86 results on '"Du, Haowei"'
Search Results
52. Expanding the phenotypic and allelic spectrum ofSMG8: Clinical observations reveal overlap withSMG9 ‐associated disease trait
- Author
-
Abdel‐Salam, Ghada M. H., primary, Duan, Ruizhi, additional, Abdel‐Hamid, Mohamed S., additional, Sayed, Inas S. M., additional, Jhangiani, Shalini N., additional, Khan, Ziad, additional, Du, Haowei, additional, Gibbs, Richard A., additional, Posey, Jennifer E., additional, Marafi, Dana, additional, and Lupski, James R., additional
- Published
- 2021
- Full Text
- View/download PDF
53. Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy
- Author
-
Marafi, Dana, primary, Fatih, Jawid M, additional, Kaiyrzhanov, Rauan, additional, Ferla, Matteo P, additional, Gijavanekar, Charul, additional, Al-Maraghi, Aljazi, additional, Liu, Ning, additional, Sites, Emily, additional, Alsaif, Hessa S, additional, Al-Owain, Mohammad, additional, Zakkariah, Mohamed, additional, El-Anany, Ehab, additional, Guliyeva, Ulviyya, additional, Guliyeva, Sughra, additional, Gaba, Colette, additional, Haseeb, Ateeq, additional, Alhashem, Amal M, additional, Danish, Enam, additional, Karageorgou, Vasiliki, additional, Beetz, Christian, additional, Subhi, Alaa A, additional, Mullegama, Sureni V, additional, Torti, Erin, additional, Sebastin, Monisha, additional, Breilyn, Margo Sheck, additional, Duberstein, Susan, additional, Abdel-Hamid, Mohamed S, additional, Mitani, Tadahiro, additional, Du, Haowei, additional, Rosenfeld, Jill A, additional, Jhangiani, Shalini N, additional, Coban Akdemir, Zeynep, additional, Gibbs, Richard A, additional, Taylor, Jenny C, additional, Fakhro, Khalid A, additional, Hunter, Jill V, additional, Pehlivan, Davut, additional, Zaki, Maha S, additional, Gleeson, Joseph G, additional, Maroofian, Reza, additional, Houlden, Henry, additional, Posey, Jennifer E, additional, Sutton, V Reid, additional, Alkuraya, Fowzan S, additional, Elsea, Sarah H, additional, and Lupski, James R, additional
- Published
- 2021
- Full Text
- View/download PDF
54. Deep clinicopathological phenotyping identifies a previously unrecognized pathogenic EMD splice variant
- Author
-
Calame, Daniel G., primary, Fatih, Jawid M., additional, Herman, Isabella, additional, Coban‐Akdemir, Zeynep, additional, Du, Haowei, additional, Mitani, Tadahiro, additional, Jhangiani, Shalini N., additional, Marafi, Dana, additional, Gibbs, Richard A., additional, Posey, Jennifer E., additional, Mehta, Vidya P., additional, Mohila, Carrie A., additional, Abid, Farida, additional, Lotze, Timothy E., additional, Pehlivan, Davut, additional, Adesina, Adekunle M., additional, and Lupski, James R., additional
- Published
- 2021
- Full Text
- View/download PDF
55. An international virtual hackathon to build tools for the analysis of structural variants within species ranging from coronaviruses to vertebrates
- Author
-
Mc Cartney, Ann M., primary, Mahmoud, Medhat, additional, Jochum, Michael, additional, Agustinho, Daniel Paiva, additional, Zorman, Barry, additional, Al Khleifat, Ahmad, additional, Dabbaghie, Fawaz, additional, K Kesharwani, Rupesh, additional, Smolka, Moritz, additional, Dawood, Moez, additional, Albin, Dreycey, additional, Aliyev, Elbay, additional, Almabrazi, Hakeem, additional, Arslan, Ahmed, additional, Balaji, Advait, additional, Behera, Sairam, additional, Billingsley, Kimberley, additional, L Cameron, Daniel, additional, Daw, Joyjit, additional, T. Dawson, Eric, additional, De Coster, Wouter, additional, Du, Haowei, additional, Dunn, Christopher, additional, Esteban, Rocio, additional, Jolly, Angad, additional, Kalra, Divya, additional, Liao, Chunxiao, additional, Liu, Yunxi, additional, Lu, Tsung-Yu, additional, M Havrilla, James, additional, M Khayat, Michael, additional, Marin, Maximillian, additional, Monlong, Jean, additional, Price, Stephen, additional, Rafael Gener, Alejandro, additional, Ren, Jingwen, additional, Sagayaradj, Sagayamary, additional, Sapoval, Nicolae, additional, Sinner, Claude, additional, C. Soto, Daniela, additional, Soylev, Arda, additional, Subramaniyan, Arun, additional, Syed, Najeeb, additional, Tadimeti, Neha, additional, Tater, Pamella, additional, Vats, Pankaj, additional, Vaughn, Justin, additional, Walker, Kimberly, additional, Wang, Gaojianyong, additional, Zeng, Qiandong, additional, Zhang, Shangzhe, additional, Zhao, Tingting, additional, Kille, Bryce, additional, Biederstedt, Evan, additional, Chaisson, Mark, additional, English, Adam, additional, Kronenberg, Zev, additional, J. Treangen, Todd, additional, Hefferon, Timothy, additional, Chin, Chen-Shan, additional, Busby, Ben, additional, and J Sedlazeck, Fritz, additional
- Published
- 2021
- Full Text
- View/download PDF
56. Chromoanagenesis Event Underlies a de novo Pericentric and Multiple Paracentric Inversions in a Single Chromosome Causing Coffin–Siris Syndrome
- Author
-
Grochowski, Christopher M., primary, Krepischi, Ana C. V., additional, Eisfeldt, Jesper, additional, Du, Haowei, additional, Bertola, Debora R., additional, Oliveira, Danyllo, additional, Costa, Silvia S., additional, Lupski, James R., additional, Lindstrand, Anna, additional, and Carvalho, Claudia M. B., additional
- Published
- 2021
- Full Text
- View/download PDF
57. Novel RETREG1 (FAM134B) founder allele is linked to HSAN2B and renal disease in a Turkish family.
- Author
-
Taşdelen, Elifcan, Calame, Daniel G., Akay, Gulsen, Mitani, Tadahiro, Fatih, Jawid M., Herman, Isabella, Du, Haowei, Coban‐Akdemir, Zeynep, Marafi, Dana, Jhangiani, Shalini N., Posey, Jennifer E., Gibbs, Richard A., Altıparmak, Taylan, Kutlay, Nüket Yürür, Lupski, James R., and Pehlivan, Davut
- Abstract
Hereditary sensory and autonomic neuropathy type 2B (HSAN2B) is a rare autosomal recessive peripheral neuropathy caused by biallelic variants in RETREG1 (formerly FAM134B). HSAN2B is characterized by sensory impairment resulting in skin ulcerations, amputations, and osteomyelitis as well as variable weakness, spasticity, and autonomic dysfunction. Here, we report four affected individuals with recurrent osteomyelitis, ulceration, and amputation of hands and feet, sensory neuropathy, hyperhidrosis, urinary incontinence, and renal failure from a family without any known shared parental ancestry. Due to the history of chronic recurrent multifocal osteomyelitis and microcytic anemia, a diagnosis of Majeed syndrome was considered; however, sequencing of LPIN2 was negative. Family‐based exome sequencing (ES) revealed a novel homozygous ultrarare RETREG1 variant NM_001034850.2:c.321G>A;p.Trp107Ter. Electrophysiological studies of the proband demonstrated axonal sensorimotor neuropathy predominantly in the lower extremities. Consistent with the lack of shared ancestry, the coefficient of inbreeding calculated from ES data was low (F = 0.002), but absence of heterozygosity (AOH) analysis demonstrated a 7.2 Mb AOH block surrounding the variant consistent with a founder allele. Two of the four affected individuals had unexplained renal failure which has not been reported in HSAN2B cases to date. Therefore, this report describes a novel RETREG1 founder allele and suggests renal failure may be an unrecognized feature of the RETREG1‐disease spectrum. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
58. Risk of sudden cardiac death in EXOSC5‐related disease
- Author
-
Calame, Daniel G., primary, Herman, Isabella, additional, Fatih, Jawid M., additional, Du, Haowei, additional, Akay, Gulsen, additional, Jhangiani, Shalini N., additional, Coban‐Akdemir, Zeynep, additional, Milewicz, Dianna M., additional, Gibbs, Richard A., additional, Posey, Jennifer E., additional, Marafi, Dana, additional, Hunter, Jill V., additional, Fan, Yuxin, additional, Lupski, James R., additional, and Miyake, Christina Y., additional
- Published
- 2021
- Full Text
- View/download PDF
59. Biallelic Pathogenic Variants in TNNT3 Associated With Congenital Myopathy
- Author
-
Calame, Daniel G., primary, Fatih, Jawid, additional, Herman, Isabella, additional, Akdemir, Zeynep Coban, additional, Du, Haowei, additional, Jhangiani, Shalini N., additional, Gibbs, Richard A., additional, Marafi, Dana, additional, Pehlivan, Davut, additional, Posey, Jennifer E., additional, Lotze, Timothy, additional, Mancias, Pedro, additional, Bhattacharjee, Meenakshi Bidwai, additional, and Lupski, James R., additional
- Published
- 2021
- Full Text
- View/download PDF
60. A novel homozygousSLC13A5whole‐gene deletion generated byAlu/Alu‐mediated rearrangement in an Iraqi family with epileptic encephalopathy
- Author
-
Duan, Ruizhi, primary, Saadi, Nebal Waill, additional, Grochowski, Christopher M., additional, Bhadila, Ghalia, additional, Faridoun, Afnan, additional, Mitani, Tadahiro, additional, Du, Haowei, additional, Fatih, Jawid M., additional, Jhangiani, Shalini N., additional, Akdemir, Zeynep C., additional, Gibbs, Richard A., additional, Pehlivan, Davut, additional, Posey, Jennifer E., additional, Marafi, Dana, additional, and Lupski, James R., additional
- Published
- 2021
- Full Text
- View/download PDF
61. Abstract PO-133: Breast tumors maintain a reservoir of subclonal diversity during primary expansion
- Author
-
Minussi, Darlan Conterno, primary, Nicholson, Michael, additional, Ye, Hanghui, additional, Davis, Alexander, additional, Wang, Kaile, additional, Sei, Emi, additional, Du, Haowei, additional, Rabbani, Mashiat, additional, Peng, Cheng, additional, Hu, Min, additional, Bai, Shanshan, additional, McDonald, Thomas, additional, Schalck, Aislyn, additional, Casasent, Anna, additional, Barrera, Angelica, additional, Chen, Hui, additional, Lim, Bora, additional, Arun, Banu, additional, Meric-Bernstam, Funda, additional, Michor, Franziska, additional, and Navin, Nicholas, additional
- Published
- 2020
- Full Text
- View/download PDF
62. Quantitative dissection of multilocus pathogenic variation in an Egyptian infant with severe neurodevelopmental disorder resulting from multiple molecular diagnoses.
- Author
-
Herman, Isabella, Jolly, Angad, Du, Haowei, Dawood, Moez, Abdel‐Salam, Ghada M. H., Marafi, Dana, Mitani, Tadahiro, Calame, Daniel G., Coban‐Akdemir, Zeynep, Fatih, Jawid M., Hegazy, Ibrahim, Jhangiani, Shalini N., Gibbs, Richard A., Pehlivan, Davut, Posey, Jennifer E., and Lupski, James R.
- Abstract
Genomic sequencing and clinical genomics have demonstrated that substantial subsets of atypical and/or severe disease presentations result from multilocus pathogenic variation (MPV) causing blended phenotypes. In an infant with a severe neurodevelopmental disorder, four distinct molecular diagnoses were found by exome sequencing (ES). The blended phenotype that includes brain malformation, dysmorphism, and hypotonia was dissected using the Human Phenotype Ontology (HPO). ES revealed variants in CAPN3 (c.259C > G:p.L87V), MUSK (c.1781C > T:p.A594V), NAV2 (c.1996G > A:p.G666R), and ZC4H2 (c.595A > C:p.N199H). CAPN3, MUSK, and ZC4H2 are established disease genes linked to limb‐girdle muscular dystrophy (OMIM# 253600), congenital myasthenia (OMIM# 616325), and Wieacker–Wolff syndrome (WWS; OMIM# 314580), respectively. NAV2 is a retinoic‐acid responsive novel disease gene candidate with biological roles in neurite outgrowth and cerebellar dysgenesis in mouse models. Using semantic similarity, we show that no gene identified by ES individually explains the proband phenotype, but rather the totality of the clinically observed disease is explained by the combination of disease‐contributing effects of the identified genes. These data reveal that multilocus pathogenic variation can result in a blended phenotype with each gene affecting a different part of the nervous system and nervous system‐muscle connection. We provide evidence from this n = 1 study that in patients with MPV and complex blended phenotypes resulting from multiple molecular diagnoses, quantitative HPO analysis can allow for dissection of phenotypic contribution of both established disease genes and novel disease gene candidates not yet proven to cause human disease. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
63. Expanding the phenotypic and allelic spectrum of SMG8: Clinical observations reveal overlap with SMG9‐associated disease trait.
- Author
-
Abdel‐Salam, Ghada M. H., Duan, Ruizhi, Abdel‐Hamid, Mohamed S., Sayed, Inas S. M., Jhangiani, Shalini N., Khan, Ziad, Du, Haowei, Gibbs, Richard A., Posey, Jennifer E., Marafi, Dana, and Lupski, James R.
- Abstract
SMG8 (MIM *617315) is a regulatory subunit involved in nonsense‐mediated mRNA decay (NMD), a cellular protective pathway that regulates mRNA transcription, transcript stability, and degrades transcripts containing premature stop codons. SMG8 binds SMG9 and SMG1 to form the SMG1C complex and inhibit the kinase activity of SMG1. Biallelic deleterious variants in SMG9 are known to cause a heart and brain malformation syndrome (HBMS; MIM #616920), whereas biallelic deleterious variants in SMG8 were recently described to cause a novel neurodevelopmental disorder (NDD) with dysmorphic facies and cataracts, now defined as Alzahrani–Kuwahara syndrome (ALKUS: MIM #619268). Only eight subjects from four families with ALKUS have been described to date. Through research reanalysis of a nondiagnostic clinical exome, we identified a subject from a fifth unrelated family with a homozygous deleterious variant in SMG8 and features consistent with ALKUS. Interestingly, the subject also had unilateral microphthalmia, a clinical feature that has been described in SMG9‐related disorder. Our study expands the phenotypic spectrum of SMG8‐related disorder, demonstrates an overlapping phenotype between SMG8‐ and SMG9‐related rare disease traits, provides further evidence for the SMG8 and SMG9 protein interactions, and highlights the importance of revisiting nondiagnostic exome data to identify and affirm emerging novel genes for rare disease traits. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
64. Congenital diaphragmatic hernia as a prominent feature of aSPECC1L ‐relatedsyndrome
- Author
-
Wild, K. Taylor, primary, Gordon, Tia, additional, Bhoj, Elizabeth J., additional, Du, Haowei, additional, Jhangiani, Shalini N., additional, Posey, Jennifer E., additional, Lupski, James R., additional, Scott, Daryl A., additional, and Zackai, Elaine H., additional
- Published
- 2020
- Full Text
- View/download PDF
65. Methods developed during the first National Center for Biotechnology Information Structural Variation Codeathon at Baylor College of Medicine
- Author
-
Mahmoud, Medhat, primary, Gener, Alejandro Rafael, additional, Khayat, Michael M., additional, English, Adam C., additional, Balaji, Advait, additional, Zhou, Anbo, additional, Hehn, Andreas, additional, Fungtammasan, Arkarachai, additional, Chrisman, Brianna Sierra, additional, Chin, Chen-Shan, additional, Lin, Chiao-Feng, additional, Lo, Chun-Hsuan, additional, Liao, Chunxiao, additional, Carvalho, Claudia M. B., additional, Diesh, Colin, additional, Symer, David E., additional, Kalra, Divya, additional, Albin, Dreycey, additional, Aliyev, Elbay, additional, Dawson, Eric T., additional, Venner, Eric, additional, Foertter, Fernanda, additional, Bae, Gigon, additional, Du, Haowei, additional, Daw, Joyjit, additional, Wang, Junzhou, additional, Akagi, Keiko, additional, Phan, Lon, additional, Jochum, Michael, additional, Edrisi, Mohammadamin, additional, Shah, Nirav N., additional, Wang, Qi, additional, Fullem, Robert, additional, Zheng, Rong, additional, Kalla, Sara E, additional, Mitra, Shakuntala, additional, Treangen, Todd J., additional, Mahaganapathy, Vaidhyanathan, additional, Malladi, Venkat Sai, additional, Menon, Vipin K, additional, Fu, Yilei, additional, Yin, Yongze, additional, Feng, Yuanqing, additional, Hefferon, Tim, additional, Sedlazeck, Fritz J., additional, and Busby, Ben, additional
- Published
- 2020
- Full Text
- View/download PDF
66. BiallelicGRM7variants cause epilepsy, microcephaly, and cerebral atrophy
- Author
-
Marafi, Dana, primary, Mitani, Tadahiro, additional, Isikay, Sedat, additional, Hertecant, Jozef, additional, Almannai, Mohammed, additional, Manickam, Kandamurugu, additional, Abou Jamra, Rami, additional, El‐Hattab, Ayman W., additional, Rajah, Jaishen, additional, Fatih, Jawid M., additional, Du, Haowei, additional, Karaca, Ender, additional, Bayram, Yavuz, additional, Punetha, Jaya, additional, Rosenfeld, Jill A., additional, Jhangiani, Shalini N., additional, Boerwinkle, Eric, additional, Akdemir, Zeynep C., additional, Erdin, Serkan, additional, Hunter, Jill V., additional, Gibbs, Richard A., additional, Pehlivan, Davut, additional, Posey, Jennifer E., additional, and Lupski, James R., additional
- Published
- 2020
- Full Text
- View/download PDF
67. Integrated Sequencing & Array Comparative Genomic Hybridization in Familial Parkinson’s Disease
- Author
-
Robak, Laurie A., primary, Du, Renqian, additional, Yuan, Bo, additional, Gu, Shen, additional, Alfradique-Dunham, Isabel, additional, Kondapalli, Vismaya, additional, Hinojosa, Evelyn, additional, Stillwell, Amanda, additional, Young, Emily, additional, Zhang, Chaofan, additional, Song, Xiaofei, additional, Du, Haowei, additional, Gambin, Tomasz, additional, Jhangiani, Shalini N., additional, Akdemir, Zeynep Coban, additional, Muzny, Donna M., additional, Tejomurtula, Anusha, additional, Ross, Owen A., additional, Shaw, Chad, additional, Jankovic, Joseph, additional, Bi, Weimin, additional, Posey, Jennifer E., additional, Lupski, James R., additional, and Shulman, Joshua M., additional
- Published
- 2019
- Full Text
- View/download PDF
68. Bi-allelic Pathogenic Variants in TUBGCP2 Cause Microcephaly and Lissencephaly Spectrum Disorders
- Author
-
Mitani, Tadahiro, primary, Punetha, Jaya, additional, Akalin, Ibrahim, additional, Pehlivan, Davut, additional, Dawidziuk, Mateusz, additional, Coban Akdemir, Zeynep, additional, Yilmaz, Sarenur, additional, Aslan, Ezgi, additional, Hunter, Jill V., additional, Hijazi, Hadia, additional, Grochowski, Christopher M., additional, Jhangiani, Shalini N., additional, Karaca, Ender, additional, Fatih, Jawid M., additional, Iwanowski, Piotr, additional, Gambin, Tomasz, additional, Wlasienko, Pawel, additional, Goszczanska-Ciuchta, Alicja, additional, Bekiesinska-Figatowska, Monika, additional, Hosseini, Masoumeh, additional, Arzhangi, Sanaz, additional, Najmabadi, Hossein, additional, Rosenfeld, Jill A., additional, Du, Haowei, additional, Marafi, Dana, additional, Blaser, Susan, additional, Teitelbaum, Ronni, additional, Silver, Rachel, additional, Posey, Jennifer E., additional, Ropers, Hans-Hilger, additional, Gibbs, Richard A., additional, Wiszniewski, Wojciech, additional, Lupski, James R., additional, Chitayat, David, additional, Kahrizi, Kimia, additional, and Gawlinski, Pawel, additional
- Published
- 2019
- Full Text
- View/download PDF
69. A novel homozygous SLC13A5 whole‐gene deletion generated by Alu/Alu‐mediated rearrangement in an Iraqi family with epileptic encephalopathy.
- Author
-
Duan, Ruizhi, Saadi, Nebal Waill, Grochowski, Christopher M., Bhadila, Ghalia, Faridoun, Afnan, Mitani, Tadahiro, Du, Haowei, Fatih, Jawid M., Jhangiani, Shalini N., Akdemir, Zeynep C., Gibbs, Richard A., Pehlivan, Davut, Posey, Jennifer E., Marafi, Dana, and Lupski, James R.
- Abstract
Biallelic loss‐of‐function (LoF) of SLC13A5 (solute carrier family 13, member 5) induced deficiency in sodium/citrate transporter (NaCT) causes autosomal recessive developmental epileptic encephalopathy 25 with hypoplastic amelogenesis imperfecta (DEE25; MIM #615905). Many pathogenic SLC13A5 single nucleotide variants (SNVs) and small indels have been described; however, no cases with copy number variants (CNVs) have been sufficiently investigated. We describe a consanguineous Iraqi family harboring an 88.5 kb homozygous deletion including SLC13A5 in Chr17p13.1. The three affected male siblings exhibit neonatal‐onset epilepsy with fever‐sensitivity, recurrent status epilepticus, global developmental delay/intellectual disability (GDD/ID), and other variable neurological findings as shared phenotypical features of DEE25. Two of the three affected subjects exhibit hypoplastic amelogenesis imperfecta (AI), while the proband shows no evidence of dental abnormalities or AI at 2 years of age with apparently unaffected primary dentition. Characterization of the genomic architecture at this locus revealed evidence for genomic instability generated by an Alu/Alu‐mediated rearrangement; confirmed by break‐point junction Sanger sequencing. This multiplex family from a distinct population elucidates the phenotypic consequence of complete LoF of SLC13A5 and illustrates the importance of read‐depth‐based CNV detection in comprehensive exome sequencing analysis to solve cases that otherwise remain molecularly unsolved. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
70. Neurodevelopmental disorder in an Egyptian family with a biallelic ALKBH8 variant.
- Author
-
Saad, Ahmed K., Maraf, Dana, Mitani, Tadahiro, Du, Haowei, Rafat, Karima, Fatih, Jawid M., Jhangiani, Shalini N., Coban-Akdemir, Zeynep, Gibbs, Richard A., Pehlivan, Davut, Hunter, Jill V., Posey, Jennifer E., Zaki, Maha S., and Lupski, James R.
- Abstract
Alkylated DNA repair protein AlkB homolog 8 (ALKBH8) is a member of the AlkB family of dioxygenases. ALKBH8 is a methyltransferase of the highly variable wobble nucleoside position in the anticodon loop of tRNA and thus plays a critical role in tRNA modification by preserving codon recognition and preventing errors in amino acid incorporation during translation. Moreover, its activity catalyzes uridine modifications that are proposed to be critical for accurate protein translation. Previously, two distinct homozygous truncating variants in the final exon of ALKBH8 were described in two unrelated large Saudi Arabian kindreds with intellectual developmental disorder and autosomal recessive 71 (MRT71) syndrome (MIM# 618504). Here, we report a third family—of Egyptian descent—harboring a novel homozygous frame‐shift variant in the last exon of ALKBH8. Two affected siblings in this family exhibit global developmental delay and intellectual disability as shared characteristic features of MRT71 syndrome, and we further characterize their observed dysmorphic features and brain MRI findings. This description of a third family with a truncating ALKBH8 variant from a distinct population broadens the phenotypic and genotypic spectrum of MRT71 syndrome, affirms that perturbations in tRNA biogenesis can contribute to neurogenetic disease traits, and firmly establishes ALKBH8 as a novel neurodevelopmental disease gene. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
71. HMZDupFinder: a robust computational approach for detecting intragenic homozygous duplications from exome sequencing data.
- Author
-
Du, Haowei, Dardas, Zain, Jolly, Angad, Grochowski, Christopher M, Jhangiani, Shalini N, Li, He, Muzny, Donna, Fatih, Jawid M, Yesil, Gozde, Elçioglu, Nursel H, Gezdirici, Alper, Marafi, Dana, Pehlivan, Davut, Calame, Daniel G, Carvalho, Claudia M B, Posey, Jennifer E, Gambin, Tomasz, Coban-Akdemir, Zeynep, and Lupski, James R
- Published
- 2024
- Full Text
- View/download PDF
72. Biallelic loss-of-function variants in the splicing regulator NSRP1cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy
- Author
-
Calame, Daniel G., Bakhtiari, Somayeh, Logan, Rachel, Coban-Akdemir, Zeynep, Du, Haowei, Mitani, Tadahiro, Fatih, Jawid M., Hunter, Jill V., Herman, Isabella, Pehlivan, Davut, Jhangiani, Shalini N., Person, Richard, Schnur, Rhonda E., Jin, Sheng Chih, Bilguvar, Kaya, Posey, Jennifer E., Koh, Sookyong, Firouzabadi, Saghar G., Alehabib, Elham, Tafakhori, Abbas, Esmkhani, Sahra, Gibbs, Richard A., Noureldeen, Mahmoud M., Zaki, Maha S., Marafi, Dana, Darvish, Hossein, Kruer, Michael C., and Lupski, James R.
- Abstract
Alternative splicing plays a critical role in mouse neurodevelopment, regulating neurogenesis, cortical lamination, and synaptogenesis, yet few human neurodevelopmental disorders are known to result from pathogenic variation in splicing regulator genes. Nuclear Speckle Splicing Regulator Protein 1 (NSRP1) is a ubiquitously expressed splicing regulator not known to underlie a Mendelian disorder.
- Published
- 2021
- Full Text
- View/download PDF
73. Congenital diaphragmatic hernia as a prominent feature of a SPECC1L‐related syndrome.
- Author
-
Wild, K. Taylor, Gordon, Tia, Bhoj, Elizabeth J., Du, Haowei, Jhangiani, Shalini N., Posey, Jennifer E., Lupski, James R., Scott, Daryl A., and Zackai, Elaine H.
- Abstract
Congenital diaphragmatic hernias (CDH) confer substantial morbidity and mortality. Genetic defects, including chromosomal anomalies, copy number variants, and sequence variants are identified in ~30% of patients with CDH. A genetic etiology is not yet found in 70% of patients, however there is a growing number of genetic syndromes and single gene disorders associated with CDH. While there have been two reported individuals with X‐linked Opitz G/BBB syndrome with MID1 mutations who have CDH as an associated feature, CDH appears to be a much more prominent feature of a SPECC1L‐related autosomal dominant Opitz G/BBB syndrome. Features unique to autosomal dominant Opitz G/BBB syndrome include branchial fistulae, omphalocele, and a bicornuate uterus. Here we present one new individual and five previously reported individuals with CDH found to have SPECC1L mutations. These cases provide strong evidence that SPECC1L is a bona fide CDH gene. We conclude that a SPECC1L‐related Opitz G/BBB syndrome should be considered in any patient with CDH who has additional features of hypertelorism, a prominent forehead, a broad nasal bridge, anteverted nares, cleft lip/palate, branchial fistulae, omphalocele, and/or bicornuate uterus. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
74. Considerations for reporting variants in novel candidate genes identified during clinical genomic testing
- Author
-
Chong, Jessica X., Berger, Seth I., Baxter, Samantha, Smith, Erica, Xiao, Changrui, Calame, Daniel G., Hawley, Megan H., Rivera-Munoz, E. Andres, DiTroia, Stephanie, Abouhala, Siwaar, Albert, Jessica, Almalvez, Miguel, Alvarez, Raquel, Amin, Mutaz, Anderson, Peter, Aradhya, Swaroop, Ashley, Euan, Assimes, Themistocles, Auriga, Light, Austin-Tse, Christina, Bamshad, Mike, Barseghyan, Hayk, Baxter, Samantha, Behera, Sairam, Beheshti, Shaghayegh, Bejerano, Gill, Berger, Seth, Bernstein, Jon, Best, Sabrina, Blankenmeister, Benjamin, Blue, Elizabeth, Boerwinkle, Eric, Bonkowski, Emily, Bonner, Devon, Boone, Philip, Bornhorst, Miriam, Brand, Harrison, Buckingham, Kati, Calame, Daniel, Carter, Jennefer, Casadei, Silvia, Chadwick, Lisa, Chavez, Clarisa, Chen, Ziwei, Chinn, Ivan, Chong, Jessica, Coban-Akdemir, Zeynep, Cohen, Andrea J., Conner, Sarah, Conomos, Matthew, Coveler, Karen, Cui, Ya Allen, Currin, Sara, Daber, Robert, Dardas, Zain, Davis, Colleen, Dawood, Moez, de Dios, Ivan, de Esch, Celine, Delaney, Meghan, Delot, Emmanuele, DiTroia, Stephanie, Doddapaneni, Harsha, Du, Haowei, Duan, Ruizhi, Dugan-Perez, Shannon, Duong, Nhat, Duyzend, Michael, Eichler, Evan, Emami, Sara, Fraser, Jamie, Fusaro, Vincent, Galey, Miranda, Ganesh, Vijay, Garcia, Brandon, Garimella, Kiran, Gibbs, Richard, Gifford, Casey, Ginsburg, Amy, Goddard, Page, Gogarten, Stephanie, Gogate, Nikhita, Gordon, William, Gorzynski, John E., Greenleaf, William, Grochowski, Christopher, Groopman, Emily, Sousa, Rodrigo Guarischi, Gudmundsson, Sanna, Gulati, Ashima, Hall, Stacey, Harvey, William, Hawley, Megan, Heavner, Ben, Horike-Pyne, Martha, Hu, Jianhong, Huang, Yongqing, Hwang, James, Jarvik, Gail, Jensen, Tanner, Jhangiani, Shalini, Jimenez-Morales, David, Jin, Christopher, Saad, Ahmed K., Kahn-Kirby, Amanda, Kain, Jessica, Kaur, Parneet, Keehan, Laura, Knoblach, Susan, Ko, Arthur, Kundaje, Anshul, Kundu, Soumya, Lancaster, Samuel M., Larsson, Katie, Lee, Arthur, Lemire, Gabrielle, Lewis, Richard, Li, Wei, Li, Yidan, Liu, Pengfei, LoTempio, Jonathan, Lupski, James (Jim), Ma, Jialan, MacArthur, Daniel, Mahmoud, Medhat, Malani, Nirav, Mangilog, Brian, Marafi, Dana, Marmolejos, Sofia, Marten, Daniel, Martinez, Eva, Marvin, Colby, Marwaha, Shruti, Mastrorosa, Francesco Kumara, Matalon, Dena, May, Susanne, McGee, Sean, Meador, Lauren, Mefford, Heather, Mendez, Hector Rodrigo, Miller, Alexander, Miller, Danny E., Mitani, Tadahiro, Montgomery, Stephen, Moyses, Mariana, Munderloh, Chloe, Muzny, Donna, Nelson, Sarah, Nguyen, Thuy-mi P., Nguyen, Jonathan, Nussbaum, Robert, Nykamp, Keith, O'Callaghan, William, O'Heir, Emily, O'Leary, Melanie, Olsen, Jeren, Osei-Owusu, Ikeoluwa, O'Donnell-Luria, Anne, Padhi, Evin, Pais, Lynn, Pan, Miao, Panchal, Piyush, Patterson, Karynne, Payne, Sheryl, Pehlivan, Davut, Petrowski, Paul, Pham, Alicia, Pitsava, Georgia, Podesta, Astaria Sara, Ponce, Sarah, Porter, Elizabeth, Posey, Jennifer, Prosser, Jaime, Quertermous, Thomas, Rai, Archana, Ramani, Arun, Rehm, Heidi, Reuter, Chloe, Reuter, Jason, Richardson, Matthew, Rivera-Munoz, Andres, Rubio, Oriane, Sabo, Aniko, Salani, Monica, Samocha, Kaitlin, Sanchis-Juan, Alba, Savage, Sarah, Scott, Evette, Scott, Stuart, Sedlazeck, Fritz, Shah, Gulalai, Shojaie, Ali, Singh, Mugdha, Smith, Kevin, Smith, Josh, Snow, Hana, Snyder, Michael, Socarras, Kayla, Starita, Lea, Stark, Brigitte, Stenton, Sarah, Stergachis, Andrew, Stilp, Adrienne, Sutton, V. Reid, Tai, Jui-Cheng, Talkowski, Michael (Mike), Tise, Christina, Tong, Catherine (Cat), Tsao, Philip, Ungar, Rachel, VanNoy, Grace, Vilain, Eric, Voutos, Isabella, Walker, Kim, Wei, Chia-Lin, Weisburd, Ben, Weiss, Jeff, Wellington, Chris, Weng, Ziming, Westheimer, Emily, Wheeler, Marsha, Wheeler, Matthew, Wiel, Laurens, Wilson, Michael, Wojcik, Monica, Wong, Quenna, Xiao, Changrui, Yadav, Rachita, Yi, Qian, Yuan, Bo, Zhao, Jianhua, Zhen, Jimmy, Zhou, Harry, Bamshad, Michael J., and Rehm, Heidi L.
- Abstract
Since the first novel gene discovery for a Mendelian condition was made via exome sequencing (ES), the rapid increase in the number of genes known to underlie Mendelian conditions coupled with the adoption of exome (and more recently, genome) sequencing by diagnostic testing labs has changed the landscape of genomic testing for rare disease. Specifically, many individuals suspected to have a Mendelian condition are now routinely offered clinical ES. This commonly results in a precise genetic diagnosis but frequently overlooks the identification of novel candidate genes. Such candidates are also less likely to be identified in the absence of large-scale gene discovery research programs. Accordingly, clinical laboratories have both the opportunity, and some might argue a responsibility, to contribute to novel gene discovery which should in turn increase the diagnostic yield for many conditions. However, clinical diagnostic laboratories must necessarily balance priorities for throughput, turnaround time, cost efficiency, clinician preferences, and regulatory constraints, and often do not have the infrastructure or resources to effectively participate in either clinical translational or basic genome science research efforts. For these and other reasons, many laboratories have historically refrained from broadly sharing potentially pathogenic variants in novel genes via networks like Matchmaker Exchange, much less reporting such results to ordering providers. Efforts to report such results are further complicated by a lack of guidelines for clinical reporting and interpretation of variants in novel candidate genes. Nevertheless, there are myriad benefits for many stakeholders, including patients/families, clinicians, researchers, if clinical laboratories systematically and routinely identify, share, and report novel candidate genes. To facilitate this change in practice, we developed criteria for triaging, sharing, and reporting novel candidate genes that are most likely to be promptly validated as underlying a Mendelian condition and translated to use in clinical settings.
- Published
- 2024
- Full Text
- View/download PDF
75. Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy.
- Author
-
Marafi, Dana, Mitani, Tadahiro, Isikay, Sedat, Hertecant, Jozef, Almannai, Mohammed, Manickam, Kandamurugu, Abou Jamra, Rami, El‐Hattab, Ayman W., Rajah, Jaishen, Fatih, Jawid M., Du, Haowei, Karaca, Ender, Bayram, Yavuz, Punetha, Jaya, Rosenfeld, Jill A., Jhangiani, Shalini N., Boerwinkle, Eric, Akdemir, Zeynep C., Erdin, Serkan, and Hunter, Jill V.
- Subjects
CEREBRAL atrophy ,NEUROTRANSMITTER receptors ,GLUTAMATE receptors ,NEURAL transmission ,EPILEPSY ,LEUKODYSTROPHY ,NEUROCYSTICERCOSIS - Abstract
Objective: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G‐protein‐coupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families. Methods: Exome sequencing and family‐based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory. Results: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop‐gain variant (c.1975C>T:p.Arg659Ter). Developmental delay, neonatal‐ or infantile‐onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic–pituitary–axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late childhood. Conclusion: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
76. Abstract 2192: Single-molecule single-cell DNA sequencing identifies ongoing copy number evolution in BRCA breast cancers
- Author
-
Du, Haowei, primary, Davis, Alexander, additional, Gao, Ruli, additional, Colic, Medina, additional, Sei, Emi, additional, Hu, Min, additional, Barrera, Angelica Gutierrez, additional, Casasent, Anna, additional, Albarracin, Constance, additional, Arun, Banu, additional, and Navin, Nicholas E., additional
- Published
- 2018
- Full Text
- View/download PDF
77. Biallelic in-frame deletion in TRAPPC4 in a family with developmental delay and cerebellar atrophy.
- Author
-
Saad, Ahmed K, Marafi, Dana, Mitani, Tadahiro, Jolly, Angad, Du, Haowei, Elbendary, Hasnaa M, Jhangiani, Shalini N, Akdemir, Zeynep C, Genomics, Baylor-Hopkins Center for Mendelian, Gibbs, Richard A, Hunter, Jill V, Carvalho, Claudia M B C, Pehlivan, Davut, Posey, Jennifer E, Zaki, Maha S, Lupski, James R, and Baylor-Hopkins Center for Mendelian Genomics
- Subjects
DEVELOPMENTAL delay ,ATROPHY ,MEDICAL genetics ,MOLECULAR genetics ,GENOMICS ,RESEARCH ,GENETIC mutation ,RESEARCH methodology ,EVALUATION research ,MEDICAL cooperation ,COMPARATIVE studies ,CEREBELLUM diseases ,RESEARCH funding - Published
- 2020
- Full Text
- View/download PDF
78. Hourly operation strategy of a CCHP system with GSHP and thermal energy storage (TES) under variable loads : a case study
- Author
-
Wei Liu, Guanyi Chen, Jian Zuo, Haowei Du, Zhihua Zhou, Beibei Yan, Liu, Wei, Chen, Guanyi, Yan, Beibei, Zhou, Zhihua, Du, Haowei, and Zuo, Jian
- Subjects
Chiller ,Engineering ,Waste management ,business.industry ,Mechanical Engineering ,Nuclear engineering ,thermal energy storage ,Building and Construction ,Cooling capacity ,Thermal energy storage ,GSHP ,Power (physics) ,Electricity generation ,Internal combustion engine ,CCHP system ,Storage tank ,Electrical and Electronic Engineering ,business ,Absorption (electromagnetic radiation) ,operation strategy ,Civil and Structural Engineering - Abstract
Due to the national strategy of energy saving and environmental pollutant reduction, combined cooling, heating and power (CCHP) has been employed in China. A CCHP system with thermal energy storage (TES) is used as an energy station, usually consisting of a power generation unit (PGU), an absorption machine (AM), two ground source heat pumps (GSHPs), a storage tank (ST) and two electric chillers (ECs). The available PGU was compared between the gas turbine and the internal combustion engine (ICE), and the hourly operating strategies with different cooling and heating loads were analyzed. The environmental impacts were also calculated. The results show that the ICE is more suitable for the energy station. The TES reduces by 15.8% of the total installed cooling capacity and 37.5% of the total installed heating capacity of the CCHP system. The hourly operating strategies should be changed with the weather condition. The results are very valuable in guiding a CCHP system applied in engineering projects. Refereed/Peer-reviewed
- Published
- 2015
79. Genomic Balancing Act: Deciphering DNA rearrangements in the Complex Chromosomal Aberration involving 5p15.2, 2q31.1 and 18q21.32.
- Author
-
Lupski J, Dardas Z, Marafi D, Duan R, Fatih J, El-Rashidy O, Grochowski C, Carvalho C, Jhangiani S, Bi W, Du H, Gibbs R, Posey J, Calame D, and Zaki M
- Abstract
Despite extensive research into the genetic underpinnings of neurodevelopmental disorders (NDD), many clinical cases remain unresolved. We studied a female proband with a NDD, mildly dysmorphic facial features, and brain stem hypoplasia on neuroimaging. Comprehensive genomic analyses revealed a terminal 5p loss and terminal 18q gain in the proband while a diploid copy number for chromosomes 5 and 18 in both parents. Genomic investigations in the proband identified an unbalanced translocation t(5;18) with additional genetic material from chromosome 2 (2q31.3) inserted at the breakpoint, pointing to a complex chromosomal rearrangement (CCR) involving 5p15.2, 2q31.3, and 18q21.32. Breakpoint junction analyses enabled by long read genome sequencing unveiled the presence of four distinct junctions in the father, who is carrier of a balanced CCR. The proband inherited from the father both the abnormal chromosome 5 resulting in segmental aneusomies of chr5 (loss) and chr18 (gain) and a der(2) homologue. Evidences suggest a chromoplexy mechanism for this CCR derivation, involving double-strand breaks (DSBs) repaired by non-homologous end joining (NHEJ) or alternative end joining (alt-EJ). The complexity of the CCR and the segregation of homologues elucidate the genetic model for this family. This study demonstrates the importance of combining multiple genomic technologies to uncover genetic causes of complex neurodevelopmental syndrome and to better understand genetic disease mechanisms., Competing Interests: Additional Declarations: J.R.L. has stock ownership in 23andMe, is a paid consultant for Genome International, and is a co-inventor on multiple U.S. and European patents related to molecular diagnostics for inherited neuropathies, genomic disorders, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical genomic sequencing (both ES and GS) offered in the Baylor Genetics Laboratory (http://bmgl.com). J.R.L. serves on the Scientific Advisory Board of BG.
- Published
- 2024
- Full Text
- View/download PDF
80. Biallelic variation in the choline and ethanolamine transporter FLVCR1 underlies a pleiotropic disease spectrum from adult neurodegeneration to severe developmental disorders.
- Author
-
Calame DG, Wong JH, Panda P, Nguyen DT, Leong NCP, Sangermano R, Patankar SG, Abdel-Hamid M, AlAbdi L, Safwat S, Flannery KP, Dardas Z, Fatih JM, Murali C, Kannan V, Lotze TE, Herman I, Ammouri F, Rezich B, Efthymiou S, Alavi S, Murphy D, Firoozfar Z, Nasab ME, Bahreini A, Ghasemi M, Haridy NA, Goldouzi HR, Eghbal F, Karimiani EG, Srinivasan VM, Gowda VK, Du H, Jhangiani SN, Coban-Akdemir Z, Marafi D, Rodan L, Isikay S, Rosenfeld JA, Ramanathan S, Staton M, Kerby C Oberg, Clark RD, Wenman C, Loughlin S, Saad R, Ashraf T, Male A, Tadros S, Boostani R, Abdel-Salam GMH, Zaki M, Abdalla E, Manzini MC, Pehlivan D, Posey JE, Gibbs RA, Houlden H, Alkuraya FS, Bujakowska K, Maroofian R, Lupski JR, and Nguyen LN
- Abstract
FLVCR1 encodes Feline leukemia virus subgroup C receptor 1 (FLVCR1), a solute carrier (SLC) transporter within the Major Facilitator Superfamily. FLVCR1 is a widely expressed transmembrane protein with plasma membrane and mitochondrial isoforms implicated in heme, choline, and ethanolamine transport. While Flvcr1 knockout mice die in utero with skeletal malformations and defective erythropoiesis reminiscent of Diamond-Blackfan anemia, rare biallelic pathogenic FLVCR1 variants are linked to childhood or adult-onset neurodegeneration of the retina, spinal cord, and peripheral nervous system. We ascertained from research and clinical exome sequencing 27 individuals from 20 unrelated families with biallelic ultra-rare missense and predicted loss-of-function (pLoF) FLVCR1 variant alleles. We characterize an expansive FLVCR1 phenotypic spectrum ranging from adult-onset retinitis pigmentosa to severe developmental disorders with microcephaly, reduced brain volume, epilepsy, spasticity, and premature death. The most severely affected individuals, including three individuals with homozygous pLoF variants, share traits with Flvcr1 knockout mice and Diamond-Blackfan anemia including macrocytic anemia and congenital skeletal malformations. Pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1 with minimal impact on FLVCR1 stability or subcellular localization. Several variants disrupt splicing in a mini-gene assay which may contribute to genotype-phenotype correlations. Taken together, these data support an allele-specific gene dosage model in which phenotypic severity reflects residual FLVCR1 activity. This study expands our understanding of Mendelian disorders of choline and ethanolamine transport and demonstrates the importance of choline and ethanolamine in neurodevelopment and neuronal homeostasis., Competing Interests: Potential Conflict of Interest J.R.L. has stock ownership in 23andMe, is a paid consultant for Genome International, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics (BG) Laboratories. Other authors have no potential conflicts to disclose.
- Published
- 2024
- Full Text
- View/download PDF
81. Break-induced replication underlies formation of inverted triplications and generates unexpected diversity in haplotype structures.
- Author
-
Grochowski CM, Bengtsson JD, Du H, Gandhi M, Lun MY, Mehaffey MG, Park K, Höps W, Benito-Garagorri E, Hasenfeld P, Korbel JO, Mahmoud M, Paulin LF, Jhangiani SN, Muzny DM, Fatih JM, Gibbs RA, Pendleton M, Harrington E, Juul S, Lindstrand A, Sedlazeck FJ, Pehlivan D, Lupski JR, and Carvalho CMB
- Abstract
Background: The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a type of complex genomic rearrangement (CGR) hypothesized to result from replicative repair of DNA due to replication fork collapse. It is often mediated by a pair of inverted low-copy repeats (LCR) followed by iterative template switches resulting in at least two breakpoint junctions in cis . Although it has been identified as an important mutation signature of pathogenicity for genomic disorders and cancer genomes, its architecture remains unresolved and is predicted to display at least four structural variation (SV) haplotypes., Results: Here we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the genomic DNA of 24 patients with neurodevelopmental disorders identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted SV haplotypes. Using a combination of short-read genome sequencing (GS), long- read GS, optical genome mapping and StrandSeq the haplotype structure was resolved in 18 samples. This approach refined the point of template switching between inverted LCRs in 4 samples revealing a DNA segment of ∼2.2-5.5 kb of 100% nucleotide similarity. A prediction model was developed to infer the LCR used to mediate the non-allelic homology repair., Conclusions: These data provide experimental evidence supporting the hypothesis that inverted LCRs act as a recombinant substrate in replication-based repair mechanisms. Such inverted repeats are particularly relevant for formation of copy-number associated inversions, including the DUP-TRP/INV-DUP structures. Moreover, this type of CGR can result in multiple conformers which contributes to generate diverse SV haplotypes in susceptible loci .
- Published
- 2023
- Full Text
- View/download PDF
82. SNV/indel hypermutator phenotype in biallelic RAD51C variant - Fanconi anemia.
- Author
-
Zemet R, Du H, Gambin T, Lupski JR, Liu P, and Stankiewicz P
- Abstract
We previously reported a fetus with Fanconi anemia (FA), complementation group O due to compound heterozygous variants involving RAD51C . Interestingly, the trio exome sequencing analysis also detected eight apparent de novo mosaic variants with variant allele fraction (VAF) ranging between 11.5%-37%. Here, using whole genome sequencing and a 'home-brew' variant filtering pipeline and DeepMosaic module, we investigated the number and signature of de novo heterozygous and mosaic variants and the rare phenomenon of hypermutation. Eight-hundred-thirty apparent dnSNVs and 21 de novo indels had VAFs below 37.41% and were considered postzygotic somatic mosaic variants. The VAFs showed a bimodal distribution, with one component with an average VAF of 25% (range: 18.7-37.41%) (n=446), representing potential postzygotic first mitotic events, and the other component with an average VAF of 12.5% (range: 9.55-18.69%) (n=384), describing potential second mitotic events. No increased rate of CNV formation was observed. The mutational pattern analysis for somatic single base substitution showed SBS40, SBS5, and SBS3 as the top recognized signatures. SBS3 is a known signature associated with homologous recombination-based DNA damage repair error. Our data demonstrate that biallelic RAD51C variants show evidence for defective genomic DNA damage repair and thereby result in a hypermutator phenotype with the accumulation of postzygotic de novo mutations, at least in the prenatal period. This 'genome hypermutator phenomenon' might contribute to the observed hematological manifestations and the predisposition to tumors in patients with FA, and pregnancy loss in general. We propose that other FA groups should be investigated for genome-wide de novo variants.
- Published
- 2023
- Full Text
- View/download PDF
83. Developmental genomics of limb malformations: Allelic series in association with gene dosage effects contribute to the clinical variability.
- Author
-
Duan R, Hijazi H, Gulec EY, Eker HK, Costa SR, Sahin Y, Ocak Z, Isikay S, Ozalp O, Bozdogan S, Aslan H, Elcioglu N, Bertola DR, Gezdirici A, Du H, Fatih JM, Grochowski CM, Akay G, Jhangiani SN, Karaca E, Gu S, Coban-Akdemir Z, Posey JE, Bayram Y, Sutton VR, Carvalho CMB, Pehlivan D, Gibbs RA, and Lupski JR
- Abstract
Genetic heterogeneity, reduced penetrance, and variable expressivity, the latter including asymmetric body axis plane presentations, have all been described in families with congenital limb malformations (CLMs). Interfamilial and intrafamilial heterogeneity highlight the complexity of the underlying genetic pathogenesis of these developmental anomalies. Family-based genomics by exome sequencing (ES) and rare variant analyses combined with whole-genome array-based comparative genomic hybridization were implemented to investigate 18 families with limb birth defects. Eleven of 18 (61%) families revealed explanatory variants, including 7 single-nucleotide variant alleles and 3 copy number variants (CNVs), at previously reported "disease trait associated loci": BHLHA9 , GLI3, HOXD cluster, HOXD13 , NPR2 , and WNT10B . Breakpoint junction analyses for all three CNV alleles revealed mutational signatures consistent with microhomology-mediated break-induced replication, a mechanism facilitated by Alu/Alu -mediated rearrangement. Homozygous duplication of BHLHA9 was observed in one Turkish kindred and represents a novel contributory genetic mechanism to Gollop-Wolfgang Complex (MIM: 228250), where triplication of the locus has been reported in one family from Japan (i.e., 4n = 2n + 2n versus 4n = 3n + 1n allelic configurations). Genes acting on limb patterning are sensitive to a gene dosage effect and are often associated with an allelic series. We extend an allele-specific gene dosage model to potentially assist, in an adjuvant way, interpretations of interconnections among an allelic series, clinical severity, and reduced penetrance of the BHLHA9 -related CLM spectrum., Competing Interests: J.R.L. has stock ownership in 23andMe, is a paid consultant for the Regeneron Genetics Center, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing and genomic testing (ES, WGS, CMA, and aCGH) conducted at Baylor Genetics (BG). J.R.L. serves on the Scientific Advisory Board (SAB) of BG., (© 2022 The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
84. Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy.
- Author
-
Marafi D, Fatih JM, Kaiyrzhanov R, Ferla MP, Gijavanekar C, Al-Maraghi A, Liu N, Sites E, Alsaif HS, Al-Owain M, Zakkariah M, El-Anany E, Guliyeva U, Guliyeva S, Gaba C, Haseeb A, Alhashem AM, Danish E, Karageorgou V, Beetz C, Subhi AA, Mullegama SV, Torti E, Sebastin M, Breilyn MS, Duberstein S, Abdel-Hamid MS, Mitani T, Du H, Rosenfeld JA, Jhangiani SN, Coban Akdemir Z, Gibbs RA, Taylor JC, Fakhro KA, Hunter JV, Pehlivan D, Zaki MS, Gleeson JG, Maroofian R, Houlden H, Posey JE, Sutton VR, Alkuraya FS, Elsea SH, and Lupski JR
- Subjects
- Glutamine metabolism, Histidine metabolism, Humans, Metabolome, Nitrogen metabolism, Epilepsy, Generalized diagnosis, Epilepsy, Generalized genetics, Sodium-Calcium Exchanger genetics
- Abstract
The solute carrier (SLC) superfamily encompasses >400 transmembrane transporters involved in the exchange of amino acids, nutrients, ions, metals, neurotransmitters and metabolites across biological membranes. SLCs are highly expressed in the mammalian brain; defects in nearly 100 unique SLC-encoding genes (OMIM: https://www.omim.org) are associated with rare Mendelian disorders including developmental and epileptic encephalopathy and severe neurodevelopmental disorders. Exome sequencing and family-based rare variant analyses on a cohort with neurodevelopmental disorders identified two siblings with developmental and epileptic encephalopathy and a shared deleterious homozygous splicing variant in SLC38A3. The gene encodes SNAT3, a sodium-coupled neutral amino acid transporter and a principal transporter of the amino acids asparagine, histidine, and glutamine, the latter being the precursor for the neurotransmitters GABA and glutamate. Additional subjects with a similar developmental and epileptic encephalopathy phenotype and biallelic predicted-damaging SLC38A3 variants were ascertained through GeneMatcher and collaborations with research and clinical molecular diagnostic laboratories. Untargeted metabolomic analysis was performed to identify novel metabolic biomarkers. Ten individuals from seven unrelated families from six different countries with deleterious biallelic variants in SLC38A3 were identified. Global developmental delay, intellectual disability, hypotonia, and absent speech were common features while microcephaly, epilepsy, and visual impairment were present in the majority. Epilepsy was drug-resistant in half. Metabolomic analysis revealed perturbations of glutamate, histidine, and nitrogen metabolism in plasma, urine, and CSF of selected subjects, potentially representing biomarkers of disease. Our data support the contention that SLC38A3 is a novel disease gene for developmental and epileptic encephalopathy and illuminate the likely pathophysiology of the disease as perturbations in glutamine homeostasis., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2022
- Full Text
- View/download PDF
85. Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.
- Author
-
Zhang C, Jolly A, Shayota BJ, Mazzeu JF, Du H, Dawood M, Soper PC, Ramalho de Lima A, Ferreira BM, Coban-Akdemir Z, White J, Shears D, Thomson FR, Douglas SL, Wainwright A, Bailey K, Wordsworth P, Oldridge M, Lester T, Calder AD, Dumic K, Banka S, Donnai D, Jhangiani SN, Potocki L, Chung WK, Mora S, Northrup H, Ashfaq M, Rosenfeld JA, Mason K, Pollack LC, McConkie-Rosell A, Kelly W, McDonald M, Hauser NS, Leahy P, Powell CM, Boy R, Honjo RS, Kok F, Martelli LR, Filho VO, Genomics England Research Consortium, Muzny DM, Gibbs RA, Posey JE, Liu P, Lupski JR, Sutton VR, and Carvalho CMB
- Abstract
Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated ( DVL1 , DVL3 , FZD2 , NXN , ROR2 , and WNT5A ). RS is characterized by skeletal dysplasia and distinctive facial and physical characteristics. To further explore the genetic heterogeneity, paralog contribution, and phenotypic variability of RS, we investigated a cohort of 22 individuals clinically diagnosed with RS from 18 unrelated families. Pathogenic or likely pathogenic variants in genes associated with RS or RS phenocopies were identified in all 22 individuals, including the first variant to be reported in DVL2 . We retrospectively collected medical records of 16 individuals from this cohort and extracted clinical descriptions from 52 previously published cases. We performed Human Phenotype Ontology (HPO) based quantitative phenotypic analyses to dissect allele-specific phenotypic differences. Individuals with FZD2 variants clustered into two groups with demonstrable phenotypic differences between those with missense and truncating alleles. Probands with biallelic NXN variants clustered together with the majority of probands carrying DVL1 , DVL2 , and DVL3 variants, demonstrating no phenotypic distinction between the NXN -autosomal recessive and dominant forms of RS. While phenotypically similar diseases on the RS differential matched through HPO analysis, clustering using phenotype similarity score placed RS-associated phenotypes in a unique cluster containing WNT5A , FZD2 , and ROR2 apart from non-RS-associated paralogs. Through human phenotype analyses of this RS cohort and OMIM clinical synopses of Mendelian disease, this study begins to tease apart specific biologic roles for non-canonical WNT-pathway proteins., Competing Interests: BCM and Miraca Holdings have formed a joint venture with shared ownership and governance of BG, which performs clinical microarray analysis (CMA), clinical ES (cES), and clinical biochemical studies. V.R.S. and P.L. receive professional services compensation from BG and J.R.L. serves on the Scientific Advisory Board of the BG. J.R.L. has stock ownership in 23andMe, is a paid consultant for the Regeneron Genetics Center, and is a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. W.K.C. is a is a paid consultant for the Regeneron Genetics Center. P.C.S. and S.M. are employees of GeneDx. The other authors declare no competing interests., (© 2021 The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
86. Biallelic in-frame deletion in TRAPPC4 in a family with developmental delay and cerebellar atrophy.
- Author
-
Saad AK, Marafi D, Mitani T, Jolly A, Du H, Elbendary HM, Jhangiani SN, Akdemir ZC, Gibbs RA, Hunter JV, Carvalho CMBC, Pehlivan D, Posey JE, Zaki MS, and Lupski JR
- Subjects
- Atrophy, Humans, Sequence Deletion genetics, Cerebellar Diseases genetics, Intellectual Disability
- Published
- 2020
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.