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10 results on '"Eyaid, Wafaa"'

1. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

Author

Kaiyrzhanov, Rauan, Rad, Aboulfazl, Lin, Sheng-Jia, Bertoli-Avella, Aida, Kallemeijn, Wouter W, Godwin, Annie, Zaki, Maha S, Huang, Kevin, Lau, Tracy, Petree, Cassidy, Efthymiou, Stephanie, Ghayoor Karimiani, Ehsan, Hempel, Maja, Normand, Elizabeth A, Rudnik-Schöneborn, Sabine, Schatz, Ulrich A, Baggelaar, Marc P, Ilyas, Muhammad, Sultan, Tipu, Alvi, Javeria Raza, Ganieva, Manizha, Fowler, Ben, Aanicai, Ruxandra, Akay Tayfun, Gulsen, Al Saman, Abdulaziz, Alswaid, Abdulrahman, Amiri, Nafise, Asilova, Nilufar, Shotelersuk, Vorasuk, Yeetong, Patra, Azam, Matloob, Babaei, Meisam, Bahrami Monajemi, Gholamreza, Mohammadi, Pouria, Samie, Saeed, Banu, Selina Husna, Basto, Jorge Pinto, Kortüm, Fanny, Bauer, Mislen, Bauer, Peter, Beetz, Christian, Garshasbi, Masoud, Hameed Issa, Awatif, Eyaid, Wafaa, Ahmed, Hind, Hashemi, Narges, Hassanpour, Kazem, Herman, Isabella, Ibrohimov, Sherozjon, Abdul-Majeed, Ban A, Imdad, Maria, Isrofilov, Maksudjon, Kaiyal, Qassem, Khan, Suliman, Kirmse, Brian, Koster, Janet, Lourenço, Charles Marques, Mitani, Tadahiro, Moldovan, Oana, Murphy, David, Najafi, Maryam, Pehlivan, Davut, Rocha, Maria Eugenia, Salpietro, Vincenzo, Schmidts, Miriam, Shalata, Adel, Mahroum, Mohammad, Talbeya, Jawabreh Kassem, Taylor, Robert W, Vazquez, Dayana, Vetro, Annalisa, Waterham, Hans R, Zaman, Mashaya, Schrader, Tina A, Chung, Wendy K, Guerrini, Renzo, Lupski, James R, Gleeson, Joseph, Suri, Mohnish, Jamshidi, Yalda, Bhatia, Kailash P, Vona, Barbara, Schrader, Michael, Severino, Mariasavina, Guille, Matthew, Tate, Edward W, Varshney, Gaurav K, Houlden, Henry, Maroofian, Reza, Kaiyrzhanov, Rauan, Rad, Aboulfazl, Lin, Sheng-Jia, Bertoli-Avella, Aida, Kallemeijn, Wouter W, Godwin, Annie, Zaki, Maha S, Huang, Kevin, Lau, Tracy, Petree, Cassidy, Efthymiou, Stephanie, Ghayoor Karimiani, Ehsan, Hempel, Maja, Normand, Elizabeth A, Rudnik-Schöneborn, Sabine, Schatz, Ulrich A, Baggelaar, Marc P, Ilyas, Muhammad, Sultan, Tipu, Alvi, Javeria Raza, Ganieva, Manizha, Fowler, Ben, Aanicai, Ruxandra, Akay Tayfun, Gulsen, Al Saman, Abdulaziz, Alswaid, Abdulrahman, Amiri, Nafise, Asilova, Nilufar, Shotelersuk, Vorasuk, Yeetong, Patra, Azam, Matloob, Babaei, Meisam, Bahrami Monajemi, Gholamreza, Mohammadi, Pouria, Samie, Saeed, Banu, Selina Husna, Basto, Jorge Pinto, Kortüm, Fanny, Bauer, Mislen, Bauer, Peter, Beetz, Christian, Garshasbi, Masoud, Hameed Issa, Awatif, Eyaid, Wafaa, Ahmed, Hind, Hashemi, Narges, Hassanpour, Kazem, Herman, Isabella, Ibrohimov, Sherozjon, Abdul-Majeed, Ban A, Imdad, Maria, Isrofilov, Maksudjon, Kaiyal, Qassem, Khan, Suliman, Kirmse, Brian, Koster, Janet, Lourenço, Charles Marques, Mitani, Tadahiro, Moldovan, Oana, Murphy, David, Najafi, Maryam, Pehlivan, Davut, Rocha, Maria Eugenia, Salpietro, Vincenzo, Schmidts, Miriam, Shalata, Adel, Mahroum, Mohammad, Talbeya, Jawabreh Kassem, Taylor, Robert W, Vazquez, Dayana, Vetro, Annalisa, Waterham, Hans R, Zaman, Mashaya, Schrader, Tina A, Chung, Wendy K, Guerrini, Renzo, Lupski, James R, Gleeson, Joseph, Suri, Mohnish, Jamshidi, Yalda, Bhatia, Kailash P, Vona, Barbara, Schrader, Michael, Severino, Mariasavina, Guille, Matthew, Tate, Edward W, Varshney, Gaurav K, Houlden, Henry, and Maroofian, Reza

Abstract

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne (YnMyr) chemical proteomics in the model organisms and human cells, with the latter also being subjected further to ACBD6 peroxisomal localization studies. The affected individuals (23 males and 22 females), aged 1-50 years, typically present with a complex and progressive disease involving moderate-to-severe global developmental delay/intellectual disability (100%) with significant expressive language impairment (98%), movement disorders (97%), facial dysmorphism (95%) and mild cerebellar ataxia (85%) associated with gait impairment (94%), limb spasticity/hypertonia (76%), oculomotor (71%) and behavioural abnormalities (65%), overweight (59%), microcephaly (39%) and epilepsy (33%). The most conspicuous and common movement disorder was dystonia (94%), frequently leading to early-onset progressive postural deformities (97%), limb dystonia (55%) and cervical dystonia (31%). A jerky tremor in the upper limbs (63%), a mild head tremor (59%), parkinsonism/hypokinesia developing with advancing age (32%) and simple motor and vocal tics were among other frequent movement disorders. Midline brain malformations including corpus callosum abnormalities (70%), hypoplasia/agenesis of the anterior commissure (66%), short midbrain an

Published
2024

2. Bi-allelic ACBD6 variants lead to a neurodevelopmental syndrome with progressive and complex movement disorders

Author

Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, Kaiyrzhanov, Rauan, Rad, Aboulfazl, Lin, Sheng-Jia, Bertoli-Avella, Aida, Kallemeijn, Wouter W, Godwin, Annie, Zaki, Maha S, Huang, Kevin, Lau, Tracy, Petree, Cassidy, Efthymiou, Stephanie, Ghayoor Karimiani, Ehsan, Hempel, Maja, Normand, Elizabeth A, Rudnik-Schöneborn, Sabine, Schatz, Ulrich A, Baggelaar, Marc P, Ilyas, Muhammad, Sultan, Tipu, Alvi, Javeria Raza, Ganieva, Manizha, Fowler, Ben, Aanicai, Ruxandra, Akay Tayfun, Gulsen, Al Saman, Abdulaziz, Alswaid, Abdulrahman, Amiri, Nafise, Asilova, Nilufar, Shotelersuk, Vorasuk, Yeetong, Patra, Azam, Matloob, Babaei, Meisam, Bahrami Monajemi, Gholamreza, Mohammadi, Pouria, Samie, Saeed, Banu, Selina Husna, Basto, Jorge Pinto, Kortüm, Fanny, Bauer, Mislen, Bauer, Peter, Beetz, Christian, Garshasbi, Masoud, Hameed Issa, Awatif, Eyaid, Wafaa, Ahmed, Hind, Hashemi, Narges, Hassanpour, Kazem, Herman, Isabella, Ibrohimov, Sherozjon, Abdul-Majeed, Ban A, Imdad, Maria, Isrofilov, Maksudjon, Kaiyal, Qassem, Khan, Suliman, Kirmse, Brian, Koster, Janet, Lourenço, Charles Marques, Mitani, Tadahiro, Moldovan, Oana, Murphy, David, Najafi, Maryam, Pehlivan, Davut, Rocha, Maria Eugenia, Salpietro, Vincenzo, Schmidts, Miriam, Shalata, Adel, Mahroum, Mohammad, Talbeya, Jawabreh Kassem, Taylor, Robert W, Vazquez, Dayana, Vetro, Annalisa, Waterham, Hans R, Zaman, Mashaya, Schrader, Tina A, Chung, Wendy K, Guerrini, Renzo, Lupski, James R, Gleeson, Joseph, Suri, Mohnish, Jamshidi, Yalda, Bhatia, Kailash P, Vona, Barbara, Schrader, Michael, Severino, Mariasavina, Guille, Matthew, Tate, Edward W, Varshney, Gaurav K, Houlden, Henry, Maroofian, Reza, Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, Kaiyrzhanov, Rauan, Rad, Aboulfazl, Lin, Sheng-Jia, Bertoli-Avella, Aida, Kallemeijn, Wouter W, Godwin, Annie, Zaki, Maha S, Huang, Kevin, Lau, Tracy, Petree, Cassidy, Efthymiou, Stephanie, Ghayoor Karimiani, Ehsan, Hempel, Maja, Normand, Elizabeth A, Rudnik-Schöneborn, Sabine, Schatz, Ulrich A, Baggelaar, Marc P, Ilyas, Muhammad, Sultan, Tipu, Alvi, Javeria Raza, Ganieva, Manizha, Fowler, Ben, Aanicai, Ruxandra, Akay Tayfun, Gulsen, Al Saman, Abdulaziz, Alswaid, Abdulrahman, Amiri, Nafise, Asilova, Nilufar, Shotelersuk, Vorasuk, Yeetong, Patra, Azam, Matloob, Babaei, Meisam, Bahrami Monajemi, Gholamreza, Mohammadi, Pouria, Samie, Saeed, Banu, Selina Husna, Basto, Jorge Pinto, Kortüm, Fanny, Bauer, Mislen, Bauer, Peter, Beetz, Christian, Garshasbi, Masoud, Hameed Issa, Awatif, Eyaid, Wafaa, Ahmed, Hind, Hashemi, Narges, Hassanpour, Kazem, Herman, Isabella, Ibrohimov, Sherozjon, Abdul-Majeed, Ban A, Imdad, Maria, Isrofilov, Maksudjon, Kaiyal, Qassem, Khan, Suliman, Kirmse, Brian, Koster, Janet, Lourenço, Charles Marques, Mitani, Tadahiro, Moldovan, Oana, Murphy, David, Najafi, Maryam, Pehlivan, Davut, Rocha, Maria Eugenia, Salpietro, Vincenzo, Schmidts, Miriam, Shalata, Adel, Mahroum, Mohammad, Talbeya, Jawabreh Kassem, Taylor, Robert W, Vazquez, Dayana, Vetro, Annalisa, Waterham, Hans R, Zaman, Mashaya, Schrader, Tina A, Chung, Wendy K, Guerrini, Renzo, Lupski, James R, Gleeson, Joseph, Suri, Mohnish, Jamshidi, Yalda, Bhatia, Kailash P, Vona, Barbara, Schrader, Michael, Severino, Mariasavina, Guille, Matthew, Tate, Edward W, Varshney, Gaurav K, Houlden, Henry, and Maroofian, Reza

Published
2024

3. RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis

Author

Shintaku, Jonathan, Pernice, Wolfgang M., Eyaid, Wafaa, Jeevan, B.G.C., Brown, Zuben P., Juanola-Falgarona, Marti, Koolen, D.A., Rodenburg, R.J.T., Taylor, R.W., Hirano, Michio, Shintaku, Jonathan, Pernice, Wolfgang M., Eyaid, Wafaa, Jeevan, B.G.C., Brown, Zuben P., Juanola-Falgarona, Marti, Koolen, D.A., Rodenburg, R.J.T., Taylor, R.W., and Hirano, Michio

Abstract

Contains fulltext : 252969.pdf (Publisher’s version ) (Open Access)

Published
2022

4. RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis

Author

Shintaku, Jonathan, Pernice, Wolfgang M., Eyaid, Wafaa, Jeevan, B.G.C., Brown, Zuben P., Juanola-Falgarona, Marti, Koolen, D.A., Rodenburg, R.J.T., Taylor, R.W., Hirano, Michio, Shintaku, Jonathan, Pernice, Wolfgang M., Eyaid, Wafaa, Jeevan, B.G.C., Brown, Zuben P., Juanola-Falgarona, Marti, Koolen, D.A., Rodenburg, R.J.T., Taylor, R.W., and Hirano, Michio

Abstract

Contains fulltext : 252969.pdf (Publisher’s version ) (Open Access)

Published
2022

5. RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis

Author

Shintaku, Jonathan, Pernice, Wolfgang M., Eyaid, Wafaa, Jeevan, B. G.C., Brown, Zuben P., Juanola-Falgarona, Marti, Torres-Torronteras, Javier, Sommerville, Ewen W., Hellebrekers, Debby M.E.I., Blakely, Emma L., Donaldson, Alan, van de Laar, Ingrid, Leu, Cheng Shiun, Marti, Ramon, Frank, Joachim, Tanji, Kurenai, Koolen, David A., Rodenburg, Richard J., Chinnery, Patrick F., Smeets, H. J.M., Gorman, Gráinne S., Bonnen, Penelope E., Taylor, Robert W., Hirano, Michio, Shintaku, Jonathan, Pernice, Wolfgang M., Eyaid, Wafaa, Jeevan, B. G.C., Brown, Zuben P., Juanola-Falgarona, Marti, Torres-Torronteras, Javier, Sommerville, Ewen W., Hellebrekers, Debby M.E.I., Blakely, Emma L., Donaldson, Alan, van de Laar, Ingrid, Leu, Cheng Shiun, Marti, Ramon, Frank, Joachim, Tanji, Kurenai, Koolen, David A., Rodenburg, Richard J., Chinnery, Patrick F., Smeets, H. J.M., Gorman, Gráinne S., Bonnen, Penelope E., Taylor, Robert W., and Hirano, Michio

Abstract

Mitochondrial DNA (mtDNA) depletion/deletions syndromes (MDDS) encompass a clinically and etiologically heterogenous group of mitochondrial disorders caused by impaired mtDNA maintenance. Among the most frequent causes of MDDS are defects in nucleoside/nucleotide metabolism, which is critical for synthesis and homeostasis of the deoxynucleoside triphosphate (dNTP) substrates of mtDNA replication. A central enzyme for generating dNTPs is ribonucleotide reductase, a critical mediator of de novo nucleotide synthesis composed of catalytic RRM1 subunits in complex with RRM2 or p53R2. Here, we report 5 probands from 4 families who presented with ptosis and ophthalmoplegia as well as other clinical manifestations and multiple mtDNA deletions in muscle. We identified 3 RRM1 loss-of-function variants, including a dominant catalytic site variant (NP_001024.1: p.N427K) and 2 homozygous recessive variants at p.R381, which has evolutionarily conserved interactions with the specificity site. Atomistic molecular dynamics simulations indicate mechanisms by which RRM1 variants affect protein structure. Cultured primary skin fibroblasts of probands manifested mtDNA depletion under cycling conditions, indicating impaired de novo nucleotide synthesis. Fibroblasts also exhibited aberrant nucleoside diphosphate and dNTP pools and mtDNA ribonucleotide incorporation. Our data reveal that primary RRM1 deficiency and, by extension, impaired de novo nucleotide synthesis are causes of MDDS.

Published
2022

6. 6-Pyruvoyltetrahydropterin Synthase Deficiency: Review and Report of 28 Arab Subjects

Author

Almannai, Mohammed, Felemban, Rana, Saleh, Mohammed A, Faqeih, Eissa A, Alasmari, Ali, AlHashem, Amal, Mohamed, Sarar, Sunbul, Rawda, Al-Murshedi, Fathiya, AlThihli, Khalid, Eyaid, Wafaa, Ali, Rehab, Ben-Omran, Tawfeg, Blau, Nenad, El-Hattab, Ayman W, Alfadhel, Majid, Almannai, Mohammed, Felemban, Rana, Saleh, Mohammed A, Faqeih, Eissa A, Alasmari, Ali, AlHashem, Amal, Mohamed, Sarar, Sunbul, Rawda, Al-Murshedi, Fathiya, AlThihli, Khalid, Eyaid, Wafaa, Ali, Rehab, Ben-Omran, Tawfeg, Blau, Nenad, El-Hattab, Ayman W, and Alfadhel, Majid

Abstract

BACKGROUND: Tetrahydrobiopterin is an essential cofactor for the hydroxylation of aromatic amino acids phenylalanine, tyrosine, and tryptophan. Therefore, tetrahydrobiopterin deficiency results in hyperphenylalaninemia as well as dopamine and serotonin depletion in the central nervous system. The enzyme 6-pyruvoyltetrahydropterin synthase catalyzes the second step of de novo synthesis of tetrahydrobiopterin, and its deficiency is the most frequent cause of tetrahydrobiopterin metabolism disorders. METHOD: We conducted a retrospective chart review of 28 subjects from 24 families with molecularly confirmed 6-pyruvoyltetrahydropterin synthase deficiency from six centers in three Arab countries. We reviewed clinical, biochemical, and molecular data. We also reviewed previously published cohorts of subjects with 6-pyruvoyltetrahydropterin synthase deficiency. RESULTS: Similar to previous observations, we show that early treatment (less than two months) is associated with better outcome. We identify eight PTS variants in 24 independent families. The most common variant is (c.238A>G; p.M80V) with an allele count of 33%. We also identify one novel variant (c.2T>G; p.?). CONCLUSION: The deficiency of 6-pyruvoyltetrahydropterin synthase is relatively common in the Arab population and should be considered in individuals with hyperphenylalaninemia. More natural history studies with comprehensive biochemical and molecular genetics data are needed for a robust base for the development of future therapy.

Published
2019

7. Molecular autopsy in maternal-fetal medicine

Author

Shamseldin, Hanan E., Kurdi, Wesam, Almusafri, Fatima, Alnemer, Maha, Alkaff, Alya, Babay, Zeneb, Alhashem, Amal, Tulbah, Maha, Alsahan, Nada, Khan, Rubina, Sallout, Bahauddin, Al Mardawi, Elham, Seidahmed, Mohamed Zain, Meriki, Niema, Alsaber, Yasser, Qari, Alya, Khalifa, Ola, Eyaid, Wafaa, Rahbeeni, Zuhair, Kurdi, Ahmed, Hashem, Mais, Alshidi, Tarfa, Al-Obeid, Eman, Abdulwahab, Firdous, Ibrahim, Niema, Ewida, Nour, El-Akouri, Karen, Al Mulla, Mariam, Ben-Omran, Tawfeg, Pergande, Matthias, Cirak, Sebahattin, Al Tala, Saeed, Shaheen, Ranad, Faqeih, Eissa, Alkuraya, Fowzan S., Shamseldin, Hanan E., Kurdi, Wesam, Almusafri, Fatima, Alnemer, Maha, Alkaff, Alya, Babay, Zeneb, Alhashem, Amal, Tulbah, Maha, Alsahan, Nada, Khan, Rubina, Sallout, Bahauddin, Al Mardawi, Elham, Seidahmed, Mohamed Zain, Meriki, Niema, Alsaber, Yasser, Qari, Alya, Khalifa, Ola, Eyaid, Wafaa, Rahbeeni, Zuhair, Kurdi, Ahmed, Hashem, Mais, Alshidi, Tarfa, Al-Obeid, Eman, Abdulwahab, Firdous, Ibrahim, Niema, Ewida, Nour, El-Akouri, Karen, Al Mulla, Mariam, Ben-Omran, Tawfeg, Pergande, Matthias, Cirak, Sebahattin, Al Tala, Saeed, Shaheen, Ranad, Faqeih, Eissa, and Alkuraya, Fowzan S.

Abstract

Purpose: The application of genomic sequencing to investigate unexplained death during early human development, a form of lethality likely enriched for severe Mendelian disorders, has been limited.& para;& para;Methods: In this study, we employed exome sequencing as a molecular autopsy tool in a cohort of 44 families with at least one death or lethal fetal malformation at any stage of in utero development. Where no DNA was available from the fetus, we performed molecular autopsy by proxy, i.e., through parental testing.& para;& para;Results: Pathogenic or likely pathogenic variants were identified in 22 families (50%), and variants of unknown significance were identified in further 15 families (34%). These variants were in genes known to cause embryonic or perinatal lethality (ALPL, GUSB, SLC17A5, MRPS16, THSD1, PIEZO1, and CTSA), genes known to cause Mendelian phenotypes that do not typically include embryonic lethality (INVS, FKTN, MYBPC3, COL11A2, KRIT1, ASCC1, NEB, LZTR1, TTC21B, AGT, KLHL41, GFPT1, and WDR81) and genes with no established links to human disease that we propose as novel candidates supported by embryonic lethality of their orthologs or other lines of evidence (MS4A7, SERPINA11, FCRL4, MYBPHL, PRPF19, VPS13D, KIAA1109, MOCS3, SVOPL, FENI, HSPB11, KIF19, and EXOC3L2).& para;& para;Conclusion: Our results suggest that molecular autopsy in pregnancy losses is a practical and high-yield alternative to traditional autopsy, and an opportunity for bringing precision medicine to the clinical practice of perinatology.

Published
2018

8. Molecular autopsy in maternal-fetal medicine

Author

Shamseldin, Hanan E., Kurdi, Wesam, Almusafri, Fatima, Alnemer, Maha, Alkaff, Alya, Babay, Zeneb, Alhashem, Amal, Tulbah, Maha, Alsahan, Nada, Khan, Rubina, Sallout, Bahauddin, Al Mardawi, Elham, Seidahmed, Mohamed Zain, Meriki, Niema, Alsaber, Yasser, Qari, Alya, Khalifa, Ola, Eyaid, Wafaa, Rahbeeni, Zuhair, Kurdi, Ahmed, Hashem, Mais, Alshidi, Tarfa, Al-Obeid, Eman, Abdulwahab, Firdous, Ibrahim, Niema, Ewida, Nour, El-Akouri, Karen, Al Mulla, Mariam, Ben-Omran, Tawfeg, Pergande, Matthias, Cirak, Sebahattin, Al Tala, Saeed, Shaheen, Ranad, Faqeih, Eissa, Alkuraya, Fowzan S., Shamseldin, Hanan E., Kurdi, Wesam, Almusafri, Fatima, Alnemer, Maha, Alkaff, Alya, Babay, Zeneb, Alhashem, Amal, Tulbah, Maha, Alsahan, Nada, Khan, Rubina, Sallout, Bahauddin, Al Mardawi, Elham, Seidahmed, Mohamed Zain, Meriki, Niema, Alsaber, Yasser, Qari, Alya, Khalifa, Ola, Eyaid, Wafaa, Rahbeeni, Zuhair, Kurdi, Ahmed, Hashem, Mais, Alshidi, Tarfa, Al-Obeid, Eman, Abdulwahab, Firdous, Ibrahim, Niema, Ewida, Nour, El-Akouri, Karen, Al Mulla, Mariam, Ben-Omran, Tawfeg, Pergande, Matthias, Cirak, Sebahattin, Al Tala, Saeed, Shaheen, Ranad, Faqeih, Eissa, and Alkuraya, Fowzan S.

Abstract

Purpose: The application of genomic sequencing to investigate unexplained death during early human development, a form of lethality likely enriched for severe Mendelian disorders, has been limited.& para;& para;Methods: In this study, we employed exome sequencing as a molecular autopsy tool in a cohort of 44 families with at least one death or lethal fetal malformation at any stage of in utero development. Where no DNA was available from the fetus, we performed molecular autopsy by proxy, i.e., through parental testing.& para;& para;Results: Pathogenic or likely pathogenic variants were identified in 22 families (50%), and variants of unknown significance were identified in further 15 families (34%). These variants were in genes known to cause embryonic or perinatal lethality (ALPL, GUSB, SLC17A5, MRPS16, THSD1, PIEZO1, and CTSA), genes known to cause Mendelian phenotypes that do not typically include embryonic lethality (INVS, FKTN, MYBPC3, COL11A2, KRIT1, ASCC1, NEB, LZTR1, TTC21B, AGT, KLHL41, GFPT1, and WDR81) and genes with no established links to human disease that we propose as novel candidates supported by embryonic lethality of their orthologs or other lines of evidence (MS4A7, SERPINA11, FCRL4, MYBPHL, PRPF19, VPS13D, KIAA1109, MOCS3, SVOPL, FENI, HSPB11, KIF19, and EXOC3L2).& para;& para;Conclusion: Our results suggest that molecular autopsy in pregnancy losses is a practical and high-yield alternative to traditional autopsy, and an opportunity for bringing precision medicine to the clinical practice of perinatology.

Published
2018

9. Mutations in PNKP cause microcephaly, seizures and defects in DNA repair.

Author

Shen, Jun, Shen, Jun, Gilmore, Edward C, Marshall, Christine A, Haddadin, Mary, Reynolds, John J, Eyaid, Wafaa, Bodell, Adria, Barry, Brenda, Gleason, Danielle, Allen, Kathryn, Ganesh, Vijay S, Chang, Bernard S, Grix, Arthur, Hill, R Sean, Topcu, Meral, Caldecott, Keith W, Barkovich, A James, Walsh, Christopher A, Shen, Jun, Shen, Jun, Gilmore, Edward C, Marshall, Christine A, Haddadin, Mary, Reynolds, John J, Eyaid, Wafaa, Bodell, Adria, Barry, Brenda, Gleason, Danielle, Allen, Kathryn, Ganesh, Vijay S, Chang, Bernard S, Grix, Arthur, Hill, R Sean, Topcu, Meral, Caldecott, Keith W, Barkovich, A James, and Walsh, Christopher A

Abstract

Maintenance of DNA integrity is crucial for all cell types, but neurons are particularly sensitive to mutations in DNA repair genes, which lead to both abnormal development and neurodegeneration. We describe a previously unknown autosomal recessive disease characterized by microcephaly, early-onset, intractable seizures and developmental delay (denoted MCSZ). Using genome-wide linkage analysis in consanguineous families, we mapped the disease locus to chromosome 19q13.33 and identified multiple mutations in PNKP (polynucleotide kinase 3'-phosphatase) that result in severe neurological disease; in contrast, a splicing mutation is associated with more moderate symptoms. Unexpectedly, although the cells of individuals carrying this mutation are sensitive to radiation and other DNA-damaging agents, no such individual has yet developed cancer or immunodeficiency. Unlike other DNA repair defects that affect humans, PNKP mutations universally cause severe seizures. The neurological abnormalities in individuals with MCSZ may reflect a role for PNKP in several DNA repair pathways.

Published
2010

10. Mutations in PNKP cause microcephaly, seizures and defects in DNA repair.

Author

Shen, Jun, Shen, Jun, Gilmore, Edward C, Marshall, Christine A, Haddadin, Mary, Reynolds, John J, Eyaid, Wafaa, Bodell, Adria, Barry, Brenda, Gleason, Danielle, Allen, Kathryn, Ganesh, Vijay S, Chang, Bernard S, Grix, Arthur, Hill, R Sean, Topcu, Meral, Caldecott, Keith W, Barkovich, A James, Walsh, Christopher A, Shen, Jun, Shen, Jun, Gilmore, Edward C, Marshall, Christine A, Haddadin, Mary, Reynolds, John J, Eyaid, Wafaa, Bodell, Adria, Barry, Brenda, Gleason, Danielle, Allen, Kathryn, Ganesh, Vijay S, Chang, Bernard S, Grix, Arthur, Hill, R Sean, Topcu, Meral, Caldecott, Keith W, Barkovich, A James, and Walsh, Christopher A

Abstract

Maintenance of DNA integrity is crucial for all cell types, but neurons are particularly sensitive to mutations in DNA repair genes, which lead to both abnormal development and neurodegeneration. We describe a previously unknown autosomal recessive disease characterized by microcephaly, early-onset, intractable seizures and developmental delay (denoted MCSZ). Using genome-wide linkage analysis in consanguineous families, we mapped the disease locus to chromosome 19q13.33 and identified multiple mutations in PNKP (polynucleotide kinase 3'-phosphatase) that result in severe neurological disease; in contrast, a splicing mutation is associated with more moderate symptoms. Unexpectedly, although the cells of individuals carrying this mutation are sensitive to radiation and other DNA-damaging agents, no such individual has yet developed cancer or immunodeficiency. Unlike other DNA repair defects that affect humans, PNKP mutations universally cause severe seizures. The neurological abnormalities in individuals with MCSZ may reflect a role for PNKP in several DNA repair pathways.

Published
2010

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