دورية أكاديمية
Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families
| العنوان: | Diagnostic implications of pitfalls in causal variant identification based on 4577 molecularly characterized families |
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| المؤلفون: | AlAbdi, Lama, Maddirevula, Sateesh, Shamseldin, Hanan E., Khouj, Ebtissal, Helaby, Rana, Hamid, Halima, Almulhim, Aisha, Hashem, Mais O., Abdulwahab, Firdous, Abouyousef, Omar, Alqahtani, Mashael, Altuwaijri, Norah, Jaafar, Amal, Alshidi, Tarfa, Alzahrani, Fatema, Al-Sagheir, Afaf I., Mansour, Ahmad M., Alawaji, Ali, Aldhilan, Amal, Alhashem, Amal, Alhemidan, Amal, Nabil, Amira, Khan, Arif O., Aljohar, Aziza, Alsaleem, Badr, Tabarki, Brahim, Lourenco, Charles Marques, Faqeih, Eissa, AlShail, Essam, Almesaifri, Fatima, Mutairi, Fuad Al, Alzaidan, Hamad, Morsy, Heba, Alshihry, Hind, Alkuraya, Hisham, Girisha, Katta Mohan, Al-Fayez, Khawla, Al-Rubeaan, Khalid, kraoua, Lilia, Alnemer, Maha, Tulbah, Maha, Zaki, Maha S., Alfadhel, Majid, Abouelhoda, Mohammed, Nezarati, Marjan M., Al-Qattan, Mohammad, Shboul, Mohammad, Abanemai, Mohammed, Al-Muhaizea, Mohammad A., Al-owain, Mohammed |
| المصدر: | Nature Communications ; volume 14, issue 1 ; ISSN 2041-1723 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2023 |
| مصطلحات موضوعية: | General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary |
| الوصف: | Despite large sequencing and data sharing efforts, previously characterized pathogenic variants only account for a fraction of Mendelian disease patients, which highlights the need for accurate identification and interpretation of novel variants. In a large Mendelian cohort of 4577 molecularly characterized families, numerous scenarios in which variant identification and interpretation can be challenging are encountered. We describe categories of challenges that cover the phenotype (e.g. novel allelic disorders), pedigree structure (e.g. imprinting disorders masquerading as autosomal recessive phenotypes), positional mapping (e.g. double recombination events abrogating candidate autozygous intervals), gene (e.g. novel gene-disease assertion) and variant (e.g. complex compound inheritance). Overall, we estimate a probability of 34.3% for encountering at least one of these challenges. Importantly, our data show that by only addressing non-sequencing-based challenges, around 71% increase in the diagnostic yield can be expected. Indeed, by applying these lessons to a cohort of 314 cases with negative clinical exome or genome reports, we could identify the likely causal variant in 54.5%. Our work highlights the need to have a thorough approach to undiagnosed diseases by considering a wide range of challenges rather than a narrow focus on sequencing technologies. It is hoped that by sharing this experience, the yield of undiagnosed disease programs globally can be improved. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41467-023-40909-3 |
| الإتاحة: | https://doi.org/10.1038/s41467-023-40909-3Test https://www.nature.com/articles/s41467-023-40909-3.pdfTest https://www.nature.com/articles/s41467-023-40909-3Test |
| حقوق: | https://creativecommons.org/licenses/by/4.0Test ; https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: | edsbas.E10B4E86 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41467-023-40909-3 |
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