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2. Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders

Author

Gracia-Diaz, Carolina, Zhou, Yijing, Yang, Qian, Maroofian, Reza, Espana-Bonilla, Paula, Lee, Chul-Hwan, Zhang, Shuo, Padilla, Natàlia, Fueyo, Raquel, Waxman, Elisa A., Lei, Sunyimeng, Otrimski, Garrett, Li, Dong, Sheppard, Sarah E., Mark, Paul, Harr, Margaret H., Hakonarson, Hakon, Rodan, Lance, Jackson, Adam, Vasudevan, Pradeep, Powel, Corrina, Mohammed, Shehla, Maddirevula, Sateesh, Alzaidan, Hamad, Faqeih, Eissa A., Efthymiou, Stephanie, Turchetti, Valentina, Rahman, Fatima, Maqbool, Shazia, Salpietro, Vincenzo, Ibrahim, Shahnaz H., di Rosa, Gabriella, Houlden, Henry, Alharbi, Maha Nasser, Al-Sannaa, Nouriya Abbas, Bauer, Peter, Zifarelli, Giovanni, Estaras, Conchi, Hurst, Anna C. E., Thompson, Michelle L., Chassevent, Anna, Smith-Hicks, Constance L., de la Cruz, Xavier, Holtz, Alexander M., Elloumi, Houda Zghal, Hajianpour, M J, Rieubland, Claudine, Braun, Dominique, Banka, Siddharth, French, Deborah L., Heller, Elizabeth A., Saade, Murielle, Song, Hongjun, Ming, Guo-li, Alkuraya, Fowzan S., Agrawal, Pankaj B., Reinberg, Danny, Bhoj, Elizabeth J., Martínez-Balbás, Marian A., and Akizu, Naiara

Published
2023
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3. Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder

Author

Hengel, Holger, Hannan, Shabab B, Dyack, Sarah, MacKay, Sara B, Schatz, Ulrich, Fleger, Martin, Kurringer, Andreas, Balousha, Ghassan, Ghanim, Zaid, Alkuraya, Fowzan S, Alzaidan, Hamad, Alsaif, Hessa S, Mitani, Tadahiro, Bozdogan, Sevcan, Pehlivan, Davut, Lupski, James R, Gleeson, Joseph J, Dehghani, Mohammadreza, Mehrjardi, Mohammad YV, Sherr, Elliott H, Parks, Kendall C, Argilli, Emanuela, Begtrup, Amber, Galehdari, Hamid, Balousha, Osama, Shariati, Gholamreza, Mazaheri, Neda, Malamiri, Reza A, Pagnamenta, Alistair T, Kingston, Helen, Banka, Siddharth, Jackson, Adam, Osmond, Mathew, Consortium, Care4Rare Canada, Consortium, Genomics England Research, Rieß, Angelika, Haack, Tobias B, Nägele, Thomas, Schuster, Stefanie, Hauser, Stefan, Admard, Jakob, Casadei, Nicolas, Velic, Ana, Macek, Boris, Ossowski, Stephan, Houlden, Henry, Maroofian, Reza, and Schöls, Ludger

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Human Genome, Brain Disorders, Congenital Structural Anomalies, Pediatric, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Adult, Animals, Cell Movement, Child, Child, Preschool, Drosophila, Female, Fibroblasts, Humans, Infant, Loss of Function Mutation, Loss of Heterozygosity, Male, Mice, Mice, Knockout, Neoplasm Proteins, Neurodevelopmental Disorders, Pedigree, Proteome, Young Adult, Care4Rare Canada Consortium, Genomics England Research Consortium, BCAS3, UAS-Gal4, fibroblasts, global developmental delay, microcephaly, neurodevelopmental disorder, proteomics, pyramidal tract involvement, thin corpus callosum, transcriptomics, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

BCAS3 microtubule-associated cell migration factor (BCAS3) is a large, highly conserved cytoskeletal protein previously proposed to be critical in angiogenesis and implicated in human embryogenesis and tumorigenesis. Here, we established BCAS3 loss-of-function variants as causative for a neurodevelopmental disorder. We report 15 individuals from eight unrelated families with germline bi-allelic loss-of-function variants in BCAS3. All probands share a global developmental delay accompanied by pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic facial features, and seizures. The human phenotype is less severe compared with the Bcas3 knockout mouse model and cannot be explained by angiogenic defects alone. Consistent with being loss-of-function alleles, we observed absence of BCAS3 in probands' primary fibroblasts. By comparing the transcriptomic and proteomic data based on probands' fibroblasts with those of the knockout mouse model, we identified similar dysregulated pathways resulting from over-representation analysis, while the dysregulation of some proposed key interactors could not be confirmed. Together with the results from a tissue-specific Drosophila loss-of-function model, we demonstrate a vital role for BCAS3 in neural tissue development.

Published
2021

4. AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia

Author

Terhal, Paulien, Venhuizen, Anton J., Lessel, Davor, Tan, Wen-Hann, Alswaid, Abdulrahman, Grün, Regina, Alzaidan, Hamad I., von Kroge, Simon, Ragab, Nada, Hempel, Maja, Kubisch, Christian, Novais, Eduardo, Cristobal, Alba, Tripolszki, Kornelia, Bauer, Peter, Fischer-Zirnsak, Björn, Nievelstein, Rutger A.J., van Dijk, Atty, Nikkels, Peter, Oheim, Ralf, Hahn, Heidi, Bertoli-Avella, Aida, Maurice, Madelon M., and Kornak, Uwe

Published
2023
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5. Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals

Author

Saida, Ken, Maroofian, Reza, Sengoku, Toru, Mitani, Tadahiro, Pagnamenta, Alistair T., Marafi, Dana, Zaki, Maha S., O’Brien, Thomas J., Karimiani, Ehsan Ghayoor, Kaiyrzhanov, Rauan, Takizawa, Marina, Ohori, Sachiko, Leong, Huey Yin, Akay, Gulsen, Galehdari, Hamid, Zamani, Mina, Romy, Ratna, Carroll, Christopher J., Toosi, Mehran Beiraghi, Ashrafzadeh, Farah, Imannezhad, Shima, Malek, Hadis, Ahangari, Najmeh, Tomoum, Hoda, Gowda, Vykuntaraju K., Srinivasan, Varunvenkat M., Murphy, David, Dominik, Natalia, Elbendary, Hasnaa M., Rafat, Karima, Yilmaz, Sanem, Kanmaz, Seda, Serin, Mine, Krishnakumar, Deepa, Gardham, Alice, Maw, Anna, Rao, Tekki Sreenivasa, Alsubhi, Sarah, Srour, Myriam, Buhas, Daniela, Jewett, Tamison, Goldberg, Rachel E., Shamseldin, Hanan, Frengen, Eirik, Misceo, Doriana, Strømme, Petter, Magliocco Ceroni, José Ricardo, Kim, Chong Ae, Yesil, Gozde, Sengenc, Esma, Guler, Serhat, Hull, Mariam, Parnes, Mered, Aktas, Dilek, Anlar, Banu, Bayram, Yavuz, Pehlivan, Davut, Posey, Jennifer E., Alavi, Shahryar, Madani Manshadi, Seyed Ali, Alzaidan, Hamad, Al-Owain, Mohammad, Alabdi, Lama, Abdulwahab, Ferdous, Sekiguchi, Futoshi, Hamanaka, Kohei, Fujita, Atsushi, Uchiyama, Yuri, Mizuguchi, Takeshi, Miyatake, Satoko, Miyake, Noriko, Elshafie, Reem M., Salayev, Kamran, Guliyeva, Ulviyya, Alkuraya, Fowzan S., Gleeson, Joseph G., Monaghan, Kristin G., Langley, Katherine G., Yang, Hui, Motavaf, Mahsa, Safari, Saeid, Alipour, Mozhgan, Ogata, Kazuhiro, Brown, André E.X., Lupski, James R., Houlden, Henry, and Matsumoto, Naomichi

Published
2023
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7. The recurrent missense mutation p.(Arg367Trp) in YARS1 causes a distinct neurodevelopmental phenotype

Author

Averdunk, Luisa, Sticht, Heinrich, Surowy, Harald, Lüdecke, Hermann-Josef, Koch-Hogrebe, Margarete, Alsaif, Hessa S., Kahrizi, Kimia, Alzaidan, Hamad, Alawam, Bashayer S., Tohary, Mohamed, Kraus, Cornelia, Endele, Sabine, Wadman, Erin, Kaplan, Julie D., Efthymiou, Stephanie, Najmabadi, Hossein, Reis, André, Alkuraya, Fowzan S., and Wieczorek, Dagmar

Published
2021
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8. The morbid genome of ciliopathies: an update

Author

Shamseldin, Hanan E., Shaheen, Ranad, Ewida, Nour, Bubshait, Dalal K., Alkuraya, Hisham, Almardawi, Elham, Howaidi, Ali, Sabr, Yasser, Abdalla, Ebtesam M., Alfaifi, Abdullah Y., Alghamdi, Jameel Mohammed, Alsagheir, Afaf, Alfares, Ahmed, Morsy, Heba, Hussein, Maged H., Al–Muhaizea, Mohammad A., Shagrani, Mohammad, Al Sabban, Essam, Salih, Mustafa A., Meriki, Neama, Khan, Rubina, Almugbel, Maisoon, Qari, Alya, Tulba, Maha, Mahnashi, Mohammed, Alhazmi, Khalid, Alsalamah, Abrar K., Nowilaty, Sawsan R., Alhashem, Amal, Hashem, Mais, Abdulwahab, Firdous, Ibrahim, Niema, Alshidi, Tarfa, AlObeid, Eman, Alenazi, Mona M., Alzaidan, Hamad, Rahbeeni, Zuhair, Al–Owain, Mohammed, Sogaty, Sameera, Seidahmed, Mohammed Zain, and Alkuraya, Fowzan S.

Published
2020
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9. Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population

Author

Monies, Dorota, Abouelhoda, Mohammed, Assoum, Mirna, Moghrabi, Nabil, Rafiullah, Rafiullah, Almontashiri, Naif, Alowain, Mohammed, Alzaidan, Hamad, Alsayed, Moeen, Subhani, Shazia, Cupler, Edward, Faden, Maha, Alhashem, Amal, Qari, Alya, Chedrawi, Aziza, Aldhalaan, Hisham, Kurdi, Wesam, Khan, Sameena, Rahbeeni, Zuhair, Alotaibi, Maha, Goljan, Ewa, Elbardisy, Hadeel, ElKalioby, Mohamed, Shah, Zeeshan, Alruwaili, Hibah, Jaafar, Amal, Albar, Ranad, Akilan, Asma, Tayeb, Hamsa, Tahir, Asma, Fawzy, Mohammed, Nasr, Mohammed, Makki, Shaza, Alfaifi, Abdullah, Akleh, Hanna, Yamani, Suad, Bubshait, Dalal, Mahnashi, Mohammed, Basha, Talal, Alsagheir, Afaf, Abu Khaled, Musad, Alsaleem, Khalid, Almugbel, Maisoon, Badawi, Manal, Bashiri, Fahad, Bohlega, Saeed, Sulaiman, Raashida, Tous, Ehab, Ahmed, Syed, Algoufi, Talal, Al-Mousa, Hamoud, Alaki, Emadia, Alhumaidi, Susan, Alghamdi, Hadeel, Alghamdi, Malak, Sahly, Ahmed, Nahrir, Shapar, Al-Ahmari, Ali, Alkuraya, Hisham, Almehaidib, Ali, Abanemai, Mohammed, Alsohaibaini, Fahad, Alsaud, Bandar, Arnaout, Rand, Abdel-Salam, Ghada M.H., Aldhekri, Hasan, AlKhater, Suzan, Alqadi, Khalid, Alsabban, Essam, Alshareef, Turki, Awartani, Khalid, Banjar, Hanaa, Alsahan, Nada, Abosoudah, Ibraheem, Alashwal, Abdullah, Aldekhail, Wajeeh, Alhajjar, Sami, Al-Mayouf, Sulaiman, Alsemari, Abdulaziz, Alshuaibi, Walaa, Altala, Saeed, Altalhi, Abdulhadi, Baz, Salah, Hamad, Muddathir, Abalkhail, Tariq, Alenazi, Badi, Alkaff, Alya, Almohareb, Fahad, Al Mutairi, Fuad, Alsaleh, Mona, Alsonbul, Abdullah, Alzelaye, Somaya, Bahzad, Shakir, Manee, Abdulaziz Bin, Jarrad, Ola, Meriki, Neama, Albeirouti, Bassem, Alqasmi, Amal, AlBalwi, Mohammed, Makhseed, Nawal, Hassan, Saeed, Salih, Isam, Salih, Mustafa A., Shaheen, Marwan, Sermin, Saadeh, Shahrukh, Shamsad, Hashmi, Shahrukh, Shawli, Ayman, Tajuddin, Ameen, Tamim, Abdullah, Alnahari, Ahmed, Ghemlas, Ibrahim, Hussein, Maged, Wali, Sami, Murad, Hatem, Meyer, Brian F., and Alkuraya, Fowzan S.

Published
2019
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11. Autozygome and high throughput confirmation of disease genes candidacy

Author

Maddirevula, Sateesh, Alzahrani, Fatema, Al-Owain, Mohammed, Al Muhaizea, Mohammad A., Kayyali, Husam R., AlHashem, Amal, Rahbeeni, Zuhair, Al-Otaibi, Maha, Alzaidan, Hamad I., Balobaid, Ameera, El Khashab, Heba Y., Bubshait, Dalal K., Faden, Maha, Yamani, Suad Al, Dabbagh, Omar, Al-Mureikhi, Mariam, Jasser, Abdulla Al, Alsaif, Hessa S., Alluhaydan, Iram, Seidahmed, Mohammed Zain, Alabbasi, Bashair Hamza, Almogarri, Ibrahim, Kurdi, Wesam, Akleh, Hana, Qari, Alya, Al Tala, Saeed M., Alhomaidi, Suzan, Kentab, Amal Y., Salih, Mustafa A., Chedrawi, Aziza, Alameer, Seham, Tabarki, Brahim, Shamseldin, Hanan E., Patel, Nisha, Ibrahim, Niema, Abdulwahab, Firdous, Samira, Menasria, Goljan, Ewa, Abouelhoda, Mohamed, Meyer, Brian F., Hashem, Mais, Shaheen, Ranad, AlShahwan, Saad, Alfadhel, Majid, Ben-Omran, Tawfeg, Al-Qattan, Mohammad M., Monies, Dorota, and Alkuraya, Fowzan S.

Published
2019
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14. Correction to: The recurrent missense mutation p.(Arg367Trp) in YARS1 causes a distinct neurodevelopmental phenotype

Author

Averdunk, Luisa, Sticht, Heinrich, Surowy, Harald, Lüdecke, Hermann‑Josef, Koch‑Hogrebe, Margarete, Alsaif, Hessa S., Kahrizi, Kimia, Alzaidan, Hamad, Alawam, Bashayer S., Tohary, Mohamed, Kraus, Cornelia, Endele, Sabine, Wadman, Erin, Kaplan, Julie D., Efthymiou, Stephanie, Najmabadi, Hossein, Reis, André, Alkuraya, Fowzan S., and Wieczorek, Dagmar

Published
2021
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15. AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia

Author

CMM Groep Maurice, Cancer, DT Schildpad, Integrale & Alg. Kindergen Patientenzorg, Other research (not in main researchprogram), Pathologie Pathologen staf, Regenerative Medicine and Stem Cells, Terhal, Paulien, Venhuizen, Anton J, Lessel, Davor, Tan, Wen-Hann, Alswaid, Abdulrahman, Grün, Regina, Alzaidan, Hamad I, von Kroge, Simon, Ragab, Nada, Hempel, Maja, Kubisch, Christian, Novais, Eduardo, Cristobal, Alba, Tripolszki, Kornelia, Bauer, Peter, Fischer-Zirnsak, Björn, Nievelstein, Rutger A J, van Dijk, Atty, Nikkels, Peter, Oheim, Ralf, Hahn, Heidi, Bertoli-Avella, Aida, Maurice, Madelon M, Kornak, Uwe, CMM Groep Maurice, Cancer, DT Schildpad, Integrale & Alg. Kindergen Patientenzorg, Other research (not in main researchprogram), Pathologie Pathologen staf, Regenerative Medicine and Stem Cells, Terhal, Paulien, Venhuizen, Anton J, Lessel, Davor, Tan, Wen-Hann, Alswaid, Abdulrahman, Grün, Regina, Alzaidan, Hamad I, von Kroge, Simon, Ragab, Nada, Hempel, Maja, Kubisch, Christian, Novais, Eduardo, Cristobal, Alba, Tripolszki, Kornelia, Bauer, Peter, Fischer-Zirnsak, Björn, Nievelstein, Rutger A J, van Dijk, Atty, Nikkels, Peter, Oheim, Ralf, Hahn, Heidi, Bertoli-Avella, Aida, Maurice, Madelon M, and Kornak, Uwe

Published
2023

16. Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders

Author

National Institutes of Health (US), Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), University of Alabama at Birmingham, Ministerio de Ciencia e Innovación (España), Ministerio de Educación y Ciencia (España), Manchester Biomedical Research Centre, European Commission, National Institute for Health Research (UK), Wellcome Trust, Cancer Research UK, Medical Research Council (UK), Wellcome Sanger Institute, Gracia-Díaz, Carolina, Zhou, Yijing, Yang, Qian, Maroofian, Reza, España-Bonilla, Paula, Lee, Chul-Hwan, Zhang, Shuo, Padilla, Natàlia, Fueyo, Raquel, Waxman, Elisa A., Lei, Sunyimeng, Otrimski, Garrett, Li, Dong, Sheppard, Sarah E., Mark, Paul, Harr, Margaret H., Hakonarson, Hakon, Rodan, Lance, Jackson, Adam, Vasudevan, Pradeep, Powel, Corrina, Mohammed, Shehla, Maddirevula, Sateesh, Alzaidan, Hamad, Faqeih, Eissa A., Efthymiou, Stephanie, Turchetti, Valentina, Rahman, Fátima, Maqbool, Shazia, Salpietro, Vincenzo, Ibrahim, Shahnaz H., di Rosa, Gabriella, Houlden, Henry, Alharbi, Maha Nasser, Al-Sannaa, Nouriya Abbas, Bauer, Peter, Zifarelli, Giovanni, Estaras, Conchi, Hurst, Anna C. E., Thompson, Michelle L., Chassevent, Anna, Smith-Hicks, Constance L., Cruz, Xavier de la, Holtz, Alexander M., Elloumi, Houda Zghal, Hajianpour, M. J., Rieubland, Claudine, Braun, Dominique, Banka, Siddharth, French, Deborah L., Heller, Elizabeth A., Saade, Murielle, Song, Hongjun, Ming, Guo-Li, Alkuraya, Fowzan S., Agrawal, Pankaj B., Reinberg, Danny, Bhoj, Elizabeth J., Martínez-Balbás, Marian, Akizu, Naiara, National Institutes of Health (US), Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), University of Alabama at Birmingham, Ministerio de Ciencia e Innovación (España), Ministerio de Educación y Ciencia (España), Manchester Biomedical Research Centre, European Commission, National Institute for Health Research (UK), Wellcome Trust, Cancer Research UK, Medical Research Council (UK), Wellcome Sanger Institute, Gracia-Díaz, Carolina, Zhou, Yijing, Yang, Qian, Maroofian, Reza, España-Bonilla, Paula, Lee, Chul-Hwan, Zhang, Shuo, Padilla, Natàlia, Fueyo, Raquel, Waxman, Elisa A., Lei, Sunyimeng, Otrimski, Garrett, Li, Dong, Sheppard, Sarah E., Mark, Paul, Harr, Margaret H., Hakonarson, Hakon, Rodan, Lance, Jackson, Adam, Vasudevan, Pradeep, Powel, Corrina, Mohammed, Shehla, Maddirevula, Sateesh, Alzaidan, Hamad, Faqeih, Eissa A., Efthymiou, Stephanie, Turchetti, Valentina, Rahman, Fátima, Maqbool, Shazia, Salpietro, Vincenzo, Ibrahim, Shahnaz H., di Rosa, Gabriella, Houlden, Henry, Alharbi, Maha Nasser, Al-Sannaa, Nouriya Abbas, Bauer, Peter, Zifarelli, Giovanni, Estaras, Conchi, Hurst, Anna C. E., Thompson, Michelle L., Chassevent, Anna, Smith-Hicks, Constance L., Cruz, Xavier de la, Holtz, Alexander M., Elloumi, Houda Zghal, Hajianpour, M. J., Rieubland, Claudine, Braun, Dominique, Banka, Siddharth, French, Deborah L., Heller, Elizabeth A., Saade, Murielle, Song, Hongjun, Ming, Guo-Li, Alkuraya, Fowzan S., Agrawal, Pankaj B., Reinberg, Danny, Bhoj, Elizabeth J., Martínez-Balbás, Marian, and Akizu, Naiara

Abstract

Genetic variants in chromatin regulators are frequently found in neurodevelopmental disorders, but their effect in disease etiology is rarely determined. Here, we uncover and functionally define pathogenic variants in the chromatin modifier EZH1 as the cause of dominant and recessive neurodevelopmental disorders in 19 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 methyltransferases of the PRC2 complex. Unlike the other PRC2 subunits, which are involved in cancers and developmental syndromes, the implication of EZH1 in human development and disease is largely unknown. Using cellular and biochemical studies, we demonstrate that recessive variants impair EZH1 expression causing loss of function effects, while dominant variants are missense mutations that affect evolutionarily conserved aminoacids, likely impacting EZH1 structure or function. Accordingly, we found increased methyltransferase activity leading to gain of function of two EZH1 missense variants. Furthermore, we show that EZH1 is necessary and sufficient for differentiation of neural progenitor cells in the developing chick embryo neural tube. Finally, using human pluripotent stem cell-derived neural cultures and forebrain organoids, we demonstrate that EZH1 variants perturb cortical neuron differentiation. Overall, our work reveals a critical role of EZH1 in neurogenesis regulation and provides molecular diagnosis for previously undefined neurodevelopmental disorders.

Published
2023

17. Clinical, radiological, and genetic characterization of SLC13A5 variants in Saudi families: Genotype phenotype correlation and brief review of the literature

Author

AlQudairy, Hanan, primary, AlDhalaan, Hesham, additional, AlRuways, Sarah, additional, AlMutairi, Nouf, additional, AlNakiyah, Maha, additional, AlGhofaili, Reema, additional, AlBakheet, Albandary, additional, Alomrani, Adeeb, additional, Alharbi, Omar A., additional, Tous, Ehab, additional, AlSayed, Moeen, additional, AlZaidan, Hamad, additional, AlRasheed, Maha M., additional, AlOdaib, Ali, additional, and Kaya, Namik, additional

Published
2023
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18. The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes

Author

Monies, Dorota, Abouelhoda, Mohamed, AlSayed, Moeenaldeen, Alhassnan, Zuhair, Alotaibi, Maha, Kayyali, Husam, Al-Owain, Mohammed, Shah, Ayaz, Rahbeeni, Zuhair, Al-Muhaizea, Mohammad A., Alzaidan, Hamad I., Cupler, Edward, Bohlega, Saeed, Faqeih, Eissa, Faden, Maha, Alyounes, Banan, Jaroudi, Dyala, Goljan, Ewa, Elbardisy, Hadeel, Akilan, Asma, Albar, Renad, Aldhalaan, Hesham, Gulab, Shamshad, Chedrawi, Aziza, Al Saud, Bandar K, Kurdi, Wesam, Makhseed, Nawal, Alqasim, Tahani, El Khashab, Heba Y., Al-Mousa, Hamoud, Alhashem, Amal, Kanaan, Imaduddin, Algoufi, Talal, Alsaleem, Khalid, Basha, Talal A., Al-Murshedi, Fathiya, Khan, Sameena, Al-Kindy, Adila, Alnemer, Maha, Al-Hajjar, Sami, Alyamani, Suad, Aldhekri, Hasan, Al-Mehaidib, Ali, Arnaout, Rand, Dabbagh, Omar, Shagrani, Mohammad, Broering, Dieter, Tulbah, Maha, Alqassmi, Amal, Almugbel, Maisoon, AlQuaiz, Mohammed, Alsaman, Abdulaziz, Al-Thihli, Khalid, Sulaiman, Raashda A., Al-Dekhail, Wajeeh, Alsaegh, Abeer, Bashiri, Fahad A., Qari, Alya, Alhomadi, Suzan, Alkuraya, Hisham, Alsebayel, Mohammed, Hamad, Muddathir H, Szonyi, Laszlo, Abaalkhail, Faisal, Al-Mayouf, Sulaiman M., Almojalli, Hamad, Alqadi, Khalid S., Elsiesy, Hussien, Shuaib, Taghreed M., Seidahmed, Mohammed Zain, Abosoudah, Ibraheem, Akleh, Hana, AlGhonaium, Abdulaziz, Alkharfy, Turki M., Al Mutairi, Fuad, Eyaid, Wafa, Alshanbary, Abdullah, Sheikh, Farrukh R., Alsohaibani, Fahad I., Alsonbul, Abdullah, Al Tala, Saeed, Balkhy, Soher, Bassiouni, Randa, Alenizi, Ahmed S., Hussein, Maged H., Hassan, Saeed, Khalil, Mohamed, Tabarki, Brahim, Alshahwan, Saad, Oshi, Amira, Sabr, Yasser, Alsaadoun, Saad, Salih, Mustafa A., Mohamed, Sarar, Sultana, Habiba, Tamim, Abdullah, El-Haj, Moayad, Alshahrani, Saif, Bubshait, Dalal K., Alfadhel, Majid, Faquih, Tariq, El-Kalioby, Mohamed, Subhani, Shazia, Shah, Zeeshan, Moghrabi, Nabil, Meyer, Brian F., and Alkuraya, Fowzan S.

Published
2017
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19. Expanding the clinical and genetic heterogeneity of hereditary disorders of connective tissue

Author

Alazami, Anas M., Al-Qattan, Sarah M., Faqeih, Eissa, Alhashem, Amal, Alshammari, Muneera, Alzahrani, Fatema, Al-Dosari, Mohammed S., Patel, Nisha, Alsagheir, Afaf, Binabbas, Bassam, Alzaidan, Hamad, Alsiddiky, Abdulmonem, Alharbi, Nasser, Alfadhel, Majid, Kentab, Amal, Daza, Riza M., Kircher, Martin, Shendure, Jay, Hashem, Mais, Alshahrani, Saif, Rahbeeni, Zuhair, Khalifa, Ola, Shaheen, Ranad, and Alkuraya, Fowzan S.

Published
2016
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20. The morbid genome of ciliopathies: an update

Author

Shamseldin, Hanan E., primary, Shaheen, Ranad, additional, Ewida, Nour, additional, Bubshait, Dalal K., additional, Alkuraya, Hisham, additional, Almardawi, Elham, additional, Howaidi, Ali, additional, Sabr, Yasser, additional, Abdalla, Ebtesam M., additional, Alfaifi, Abdullah Y., additional, Mohammed Alghamdi, Jameel, additional, Alsagheir, Afaf, additional, Alfares, Ahmed, additional, Morsy, Heba, additional, Hussein, Maged H., additional, Al-Muhaizea, Mohammad A., additional, Shagrani, Mohammad, additional, Al Sabban, Essam, additional, Salih, Mustafa A., additional, Meriki, Neama, additional, Khan, Rubina, additional, Almugbel, Maisoon, additional, Qari, Alya, additional, Tulba, Maha, additional, Mahnashi, Mohammed, additional, Alhazmi, Khalid, additional, Alsalamah, Abrar K., additional, Nowilaty, Sawsan R., additional, Alhashem, Amal, additional, Hashem, Mais, additional, Abdulwahab, Firdous, additional, Ibrahim, Niema, additional, Alshidi, Tarfa, additional, AlObeid, Eman, additional, Alenazi, Mona M., additional, Alzaidan, Hamad, additional, Rahbeeni, Zuhair, additional, Al-Owain, Mohammed, additional, Sogaty, Sameera, additional, Zain Seidahmed, Mohammed, additional, and Alkuraya, Fowzan S., additional

Published
2022
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22. Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

Author

Sanderson, Leslie E., Lanko, Kristina, Alsagob, Maysoon, Almass, Rawan, Al-Ahmadi, Nada, Najafi, Maryam, Al-Muhaizea, Mohammad A., Alzaidan, Hamad, Aldhalaan, Hesham, Perenthaler, Elena, Van Der Linde, Herma C., Nikoncuk, Anita, Kühn, Nikolas A., Antony, Dinu, Owaidah, Tarek Mustafa, Raskin, Salmo, Vieira, Luana Gabriela Dalla Rosa, Mombach, Romulo, Ahangari, Najmeh, Silveira, Tainá Regina Damaceno, Ameziane, Najim, Rolfs, Arndt, Alharbi, Aljohara, Sabbagh, Raghda M., Alahmadi, Khalid, Alawam, Bashayer, Ghebeh, Hazem, Alhargan, Aljouhra, Albader, Anoud A., Binhumaid, Faisal S., Goljan, Ewa, Monies, Dorota, Mustafa, Osama M., Aldosary, Mazhor, Albakheet, Albandary, Alyounes, Banan, Almutairi, Faten, Al-Odaib, Ali, Aksoy, Durdane Bekar, Basak, A. Nazli, Palvadeau, Robin, Trabzuni, Daniah, Rosenfeld, Jill A., Karimiani, Ehsan Ghayoor, Meyer, Brian F., Karakas, Bedri, Al-Mohanna, Futwan, Arold, Stefan T., Colak, Dilek, Maroofian, Reza, Houlden, Henry, Bertoli-Avella, Aida M., Schmidts, Miriam, Barakat, Tahsin Stefan, Van Ham, Tjakko J., Kaya, Namik, Sanderson, Leslie E., Lanko, Kristina, Alsagob, Maysoon, Almass, Rawan, Al-Ahmadi, Nada, Najafi, Maryam, Al-Muhaizea, Mohammad A., Alzaidan, Hamad, Aldhalaan, Hesham, Perenthaler, Elena, Van Der Linde, Herma C., Nikoncuk, Anita, Kühn, Nikolas A., Antony, Dinu, Owaidah, Tarek Mustafa, Raskin, Salmo, Vieira, Luana Gabriela Dalla Rosa, Mombach, Romulo, Ahangari, Najmeh, Silveira, Tainá Regina Damaceno, Ameziane, Najim, Rolfs, Arndt, Alharbi, Aljohara, Sabbagh, Raghda M., Alahmadi, Khalid, Alawam, Bashayer, Ghebeh, Hazem, Alhargan, Aljouhra, Albader, Anoud A., Binhumaid, Faisal S., Goljan, Ewa, Monies, Dorota, Mustafa, Osama M., Aldosary, Mazhor, Albakheet, Albandary, Alyounes, Banan, Almutairi, Faten, Al-Odaib, Ali, Aksoy, Durdane Bekar, Basak, A. Nazli, Palvadeau, Robin, Trabzuni, Daniah, Rosenfeld, Jill A., Karimiani, Ehsan Ghayoor, Meyer, Brian F., Karakas, Bedri, Al-Mohanna, Futwan, Arold, Stefan T., Colak, Dilek, Maroofian, Reza, Houlden, Henry, Bertoli-Avella, Aida M., Schmidts, Miriam, Barakat, Tahsin Stefan, Van Ham, Tjakko J., and Kaya, Namik

Abstract

Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.

Published
2021

23. Brain monoamine vesicular transport disease caused by homozygous SLC18A2variants: A study in 42 affected individuals

Author

Saida, Ken, Maroofian, Reza, Sengoku, Toru, Mitani, Tadahiro, Pagnamenta, Alistair T., Marafi, Dana, Zaki, Maha S., O’Brien, Thomas J., Karimiani, Ehsan Ghayoor, Kaiyrzhanov, Rauan, Takizawa, Marina, Ohori, Sachiko, Leong, Huey Yin, Akay, Gulsen, Galehdari, Hamid, Zamani, Mina, Romy, Ratna, Carroll, Christopher J., Toosi, Mehran Beiraghi, Ashrafzadeh, Farah, Imannezhad, Shima, Malek, Hadis, Ahangari, Najmeh, Tomoum, Hoda, Gowda, Vykuntaraju K., Srinivasan, Varunvenkat M., Murphy, David, Dominik, Natalia, Elbendary, Hasnaa M., Rafat, Karima, Yilmaz, Sanem, Kanmaz, Seda, Serin, Mine, Krishnakumar, Deepa, Gardham, Alice, Maw, Anna, Rao, Tekki Sreenivasa, Alsubhi, Sarah, Srour, Myriam, Buhas, Daniela, Jewett, Tamison, Goldberg, Rachel E., Shamseldin, Hanan, Frengen, Eirik, Misceo, Doriana, Strømme, Petter, Magliocco Ceroni, José Ricardo, Kim, Chong Ae, Yesil, Gozde, Sengenc, Esma, Guler, Serhat, Hull, Mariam, Parnes, Mered, Aktas, Dilek, Anlar, Banu, Bayram, Yavuz, Pehlivan, Davut, Posey, Jennifer E., Alavi, Shahryar, Madani Manshadi, Seyed Ali, Alzaidan, Hamad, Al-Owain, Mohammad, Alabdi, Lama, Abdulwahab, Ferdous, Sekiguchi, Futoshi, Hamanaka, Kohei, Fujita, Atsushi, Uchiyama, Yuri, Mizuguchi, Takeshi, Miyatake, Satoko, Miyake, Noriko, Elshafie, Reem M., Salayev, Kamran, Guliyeva, Ulviyya, Alkuraya, Fowzan S., Gleeson, Joseph G., Monaghan, Kristin G., Langley, Katherine G., Yang, Hui, Motavaf, Mahsa, Safari, Saeid, Alipour, Mozhgan, Ogata, Kazuhiro, Brown, André E.X., Lupski, James R., Houlden, Henry, and Matsumoto, Naomichi

Abstract

Brain monoamine vesicular transport disease is an infantile-onset movement disorder that mimics cerebral palsy. In 2013, the homozygous SLC18A2variant, p.Pro387Leu, was first reported as a cause of this rare disorder, and dopamine agonists were efficient for treating affected individuals from a single large family. To date, only 6 variants have been reported. In this study, we evaluated genotype–phenotype correlations in individuals with biallelic SLC18A2variants.

Published
2023
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24. Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking

Author

Sanderson, Leslie E, primary, Lanko, Kristina, additional, Alsagob, Maysoon, additional, Almass, Rawan, additional, Al-Ahmadi, Nada, additional, Najafi, Maryam, additional, Al-Muhaizea, Mohammad A, additional, Alzaidan, Hamad, additional, AlDhalaan, Hesham, additional, Perenthaler, Elena, additional, van der Linde, Herma C, additional, Nikoncuk, Anita, additional, Kühn, Nikolas A, additional, Antony, Dinu, additional, Owaidah, Tarek Mustafa, additional, Raskin, Salmo, additional, Vieira, Luana Gabriela Dalla Rosa, additional, Mombach, Romulo, additional, Ahangari, Najmeh, additional, Silveira, Tainá Regina Damaceno, additional, Ameziane, Najim, additional, Rolfs, Arndt, additional, Alharbi, Aljohara, additional, Sabbagh, Raghda M, additional, AlAhmadi, Khalid, additional, Alawam, Bashayer, additional, Ghebeh, Hazem, additional, AlHargan, Aljouhra, additional, Albader, Anoud A, additional, Binhumaid, Faisal S, additional, Goljan, Ewa, additional, Monies, Dorota, additional, Mustafa, Osama M, additional, Aldosary, Mazhor, additional, AlBakheet, Albandary, additional, Alyounes, Banan, additional, Almutairi, Faten, additional, Al-Odaib, Ali, additional, Aksoy, Durdane Bekar, additional, Basak, A Nazli, additional, Palvadeau, Robin, additional, Trabzuni, Daniah, additional, Rosenfeld, Jill A, additional, Karimiani, Ehsan Ghayoor, additional, Meyer, Brian F, additional, Karakas, Bedri, additional, Al-Mohanna, Futwan, additional, Arold, Stefan T, additional, Colak, Dilek, additional, Maroofian, Reza, additional, Houlden, Henry, additional, Bertoli-Avella, Aida M, additional, Schmidts, Miriam, additional, Barakat, Tahsin Stefan, additional, van Ham, Tjakko J, additional, and Kaya, Namik, additional

Published
2021
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25. Bi-allelic Mutations in FAM149B1 Cause Abnormal Primary Cilium and a Range of Ciliopathy Phenotypes in Humans

Author

Shaheen, Ranad, Jiang, Nan, Alzahrani, Fatema, Ewida, Nour, Al-Sheddi, Tarfa, Alobeid, Eman, Musaev, Damir, Stanley, Valentina, Hashem, Mais, Ibrahim, Niema, Abdulwahab, Firdous, Alshenqiti, Abduljabbar, Sonmez, Fatma Mujgan, Saqati, Nadia, Alzaidan, Hamad, Al-Qattan, Mohammad M., Al-Mohanna, Futwan, Gleeson, Joseph G., and Alkuraya, Fowzan S.

Published
2019
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26. Exploiting the Autozygome to Support Previously Published Mendelian Gene-Disease Associations: An Update

Author

Maddirevula, Sateesh, primary, Shamseldin, Hanan E., additional, Sirr, Amy, additional, AlAbdi, Lama, additional, Lo, Russell S., additional, Ewida, Nour, additional, Al-Qahtani, Mashael, additional, Hashem, Mais, additional, Abdulwahab, Firdous, additional, Aboyousef, Omar, additional, Kaya, Namik, additional, Monies, Dorota, additional, Salem, May H., additional, Al Harbi, Naffaa, additional, Aldhalaan, Hesham M., additional, Alzaidan, Hamad, additional, Almanea, Hadeel M., additional, Alsalamah, Abrar K., additional, Al Mutairi, Fuad, additional, Ismail, Samira, additional, Abdel-Salam, Ghada M. H., additional, Alhashem, Amal, additional, Asery, Ali, additional, Faqeih, Eissa, additional, AlQassmi, Amal, additional, Al-Hamoudi, Waleed, additional, Algoufi, Talal, additional, Shagrani, Mohammad, additional, Dudley, Aimée M., additional, and Alkuraya, Fowzan S., additional

Published
2020
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28. Front Cover

Author

Alkuraya, Hisham, primary, Patel, Nisha, additional, Ibrahim, Niema, additional, Al Ghamdi, Bandar, additional, Alsulaiman, Sulaiman M., additional, Nowilaty, Sawsan R., additional, Abboud, Emad, additional, Alturki, Ramadan, additional, Alkharashi, Abdullah, additional, Eyaid, Wafaa, additional, Almasseri, Zainab, additional, Alzaidan, Hamad, additional, Alotaibi, Mohammed D., additional, Abu El‐Asrar, Ahmed M., additional, Alamro, Bandar, additional, Helaby, Rana, additional, Elshaer, Amani, additional, Almontashiri, Naif A.M., additional, Al‐Hussaini, Abdulrahman A., additional, and Alkuraya, Fowzan S., additional

Published
2020
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30. Lethal variants in humans: lessons learned from a large molecular autopsy cohort.

Author

Shamseldin, Hanan E., AlAbdi, Lama, Maddirevula, Sateesh, Alsaif, Hessa S., Alzahrani, Fatema, Ewida, Nour, Hashem, Mais, Abdulwahab, Firdous, Abuyousef, Omar, Kuwahara, Hiroyuki, Gao, Xin, Molecular Autopsy Consortium, Aldhalaan, Hesham, Alfaifi, Abdullah, Alhashem, Amal, Alhasan, Khalid, Alnemer, Maha, Alsahan, Nada, Alyamani, Suad, and Alzaidan, Hamad

Subjects
SUDDEN death, CAUSES of death, AUTOPSY, POPULATION genetics, LEARNING, HUMAN genome
Abstract

Background: Molecular autopsy refers to DNA-based identification of the cause of death. Despite recent attempts to broaden its scope, the term remains typically reserved to sudden unexplained death in young adults. In this study, we aim to showcase the utility of molecular autopsy in defining lethal variants in humans. Methods: We describe our experience with a cohort of 481 cases in whom the cause of premature death was investigated using DNA from the index or relatives (molecular autopsy by proxy). Molecular autopsy tool was typically exome sequencing although some were investigated using targeted approaches in the earlier stages of the study; these include positional mapping, targeted gene sequencing, chromosomal microarray, and gene panels. Results: The study includes 449 cases from consanguineous families and 141 lacked family history (simplex). The age range was embryos to 18 years. A likely causal variant (pathogenic/likely pathogenic) was identified in 63.8% (307/481), a much higher yield compared to the general diagnostic yield (43%) from the same population. The predominance of recessive lethal alleles allowed us to implement molecular autopsy by proxy in 55 couples, and the yield was similarly high (63.6%). We also note the occurrence of biallelic lethal forms of typically non-lethal dominant disorders, sometimes representing a novel bona fide biallelic recessive disease trait. Forty-six disease genes with no OMIM phenotype were identified in the course of this study. The presented data support the candidacy of two other previously reported novel disease genes (FAAH2 and MSN). The focus on lethal phenotypes revealed many examples of interesting phenotypic expansion as well as remarkable variability in clinical presentation. Furthermore, important insights into population genetics and variant interpretation are highlighted based on the results. Conclusions: Molecular autopsy, broadly defined, proved to be a helpful clinical approach that provides unique insights into lethal variants and the clinical annotation of the human genome. [ABSTRACT FROM AUTHOR]

Published
2021
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31. Phenotypic delineation of the retinal arterial macroaneurysms with supravalvular pulmonic stenosis syndrome

Author

Alkuraya, Hisham, primary, Patel, Nisha, additional, Ibrahim, Niema, additional, Al Ghamdi, Bandar, additional, Alsulaiman, Sulaiman M., additional, Nowilaty, Sawsan R., additional, Abboud, Emad, additional, Alturki, Ramadan, additional, Alkharashi, Abdullah, additional, Eyaid, Wafaa, additional, Almasseri, Zainab, additional, Alzaidan, Hamad, additional, Alotaibi, Mohammed D., additional, Abu El‐Asrar, Ahmed M., additional, Alamro, Bandar, additional, Helaby, Rana, additional, Elshaer, Amani, additional, Almontashiri, Naif A.M., additional, Al‐Hussaini, Abdulrahman A., additional, and Alkuraya, Fowzan S., additional

Published
2019
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32. Phenotypic delineation of the retinal arterial macroaneurysms with supravalvular pulmonic stenosis syndrome.

Author

Alkuraya, Hisham, Patel, Nisha, Ibrahim, Niema, Al Ghamdi, Bandar, Alsulaiman, Sulaiman M., Nowilaty, Sawsan R., Abboud, Emad, Alturki, Ramadan, Alkharashi, Abdullah, Eyaid, Wafaa, Almasseri, Zainab, Alzaidan, Hamad, Alotaibi, Mohammed D., Abu El‐Asrar, Ahmed M., Alamro, Bandar, Helaby, Rana, Elshaer, Amani, Almontashiri, Naif A.M., Al‐Hussaini, Abdulrahman A., and Alkuraya, Fowzan S.

Subjects
PULMONARY stenosis, RETINAL artery, CEREBRAL hemorrhage, SYNDROMES, EARLY death
Abstract

Retinal arterial macroaneurysms with supravalvular pulmonic stenosis (RAMSVPS), also known as Familial Retinal Arterial Macroaneurysms (FRAM) syndrome, is a very rare multisystem disorder. Here, we present a case series comprising ophthalmologic and systemic evaluation of patients homozygous for RAMSVPS syndrome causative IGFBP7 variant. New clinical details on 22 previously published and 8 previously unpublished patients are described. Age at first presentation ranged from 1 to 34 years. The classical feature of macroaneurysms and vascular beading involving the retinal arteries was universal. Follow up extending up to 14 years after initial diagnosis revealed recurrent episodes of bleeding and leakage from macroaneurysms in 55% and 59% of patients, respectively. The majority of patients who underwent echocardiography (18/23) showed evidence of heart involvement, most characteristically pulmonary (valvular or supravalvular) stenosis, often requiring surgical correction (12/18). Four patients died in the course of the study from complications of pulmonary stenosis, cerebral hemorrhage, and cardiac complications. Liver involvement (usually cirrhosis) was observed in eight patients. Cerebral vascular involvement was observed in one patient, and stroke was observed in two. We conclude that RAMSVPS is a recognizable syndrome characterized by a high burden of ocular and systemic morbidity, and risk of premature death. Recommendations are proposed for early detection and management of these complications. [ABSTRACT FROM AUTHOR]

Published
2020
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33. The many faces of peroxisomal disorders: Lessons from a large Arab cohort

Author

Alshenaifi, Jumanah, primary, Ewida, Nour, additional, Anazi, Shams, additional, Shamseldin, Hanan E., additional, Patel, Nisha, additional, Maddirevula, Sateesh, additional, Al-Sheddi, Tarfa, additional, Alomar, Rana, additional, Alobeid, Eman, additional, Ibrahim, Niema, additional, Hashem, Mais, additional, Abdulwahab, Firdous, additional, Jacob, Minnie, additional, Alhashem, Amal, additional, Alzaidan, Hamad I., additional, Seidahmed, Mohammed Z., additional, Alhashemi, Nadia, additional, Rawashdeh, Rifaat, additional, Eyaid, Wafaa, additional, Al-Hassnan, Zuhair N., additional, Rahbeeni, Zuhair, additional, Alswaid, Abdulrahman, additional, Hadid, Adnan, additional, Qari, Alya, additional, Mohammed, Dia A., additional, El Khashab, Heba Y., additional, Alfadhel, Majid, additional, Abanemai, Mohammad, additional, Sunbul, Rawda, additional, Al Tala, Saeed, additional, Alkhalifi, Salwa, additional, Alkharfi, Turki, additional, Abouelhoda, Mohamed, additional, Monies, Dorota, additional, Al Tassan, Nada, additional, AlDubayan, Saud H., additional, Kurdi, Wesam, additional, Al-Owain, Mohammed, additional, Dasouki, Majed J., additional, Kentab, Amal Y., additional, Atyani, Suha, additional, Makhseed, Nawal, additional, Faqeih, Eissa, additional, Shaheen, Ranad, additional, and Alkuraya, Fowzan S., additional

Published
2018
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34. MPV17-related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects

Author

El-Hattab, Ayman W., primary, Wang, Julia, additional, Dai, Hongzheng, additional, Almannai, Mohammed, additional, Staufner, Christian, additional, Alfadhel, Majid, additional, Gambello, Michael J., additional, Prasun, Pankaj, additional, Raza, Saleem, additional, Lyons, Hernando J., additional, Afqi, Manal, additional, Saleh, Mohammed A. M., additional, Faqeih, Eissa A., additional, Alzaidan, Hamad I., additional, Alshenqiti, Abduljabbar, additional, Flore, Leigh Anne, additional, Hertecant, Jozef, additional, Sacharow, Stephanie, additional, Barbouth, Deborah S., additional, Murayama, Kei, additional, Shah, Amit A., additional, Lin, Henry C., additional, and Wong, Lee-Jun C., additional

Published
2018
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35. Expanded Newborn Screening Program in Saudi Arabia: Incidence of screened disorders

Author

Alfadhel, Majid, primary, Al Othaim, Ali, additional, Al Saif, Saif, additional, Al Mutairi, Fuad, additional, Alsayed, Moeenaldeen, additional, Rahbeeni, Zuhair, additional, Alzaidan, Hamad, additional, Alowain, Mohammed, additional, Al-Hassnan, Zuhair, additional, Saeedi, Mohamad, additional, Aljohery, Saeed, additional, Alasmari, Ali, additional, Faqeih, Eissa, additional, Alwakeel, Mansour, additional, AlMashary, Maher, additional, Almohameed, Sulaiman, additional, Alzahrani, Mohammed, additional, Migdad, Abeer, additional, Al-Dirbashi, Osama Y, additional, Rashed, Mohamed, additional, Alamoudi, Mohamed, additional, Jacob, Minnie, additional, Alahaidib, Lujane, additional, El-Badaoui, Fahd, additional, Saadallah, Amal, additional, Alsulaiman, Ayman, additional, Eyaid, Wafaa, additional, and Al-Odaib, Ali, additional

Published
2017
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36. The many faces of peroxisomal disorders: Lessons from a large Arab cohort.

Author

Alshenaifi, Jumanah, Ewida, Nour, Anazi, Shams, Shamseldin, Hanan E., Patel, Nisha, Maddirevula, Sateesh, Al‐Sheddi, Tarfa, Alomar, Rana, Alobeid, Eman, Ibrahim, Niema, Hashem, Mais, Abdulwahab, Firdous, Jacob, Minnie, Alhashem, Amal, Alzaidan, Hamad I., Seidahmed, Mohammed Z., Alhashemi, Nadia, Rawashdeh, Rifaat, Eyaid, Wafaa, and Al‐Hassnan, Zuhair N.

Subjects
PEROXISOMAL disorders, GENOTYPES, PHENOTYPES, PARAPARESIS, ZELLWEGER Syndrome, LEUKOENCEPHALOPATHIES
Abstract

Defects in the peroxisomes biogenesis and/or function result in peroxisomal disorders. In this study, we describe the largest Arab cohort to date (72 families) of clinically, biochemically and molecularly characterized patients with peroxisomal disorders. At the molecular level, we identified 43 disease‐causing variants, half of which are novel. The founder nature of many of the variants allowed us to calculate the minimum disease burden for these disorders in our population ~1:30 000, which is much higher than previous estimates in other populations. Clinically, we found an interesting trend toward genotype/phenotype correlation in terms of long‐term survival. Nearly half (40/75) of our peroxisomal disorders patients had documented survival beyond 1 year of age. Most unusual among the long‐term survivors was a multiplex family in which the affected members presented as adults with non‐specific intellectual disability and epilepsy. Other unusual presentations included the very recently described peroxisomal fatty acyl‐CoA reductase 1 disorder as well as CRD, spastic paraparesis, white matter (CRSPW) syndrome. We conclude that peroxisomal disorders are highly heterogeneous in their clinical presentation. Our data also confirm the demonstration that milder forms of Zellweger spectrum disorders cannot be ruled out by the "gold standard" very long chain fatty acids assay, which highlights the value of a genomics‐first approach in these cases. [ABSTRACT FROM AUTHOR]

Published
2019
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38. <italic>MPV17</italic>‐related mitochondrial DNA maintenance defect: New cases and review of clinical, biochemical, and molecular aspects.

Author

El‐Hattab, Ayman W., Wang, Julia, Dai, Hongzheng, Almannai, Mohammed, Staufner, Christian, Alfadhel, Majid, Gambello, Michael J., Prasun, Pankaj, Raza, Saleem, Lyons, Hernando J., Afqi, Manal, Saleh, Mohammed A. M., Faqeih, Eissa A., Alzaidan, Hamad I., Alshenqiti, Abduljabbar, Flore, Leigh Anne, Hertecant, Jozef, Sacharow, Stephanie, Barbouth, Deborah S., and Murayama, Kei

Abstract

Abstract: Mitochondrial DNA (mtDNA) maintenance defects are a group of diseases caused by deficiency of proteins involved in mtDNA synthesis, mitochondrial nucleotide supply, or mitochondrial dynamics. One of the mtDNA maintenance proteins is MPV17, which is a mitochondrial inner membrane protein involved in importing deoxynucleotides into the mitochondria. In 2006, pathogenic variants in MPV17 were first reported to cause infantile‐onset hepatocerebral mtDNA depletion syndrome and Navajo neurohepatopathy. To date, 75 individuals with MPV17‐related mtDNA maintenance defect have been reported with 39 different MPV17 pathogenic variants. In this report, we present an additional 25 affected individuals with nine novel MPV17 pathogenic variants. We summarize the clinical features of all 100 affected individuals and review the total 48 MPV17 pathogenic variants. The vast majority of affected individuals presented with an early‐onset encephalohepatopathic disease characterized by hepatic and neurological manifestations, failure to thrive, lactic acidemia, and mtDNA depletion detected mainly in liver tissue. Rarely, MPV17 deficiency can cause a late‐onset neuromyopathic disease characterized by myopathy and peripheral neuropathy with no or minimal liver involvement. Approximately half of the MPV17 pathogenic variants are missense. A genotype with biallelic missense variants, in particular homozygous p.R50Q, p.P98L, and p.R41Q, can carry a relatively better prognosis. [ABSTRACT FROM AUTHOR]

Published
2018
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39. Correction: New Findings in a Global Approach to Dissect the Whole Phenotype of PLA2G6 Gene Mutations

Author

Salih, Mustafa A., primary, Mundwiller, Emeline, additional, Khan, Arif O., additional, AlDrees, Abdulmajeed, additional, Elmalik, Salah A., additional, Hassan, Hamdy H., additional, Al-Owain, Mohammed, additional, Alkhalidi, Hisham M. S., additional, Katona, Istvan, additional, Kabiraj, Mohammad M., additional, Chrast, Roman, additional, Kentab, Amal Y., additional, Alzaidan, Hamad, additional, Rodenburg, Richard J., additional, Bosley, Thomas M., additional, Weis, Joachim, additional, Koenig, Michel, additional, Stevanin, Giovanni, additional, and Azzedine, Hamid, additional

Published
2013
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40. New Findings in a Global Approach to Dissect the Whole Phenotype of PLA2G6 Gene Mutations

Author

Salih, Mustafa A., primary, Mundwiller, Emeline, additional, Khan, Arif O., additional, AlDrees, Abdulmajeed, additional, Elmalik, Salah A., additional, Hassan, Hamdy H., additional, Al-Owain, Mohammed, additional, Alkhalidi, Hisham M. S., additional, Katona, Istvan, additional, Kabiraj, Mohammad M., additional, Chrast, Roman, additional, Kentab, Amal Y., additional, Alzaidan, Hamad, additional, Rodenburg, Richard J., additional, Bosley, Thomas M., additional, Weis, Joachim, additional, Koenig, Michel, additional, Stevanin, Giovanni, additional, and Azzedine, Hamid, additional

Published
2013
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41. New Findings in a Global Approach to Dissect the Whole Phenotype of PLA2G6 Gene Mutations.

Author

Salih, Mustafa A., Mundwiller, Emeline, Khan, Arif O., AlDrees, Abdulmajeed, Elmalik, Salah A., Hassan, Hamdy H., Al-Owain, Mohammed, Alkhalidi, Hisham M. S., Katona, Istvan, Kabiraj, Mohammad M., Chrast, Roman, Kentab, Amal Y., Alzaidan, Hamad, Rodenburg, Richard J., Bosley, Thomas M., Weis, Joachim, Koenig, Michel, Stevanin, Giovanni, and Azzedine, Hamid

Subjects
PHENOTYPES, HEALTH outcome assessment, DYSTROPHY, AXONAL transport, NEURODEGENERATION, BRAIN imaging, ELECTROPHYSIOLOGY, GENETIC mutation
Abstract

Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients’ muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation. [ABSTRACT FROM AUTHOR]

Published
2013
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42. Neurodevelopmental disorders associated variants in ADAT3 disrupt the activity of the ADAT2/ADAT3 tRNA deaminase complex and impair neuronal migration.

Author

Del-Pozo-Rodriguez J, Tilly P, Lecat R, Vaca HR, Mosser L, Brivio E, Balla T, Gomes MV, Ramos-Morales E, Schwaller N, Salinas-Giegé T, VanNoy G, England EM, Lovgren AK, O'Leary M, Chopra M, Ojeda NM, Toosi MB, Eslahi A, Alerasool M, Mojarrad M, Pais LS, Yeh RC, Gable DL, Hashem MO, Abdulwahab F, Alzaidan H, Aldhalaan H, Tous E, Alsagheir A, Alowain M, Tamim A, Alfayez K, Alhashem A, Alnuzha A, Kamel M, Al-Awam BS, Elnaggar W, Almenabawy N, O'Donnell-Luria A, Neil JE, Gleeson JG, Walsh CA, Alkuraya FS, AlAbdi L, Elkhateeb N, Selim L, Srivastava S, Nedialkova DD, Drouard L, Romier C, Bayam E, and Godin JD

Abstract

The ADAT2/ADAT3 complex catalyzes the adenosine to inosine modification at the wobble position of eukaryotic tRNAs. Mutations in ADAT3 , the catalytically inactive subunit of the ADAT2/ADAT3 complex, have been identified in patients presenting with severe neurodevelopmental disorders (NDDs). Yet, the physiological function of ADAT2/ADAT3 complex during brain development remains totally unknown. Here we showed that maintaining a proper level of ADAT2/ADAT3 catalytic activity is required for correct radial migration of projection neurons in the developing mouse cortex. In addition, we not only reported 20 new NDD patients carrying biallelic variants in ADAT3 but also deeply characterized the impact of those variants on ADAT2/ADAT3 structure, biochemical properties, enzymatic activity and tRNAs editing and abundance. We demonstrated that all the identified variants alter both the abundance and the activity of the complex leading to a significant decrease of I 34 with direct consequence on their steady-state. Using in vivo complementation assays, we correlated the severity of the migration phenotype with the degree of the loss of function caused by the variants. Altogether, our results indicate a critical role of ADAT2/ADAT3 during cortical development and provide cellular and molecular insights into the pathogenicity of ADAT3-related neurodevelopmental disorder.

Published
2024
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43. Arab founder variants: Contributions to clinical genomics and precision medicine.

Author

AlAbdi L, Maddirevula S, Aljamal B, Hamid H, Almulhim A, Hashem MO, Algoos Y, Alqahtani M, Albaloshi S, Alghamdi M, Alduaylij M, Shamseldin HE, Nadeef S, Patel N, Abdulwahab F, Abouyousef O, Alshidi T, Jaafar A, Abouelhoda M, Alhazzani A, Alfares A, Qudair A, Alsulaiman A, Alhashem A, Khan AO, Chedrawi A, Alebdi B, AlAjlan F, Alotaibi F, Alzaidan H, Banjar H, Abdelraouf H, Alkuraya H, Abumansour I, Alfayez K, Tulbah M, Alowain M, Alqahtani M, El-Kalioby M, Shboul M, Sulaiman R, Al Tala S, Khan S, Coskun S, Mrouge S, Alenazi W, Rahbeeni Z, and Alkuraya FS

Abstract

Background: Founder variants are ancestral variants shared by individuals who are not closely related. The large effect size of some of these variants in the context of Mendelian disorders offers numerous precision medicine opportunities., Methods: Using one of the largest datasets on Mendelian disorders in the Middle East, we identified 2,908 medically relevant founder variants derived from 18,360 exomes and genomes and investigated their contribution to the clinical annotation of the human genome., Findings: Strikingly, ∼34% of Arab founder variants are absent in gnomAD. We found a strong contribution of Arab founder variants to the identification of novel gene-disease links (n = 224) and the support/dispute (n = 81 support, n = 101 dispute) of previously reported candidate gene-disease links. The powerful segregation evidence generated by Arab founder variants allowed many ClinVar and Human Gene Mutation Database variants to be reclassified. Overall, 39.5% of diagnostic reports from our clinical lab are based on founder variants, and 19.41% of tested individuals carry at least one pathogenic founder variant. The presumptive loss-of-function mechanism that typically underlies autosomal recessive diseases means that Arab founder variants also offer unique opportunities in "druggable genome" research. Arab founder variants were also informative of migration patterns in the Middle East consistent with documented historical accounts., Conclusions: We highlight the contribution of founder variants from an under-represented population group to precision medicine and inform future prevention programs. Our study also sheds light on the added value of these variants in supplementing other lines of research in tracing population history., Funding: There is no funding for this work., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Published
2024
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