco, Nuria Fernandez-Hidalgo, Dukhee Betty Lew, Anne-Sophie Brunel, Caroline Thomas, Elise Launay, Andres Augusto Arias, Alexis Cuffel, Vanesa Cunill Monjo, Anna-Lena Neehus, Laura Marques, Manon Roynard, Marcela Moncada-Velez, Bengu Gerceker, Roger Colobran, Marie-Gabrielle Vigue, Gabriela Lopez-Herrera, Laura Berron-Ruiz, Nora Hilda Segura Mendez, Patricia O'Farrill Romanillos, Tom Le Voyer, Anne Puel, Christine Bellanne-Chantelot, Kacy A. Ramirez, Lazaro Lorenzo-Diaz, Noe Ramirez Alejo, Rebeca Perez de Diego, Antonio Condino-Neto, Fethi Mellouli, Carlos Rodriguez-Gallego, Torsten Witte, Jose Franco Restrepo, Mariana Jobim, Stephanie Boisson-Dupuis, Eric Jeziorski, Claire Fieschi, Guillaume Vogt, Jean Donadieu, Marlene Pasquet, Julia Vasconcelos, Fatma Omur Ardeniz, Monica Martinez-Gallo, Regis A. Campos, Luiz Fernando Jobim, Ruben Martinez-Barricarte, Kang Liu, Aurelie Cobat, Laurent Abel, Jean-Laurent Casanova, Jacinta Bustamante
Summary: Germline heterozygous mutations of GATA2 can lead to various hematological and clinical phenotypes, including mycobacterial diseases. Clinical penetrance for GATA2 deficiency-related manifestations such as mycobacterial diseases was found to be incomplete, with affected relatives spanning a wide range of ages, emphasizing the importance of genetic testing for patients at any age.
JOURNAL OF CLINICAL IMMUNOLOGY
(2021)
Article
Genetics & Heredity
Matthew J. O'Neill, Luca Sala, Isabelle Denjoy, Yuko Wada, Krystian Kozek, Lia Crotti, Federica Dagradi, Maria-Christina Kotta, Carla Spazzolini, Antoine Leenhardt, Asami Kashiwa, Joe-Elie Salem, Seiko Ohno, Ran Tao, Dan M. Roden, Minoru Horie, Fabrice Extramiana, Peter J. Schwartz, Brett M. Kroncke
Summary: This study applies a Bayesian penetrance estimation strategy to address the issue of incomplete penetrance in heterozygote carriers of genes KCNE1, KCNH2, and SCN5A associated with LQTS and BrS. Bayesian penetrance models were generated using variant-specific features and clinical data, and the posterior estimates were mapped onto protein structures. The results show that the penetrance of KCNE1 and SCN5A is equivalent to 10 and 5 clinically phenotype heterozygotes, respectively.
GENETICS IN MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Marzia De Bortoli, Viviana Meraviglia, Katarina Mackova, Laura S. Frommelt, Eva Konig, Johannes Rainer, Chiara Volani, Patrizia Benzoni, Maja Schlittler, Giada Cattelan, Benedetta M. Motta, Claudia Volpato, Werner Rauhe, Andrea Barbuti, Serena Zacchigna, Peter P. Pramstaller, Alessandra Rossini
Summary: This study used human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to establish a model for incomplete penetrance in arrhythmogenic cardiomyopathy (ACM). The results showed molecular and functional differences between ACM and asymptomatic carriers of the same mutation (ASY) hiPSC-CMs, including a higher amount of mutated PKP2 mRNA, a lower expression of the connexin-43 protein, a lower overall density of sodium current, a higher intracellular lipid accumulation, and sarcomere disorganization in ACM compared to ASY hiPSC-CMs. Differentially expressed genes were also found, supporting a predisposition for a fatty phenotype in ACM hiPSC-CMs. This indicates that hiPSC-CMs are a suitable model to study incomplete penetrance in ACM.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2023)
Article
Genetics & Heredity
Rui-Qi Bai, Wen-Bin He, Qian Peng, Su-Hui Shen, Qian-Qian Yu, Juan Du, Yue-Qiu Tan, Yue-Hong Wang, Bin-Jie Liu
Summary: This study identified a novel gene variant associated with amelogenesis imperfecta and suggested that mutations in this gene may cause the disease with incomplete penetrance.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2022)
Article
Endocrinology & Metabolism
Meihang Li, Natalija Popovic, Ying Wang, Chunbo Chen, Constantin Polychronakos
Summary: Monogenic Forms of Diabetes (MFD) account for approximately 3% of all diabetes cases and accurate diagnosis can lead to life-changing treatment adjustments. However, MFD exhibits reduced penetrance and variable expressivity, making diagnosis and management challenging. Understanding the genetic modifiers that contribute to these variations not only has clinical importance, but also provides opportunities to explore mechanisms and therapeutic strategies for more common forms of diabetes. This review discusses the penetrance and expressivity variation in different types of MFD, the factors influencing these variations, and the potential benefits of such knowledge.
REVIEWS IN ENDOCRINE & METABOLIC DISORDERS
(2023)
Article
Genetics & Heredity
Jie Wang, Chaoyue Zhao, Xin Zhang, Li Yang, Yanyan Hu
Summary: A novel heterozygous mutation in the PTH1R gene with incomplete penetrance was identified, expanding the spectrum of known PTH1R mutations.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2023)
Article
Genetics & Heredity
Rebecca Kingdom, Marcus Tuke, Andrew Wood, Robin N. Beaumont, Timothy M. Frayling, Michael N. Weedon, Caroline F. Wright
Summary: This study investigated the phenotypic effect of rare, potentially deleterious variants in genes associated with monogenic developmental disorders (DDs) in a large population cohort. The findings suggest that individuals with these variants have mild DD-related phenotypes and significant socioeconomic disadvantages in the general adult population.
AMERICAN JOURNAL OF HUMAN GENETICS
(2022)
Article
Pediatrics
Shao-Yu Chang, Naotomo Kambe, Wen-Lang Fan, Jing-Long Huang, Wen- Lee, Chao-Yi Wu
Summary: This study reported a novel C483W NOD2 mutation associated with incomplete penetrance of BS. Additionally, a new intracellular staining assay of phosphorylated-NF kappa B in CD11b(+) cells was proposed to evaluate NF kappa B autoactivation in patients with BS.
PEDIATRIC RHEUMATOLOGY
(2022)
Article
Genetics & Heredity
Dong Li, Michael E. March, Tiancheng Wang, Victoria Merengwa, Livia Sertori Finoti, Samantha A. Schrier Vergano, Hakon Hakonarson, Elizabeth J. Bhoj
Summary: This study reports a truncating variant in the USP9X gene in two non-twin female siblings. Despite the high penetrance of pathogenic variants in the USP9X gene in females, this truncating variant showed incomplete penetrance in the two patients. Genetic regulation studies related to female-specific ID syndrome failed to identify a clear cause.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2022)
Article
Cardiac & Cardiovascular Systems
Jacob A. Miller, Nicolae Moise, Seth H. Weinberg
Summary: Many cardiac diseases are characterized by an increased late sodium current. An investigation was conducted to explore the relationship between incomplete penetrance of LQT3-associated mutation and ion channel expression variability. The study found that susceptibility to the mutation primarily depends on the balance between IKr and INa conductance, with individuals having a higher IKr-to-INa ratio being less susceptible. The study also revealed mutation-specific differences in the critical repolarizing current.
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
(2023)
Article
Clinical Neurology
Ignacio J. Keller Sarmiento, Avram Fraint, Lisa Kinsley, Rizwan S. Akhtar, Vincenzo Silani, Steven J. Lubbe, Dimitri Krainc, Niccolo E. Mencacci
Summary: We report a case of young onset generalized dystonia with a previously unreported likely pathogenic THAP1 gene mutation, which was inherited from the unaffected father. Additionally, deep brain stimulation was found to have a positive effect on the cervical symptoms of dystonia.
PARKINSONISM & RELATED DISORDERS
(2022)
Article
Clinical Neurology
Takuya Hiraide, Shinobu Fukumura, Akiyo Yamamoto, Mitsuko Nakashima, Hirotomo Saitsu
Summary: Variants in the KCNJ5 gene can cause periodic paralysis and other diseases. These variants are present in the East Asian population but have low penetrance.
BRAIN & DEVELOPMENT
(2021)
Review
Immunology
Tomonori Kadowaki, Saori Kadowaki, Hidenori Ohnishi
Summary: HA20, caused by a mutation in the TNFAIP3 gene, can present as an early onset autoinflammatory disease resembling Behcet's disease. Patients in East Asia with HA20 more frequently develop recurrent fever but have lower rates of typical BD symptoms. Treatment for severe HA20 in East Asia primarily involves anti-TNF-alpha agents.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Genetics & Heredity
Flora Szeri, Agnes Miko, Nastassia Navasiolava, Ambrus Kaposi, Shana Verschuere, Beatrix Molnar, Qiaoli Li, Sharon F. Terry, Federica Boraldi, Jouni Uitto, Koen van de Wetering, Ludovic Martin, Daniela Quaglino, Olivier M. Vanakker, Kalman Tory, Tamas Aranyi
Summary: Incomplete penetrance is a source of heterogeneity in pseudoxanthoma elasticum. Two incomplete penetrant pathogenic variants were identified, but they are only deleterious when a yet unknown interacting partner of ABCC6 is mutated simultaneously.