Genetic testing has become an essential component in the diagnosis and management of a wide range of clinical conditions, from cancer to developmental disorders, especially in rare Mendelian diseases. Efforts to identify rare phenotype-associated variants have predominantly focused on protein-truncating variants, while the interpretation of missense variants presents a considerable challenge. Deep learning algorithms excel in various applications across biomedical tasks, yet accurately distinguishing between pathogenic and benign genetic variants remains an elusive goal. Specifically, even the most sophisticated models encounter difficulties in accurately assessing the pathogenicity of missense variants of uncertain significance (VUS). Our investigation of AlphaMissense (AM), the latest iteration of deep learning methods for predicting the potential functional impact of missense variants and assessing gene essentiality, reveals important limitations in its ability to identify pathogenic missense variants within a rare disease cohort. Indeed, AM struggles to accurately assess the pathogenicity of variants in intrinsically disordered regions (IDRs), leading to unreliable gene-level essentiality scores for certain genes containing IDRs. This limitation highlights the challenges in applying AM faces in the context of clinical genetics.
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http://dx.doi.org/10.1101/2024.05.22.24307756 | DOI Listing |
J Endocr Soc
January 2025
Center for Molecular Oncology, University of Connecticut School of Medicine, Farmington, CT 06030-3101, USA.
Parathyroid carcinoma (PC) and atypical parathyroid tumors (APT) are incompletely understood and pose challenges in definitive diagnosis. sequence variants have recently been linked to PC and APT. Inactivating mutations in the ubiquitously expressed tumor suppressor gene, encoding folliculin, cause Birt-Hogg-Dubé syndrome (BHD), a rare tumor predisposition syndrome.
View Article and Find Full Text PDFGene
January 2025
Department of Cardiology, Children's Hospital of Nanjing Medical University, Nanjing 210008, China. Electronic address:
Backgroud: The ALMS1 gene is predominantly localized to cilia, particularly in the photoreceptor cells of the retina, auditory neurons, kidneys, and other ciliated structures. Pathogenic mutations in this gene cause Alstrom syndrome (AS), which is characterized by dilated cardiomyopathy, retinal degeneration, neurodeafness, and centripetal obesity. However, the genetic mechanism of the ALMS1 gene remains unclear.
View Article and Find Full Text PDFDis Model Mech
January 2025
Divisions of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Gsx2 is a homeodomain transcription factor critical for development of the ventral telencephalon and hindbrain of the mouse. Loss of Gsx2 function results in severe basal ganglia dysgenesis as well as defects in the nucleus tractus solitarius (nTS) of the hindbrain together with respiratory failure at birth. De Mori et al.
View Article and Find Full Text PDFHereditas
January 2025
Key Laboratory of Reproductive Health Diseases Research and Translation of Ministry of Education & Key Laboratory of Human Reproductive Medicine and Genetic Research of Hainan Provincie & Hainan Provincial Clinical Research Center for Thalassemia, The First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, Hainan, 571101, China.
Background: The dynein cytoplasmic two heavy chain 1 (DYNC2H1) gene encodes a cytoplasmic dynein subunit. Cytoplasmic dyneins transport cargo towards the minus end of microtubules and are thus termed the "retrograde" cellular motor. Mutations in DYNC2H1 are the main causative mutations of short rib-thoracic dysplasia syndrome type III with or without polydactyly (SRTD3).
View Article and Find Full Text PDFVet Clin North Am Equine Pract
January 2025
Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA.
Several inflammatory myopathies have an infectious or immune-mediated basis in the horse. Myosin heavy chain myopathy is caused by a codominant missense variant in MYH1 and has 3 clinical presentations: immune-mediated myositis, calciphylaxis, and nonexertional rhabdomyolysis in Quarter Horse-related breeds. An infarctive form of purpura hemorrhagica affects numerous breeds, presenting with focal firm, painful muscle swelling, and subsequent infarction of multiple tissues.
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