Publications by authors named "Brian Meyer"

151 Publications

Mutation spectrum of EXT1 and EXT2 in the Saudi patients with hereditary multiple exostoses.

Orphanet J Rare Dis 2021 Feb 25;16(1):100. Epub 2021 Feb 25.

Department of Genetics, MBC 3, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh, 11211, Saudi Arabia.

Background: Hereditary Multiple Exostoses (HME), also known as Multiple Osteochondromas (MO) is a rare genetic disorder characterized by multiple benign cartilaginous bone tumors, which are caused by mutations in the genes for exostosin glycosyltransferase 1 (EXT1) and exostosin glycosyltransferase 2 (EXT2). The genetic defects have not been studied in the Saudi patients.

Aim Of Study: We investigated mutation spectrum of EXT1 and EXT2 in 22 patients from 17 unrelated families.

Methods: Genomic DNA was extracted from peripheral leucocytes. The coding regions and intron-exon boundaries of both EXT1 and EXT2 genes were screened for mutations by PCR-sequencing analysis. Gross deletions were analyzed by MLPA analysis.

Results: EXT1 mutations were detected in 6 families (35%) and 3 were novel mutations: c.739G > T (p. E247*), c.1319delG (p.R440Lfs*4), and c.1786delA (p.S596Afs*25). EXT2 mutations were detected in 7 families (41%) and 3 were novel mutations: c.541delG (p.D181Ifs*89), c.583delG (p.G195Vfs*75), and a gross deletion of approximately 10 kb including promoter and exon 1. Five patients from different families had no family history and carried de novo mutations (29%, 5/17). No EXT1 and EXT2 mutations were found in the remaining four families. In total, EXT1 and EXT2 mutations were found in 77% (13/17) of Saudi HME patients.

Conclusion: EXT1 and EXT2 mutations contribute significantly to the pathogenesis of HME in the Saudi population. In contrast to high mutation rate in EXT 1 (65%) and low mutation rate in EXT2 (25%) in other populations, the frequency of EXT2 mutations are much higher (41%) and comparable to that of EXT1 among Saudi patients. De novo mutations are also common and the six novel EXT1/EXT2 mutations further expands the mutation spectrum of HME.
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http://dx.doi.org/10.1186/s13023-021-01738-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905910PMC
February 2021

Molecular Analysis of Mutations in Vitamin D-Dependent Rickets Type 1A: c.590G > A (p.G197D) Missense Mutation Causes a RNA Splicing Error.

Front Genet 2020 27;11:607517. Epub 2020 Nov 27.

Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Context: Vitamin D-dependent rickets type 1A (VDDR1A) is a rare autosomal recessively inherited disorder due to loss-of-function mutations in the gene. encodes an enzyme of 25-hydroxyvitamin D-1α-hydroxylase for converting inactive 25-OHD to biologically active 1,25-(OH)D.

Objective: To identify underlying genetic defects in patients with VDDR1A.

Methods: Twelve patients from 7 Turkish and 2 Saudi families were investigated. The coding exons and intron-exon boundaries of the gene were amplified by Polymerase Chain Reaction (PCR) from peripheral lymphocyte DNA. PCR products were directly sequenced. The consequences of c.590G > A mutation were analyzed by and functional analysis.

Results: mutations were identified in all the patients. Two novel mutations were identified in two separate families: c.171delG (family 7) and c.398_400dupAAT (family 8). The intra-exon deletion of c.171delG resulted in a frameshift and premature stop codon 20 amino acids downstream from the mutation (p.L58Cfs20). The intra-exon duplication of c.398_400dupAAT generated a premature stop codon at the mutation site (p.W134). A missense c.590G > A (p.G197D) mutation was found in a patient from family 4 and caused a defect in pre-mRNA splicing. As a result, two populations of transcripts were detected: the majority of them with intron 3 retention (83%), and the minority (17%) being properly spliced transcripts with about 16% of wild-type enzymatic activity. The remaining nine patients from six families carried a previously reported c.1319_1325dupCCCACCC (F443Pfs24) mutation. Clinically, all the patients need continued calcitriol treatment, which was consistent with inactivation of 25-hydroxy vitamin D1α-hydroxylase activity.

Conclusion: Two novel frameshift mutations were identified and predicted to inactivate 25-hydroxyvitamin D-1α-hydroxylase. The loss of enzymatic activity by c.590G > A missense mutation was mainly caused by aberrant pre-mRNA splicing.
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http://dx.doi.org/10.3389/fgene.2020.607517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729158PMC
November 2020

Program Evaluation of Group Transcending Self Therapy: An Integrative Modular Cognitive-Behavioral Therapy for Substance Use Disorders.

Subst Abuse 2020 17;14:1178221820947653. Epub 2020 Aug 17.

Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA.

Objectives: Substance Use Disorders (SUDs) are increasingly prevalent among Veterans. Effective interventions for SUDs that also meet the clinical reality of open treatment groups are needed. (Group TST-I-CBT) was developed to address this need. Group TST-I-CBT is a four-module, 20-session treatment designed so that a person can enter at any point in the treatment. We conducted a program evaluation of Group TST-I-CBT for veterans with SUDs.

Methods: Participants were N = 68 veterans enrolled in the 28-day Substance Abuse Residential Rehabilitation Treatment Program at an urban Veterans Administration Medical Center who received either Group TST-I-CBT (N = 34) or treatment-as-usual (TAU; N = 34). Medical records were reviewed and participant treatment outcome data was retrieved. Group TST-I-CBT clients completed a knowledge and feedback form at treatment completion.

Results: Compared to TAU participants, Group TST-I-CBT participants were significantly less likely to have a positive urine drug screen (UDS) during treatment (17.6% versus 0%;  = .01) and within one month post-discharge (50% versus 17.6%;  = .04). Among Group TST-I-CBT clients, Quality of Life Inventory scores significantly increased by an average of 14 points from pre- to post-treatment, (15) = -3.31,  = .005,  = 0.83. Group TST-I-CBT clients displayed cognitive-behavioral therapy knowledge (mean correct answers ranged from 92%-100%) and rated Group TST-I-CBT as helpful, understandable, and useful (mean scores ranged from 9.3-9.6 out of 10).

Conclusions: These preliminary data indicate that Group TST-I-CBT may be an effective group therapy as part of SUD treatment. A formal randomized controlled trial of Group TST-I-CBT may be warranted.
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http://dx.doi.org/10.1177/1178221820947653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436794PMC
August 2020

Yoga for warriors: An intervention for veterans with comorbid chronic pain and PTSD.

Psychol Trauma 2020 Nov 23;12(8):888-896. Epub 2020 Jul 23.

Mental Health Service.

Objective: Comorbid chronic pain and posttraumatic stress disorder (PTSD) is common in veterans; this comorbidity is associated with increased severity and poorer prognosis when compared to each outcome alone. Yoga has been shown to be effective for chronic pain and promising for PTSD, but yoga for comorbid pain and PTSD has not been examined. This article offers empirical support for a yoga intervention for comorbid chronic pain and PTSD in a veteran population.

Method: Results are presented from a 4-year pilot yoga intervention for comorbid chronic pain and PTSD at a large, urban Veterans Affairs Medical Center. Based on the fear avoidance model of pain, the intervention used a cross-sectional, open-trial design with pre- and postmeasures. test analyses were conducted on program completers ( = 49; out of 87 initially enrolled, 44% attrition rate), who were primarily African American (69%) and male (61%) and had a mean age of 51.41 years ( = 11.32).

Results: Results indicated trend-level reductions in overall PTSD symptoms, as measured by the PTSD Checklist for DSM-5 ( = .02, = 0.38) and in symptom cluster scores of negative alterations of cognitions and mood ( = .03, = 0.36) and arousal and reactivity ( = .03, = 0.35). Veterans reported significant improvement in ability to participate in social activities ( < .001, = 0.44) and significant reductions in kinesiophobia (fear of movement or physical activity; < .001, = 0.85). On a satisfaction measure with a range of 1 () to 4 (), the mean rating was 3.74 ( = 0.33).

Conclusion: Yoga is a feasible and effective intervention for veterans with comorbid chronic pain and PTSD. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/tra0000649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909482PMC
November 2020

Mutation of SGK3, a Novel Regulator of Renal Phosphate Transport, Causes Autosomal Dominant Hypophosphatemic Rickets.

J Clin Endocrinol Metab 2020 06;105(6)

Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.

Context: Hypophosphatemic rickets (HR) is a group of rare hereditary renal phosphate wasting disorders caused by mutations in PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC9A3R1, SLC34A1, or SLC34A3.

Objective: A large kindred with 5 HR patients was recruited with dominant inheritance. The study was undertaken to investigate underlying genetic defects in HR patients.

Design: Patients and their family members were initially analyzed for PHEX and FGF23 mutations using polymerase chain reaction sequencing and copy number analysis. Exome sequencing was subsequently performed to identify novel candidate genes.

Results: PHEX and FGF23 mutations were not detected in the patients. No copy number variation was observed in the genome using CytoScan HD array analysis. Mutations in DMP1, ENPP1, CLCN5, SLC9A3R1, SLC34A1, or SLC34A3 were also not found by exome sequencing. A novel c.979-96 T>A mutation in the SGK3 gene was found to be strictly segregated in a heterozygous pattern in patients and was not present in normal family members. The mutation is located 1 bp downstream of a highly conserved adenosine branch point, resulted in exon 13 skipping and in-frame deletion of 29 amino acids, which is part of the protein kinase domain and contains a Thr-320 phosphorylation site that is required for its activation. Protein tertiary structure modelling showed significant structural change in the protein kinase domain following the deletion.

Conclusions: The c.979-96 T>A splice mutation in the SGK3 gene causes exon 13 skipping and deletion of 29 amino acids in the protein kinase domain. The SGK3 mutation may cause autosomal dominant HR.
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http://dx.doi.org/10.1210/clinem/dgz260DOI Listing
June 2020

Associations of autozygosity with a broad range of human phenotypes.

Authors:
David W Clark Yukinori Okada Kristjan H S Moore Dan Mason Nicola Pirastu Ilaria Gandin Hannele Mattsson Catriona L K Barnes Kuang Lin Jing Hua Zhao Patrick Deelen Rebecca Rohde Claudia Schurmann Xiuqing Guo Franco Giulianini Weihua Zhang Carolina Medina-Gomez Robert Karlsson Yanchun Bao Traci M Bartz Clemens Baumbach Ginevra Biino Matthew J Bixley Marco Brumat Jin-Fang Chai Tanguy Corre Diana L Cousminer Annelot M Dekker David A Eccles Kristel R van Eijk Christian Fuchsberger He Gao Marine Germain Scott D Gordon Hugoline G de Haan Sarah E Harris Edith Hofer Alicia Huerta-Chagoya Catherine Igartua Iris E Jansen Yucheng Jia Tim Kacprowski Torgny Karlsson Marcus E Kleber Shengchao Alfred Li Ruifang Li-Gao Anubha Mahajan Koichi Matsuda Karina Meidtner Weihua Meng May E Montasser Peter J van der Most Matthias Munz Teresa Nutile Teemu Palviainen Gauri Prasad Rashmi B Prasad Tallapragada Divya Sri Priyanka Federica Rizzi Erika Salvi Bishwa R Sapkota Daniel Shriner Line Skotte Melissa C Smart Albert Vernon Smith Ashley van der Spek Cassandra N Spracklen Rona J Strawbridge Salman M Tajuddin Stella Trompet Constance Turman Niek Verweij Clara Viberti Lihua Wang Helen R Warren Robyn E Wootton Lisa R Yanek Jie Yao Noha A Yousri Wei Zhao Adebowale A Adeyemo Saima Afaq Carlos Alberto Aguilar-Salinas Masato Akiyama Matthew L Albert Matthew A Allison Maris Alver Tin Aung Fereidoun Azizi Amy R Bentley Heiner Boeing Eric Boerwinkle Judith B Borja Gert J de Borst Erwin P Bottinger Linda Broer Harry Campbell Stephen Chanock Miao-Li Chee Guanjie Chen Yii-Der I Chen Zhengming Chen Yen-Feng Chiu Massimiliano Cocca Francis S Collins Maria Pina Concas Janie Corley Giovanni Cugliari Rob M van Dam Anna Damulina Maryam S Daneshpour Felix R Day Graciela E Delgado Klodian Dhana Alexander S F Doney Marcus Dörr Ayo P Doumatey Nduna Dzimiri S Sunna Ebenesersdóttir Joshua Elliott Paul Elliott Ralf Ewert Janine F Felix Krista Fischer Barry I Freedman Giorgia Girotto Anuj Goel Martin Gögele Mark O Goodarzi Mariaelisa Graff Einat Granot-Hershkovitz Francine Grodstein Simonetta Guarrera Daniel F Gudbjartsson Kamran Guity Bjarni Gunnarsson Yu Guo Saskia P Hagenaars Christopher A Haiman Avner Halevy Tamara B Harris Mehdi Hedayati David A van Heel Makoto Hirata Imo Höfer Chao Agnes Hsiung Jinyan Huang Yi-Jen Hung M Arfan Ikram Anuradha Jagadeesan Pekka Jousilahti Yoichiro Kamatani Masahiro Kanai Nicola D Kerrison Thorsten Kessler Kay-Tee Khaw Chiea Chuen Khor Dominique P V de Kleijn Woon-Puay Koh Ivana Kolcic Peter Kraft Bernhard K Krämer Zoltán Kutalik Johanna Kuusisto Claudia Langenberg Lenore J Launer Deborah A Lawlor I-Te Lee Wen-Jane Lee Markus M Lerch Liming Li Jianjun Liu Marie Loh Stephanie J London Stephanie Loomis Yingchang Lu Jian'an Luan Reedik Mägi Ani W Manichaikul Paolo Manunta Gísli Másson Nana Matoba Xue W Mei Christa Meisinger Thomas Meitinger Massimo Mezzavilla Lili Milani Iona Y Millwood Yukihide Momozawa Amy Moore Pierre-Emmanuel Morange Hortensia Moreno-Macías Trevor A Mori Alanna C Morrison Taulant Muka Yoshinori Murakami Alison D Murray Renée de Mutsert Josyf C Mychaleckyj Mike A Nalls Matthias Nauck Matt J Neville Ilja M Nolte Ken K Ong Lorena Orozco Sandosh Padmanabhan Gunnar Pálsson James S Pankow Cristian Pattaro Alison Pattie Ozren Polasek Neil Poulter Peter P Pramstaller Lluis Quintana-Murci Katri Räikkönen Sarju Ralhan Dabeeru C Rao Wouter van Rheenen Stephen S Rich Paul M Ridker Cornelius A Rietveld Antonietta Robino Frank J A van Rooij Daniela Ruggiero Yasaman Saba Charumathi Sabanayagam Maria Sabater-Lleal Cinzia Felicita Sala Veikko Salomaa Kevin Sandow Helena Schmidt Laura J Scott William R Scott Bahareh Sedaghati-Khayat Bengt Sennblad Jessica van Setten Peter J Sever Wayne H-H Sheu Yuan Shi Smeeta Shrestha Sharvari Rahul Shukla Jon K Sigurdsson Timo Tonis Sikka Jai Rup Singh Blair H Smith Alena Stančáková Alice Stanton John M Starr Lilja Stefansdottir Leon Straker Patrick Sulem Gardar Sveinbjornsson Morris A Swertz Adele M Taylor Kent D Taylor Natalie Terzikhan Yih-Chung Tham Gudmar Thorleifsson Unnur Thorsteinsdottir Annika Tillander Russell P Tracy Teresa Tusié-Luna Ioanna Tzoulaki Simona Vaccargiu Jagadish Vangipurapu Jan H Veldink Veronique Vitart Uwe Völker Eero Vuoksimaa Salma M Wakil Melanie Waldenberger Gurpreet S Wander Ya Xing Wang Nicholas J Wareham Sarah Wild Chittaranjan S Yajnik Jian-Min Yuan Lingyao Zeng Liang Zhang Jie Zhou Najaf Amin Folkert W Asselbergs Stephan J L Bakker Diane M Becker Benjamin Lehne David A Bennett Leonard H van den Berg Sonja I Berndt Dwaipayan Bharadwaj Lawrence F Bielak Murielle Bochud Mike Boehnke Claude Bouchard Jonathan P Bradfield Jennifer A Brody Archie Campbell Shai Carmi Mark J Caulfield David Cesarini John C Chambers Giriraj Ratan Chandak Ching-Yu Cheng Marina Ciullo Marilyn Cornelis Daniele Cusi George Davey Smith Ian J Deary Rajkumar Dorajoo Cornelia M van Duijn David Ellinghaus Jeanette Erdmann Johan G Eriksson Evangelos Evangelou Michele K Evans Jessica D Faul Bjarke Feenstra Mary Feitosa Sylvain Foisy Andre Franke Yechiel Friedlander Paolo Gasparini Christian Gieger Clicerio Gonzalez Philippe Goyette Struan F A Grant Lyn R Griffiths Leif Groop Vilmundur Gudnason Ulf Gyllensten Hakon Hakonarson Anders Hamsten Pim van der Harst Chew-Kiat Heng Andrew A Hicks Hagit Hochner Heikki Huikuri Steven C Hunt Vincent W V Jaddoe Philip L De Jager Magnus Johannesson Åsa Johansson Jost B Jonas J Wouter Jukema Juhani Junttila Jaakko Kaprio Sharon L R Kardia Fredrik Karpe Meena Kumari Markku Laakso Sander W van der Laan Jari Lahti Matthias Laudes Rodney A Lea Wolfgang Lieb Thomas Lumley Nicholas G Martin Winfried März Giuseppe Matullo Mark I McCarthy Sarah E Medland Tony R Merriman Andres Metspalu Brian F Meyer Karen L Mohlke Grant W Montgomery Dennis Mook-Kanamori Patricia B Munroe Kari E North Dale R Nyholt Jeffery R O'connell Carole Ober Albertine J Oldehinkel Walter Palmas Colin Palmer Gerard G Pasterkamp Etienne Patin Craig E Pennell Louis Perusse Patricia A Peyser Mario Pirastu Tinca J C Polderman David J Porteous Danielle Posthuma Bruce M Psaty John D Rioux Fernando Rivadeneira Charles Rotimi Jerome I Rotter Igor Rudan Hester M Den Ruijter Dharambir K Sanghera Naveed Sattar Reinhold Schmidt Matthias B Schulze Heribert Schunkert Robert A Scott Alan R Shuldiner Xueling Sim Neil Small Jennifer A Smith Nona Sotoodehnia E-Shyong Tai Alexander Teumer Nicholas J Timpson Daniela Toniolo David-Alexandre Tregouet Tiinamaija Tuomi Peter Vollenweider Carol A Wang David R Weir John B Whitfield Cisca Wijmenga Tien-Yin Wong John Wright Jingyun Yang Lei Yu Babette S Zemel Alan B Zonderman Markus Perola Patrik K E Magnusson André G Uitterlinden Jaspal S Kooner Daniel I Chasman Ruth J F Loos Nora Franceschini Lude Franke Chris S Haley Caroline Hayward Robin G Walters John R B Perry Tōnu Esko Agnar Helgason Kari Stefansson Peter K Joshi Michiaki Kubo James F Wilson

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Centre for Global Health Research, Usher Institute, University of Edinburgh, Edinburgh, EH8 9AG, Scotland.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019

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

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

Am J Hum Genet 2019 Oct;105(4):879

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http://dx.doi.org/10.1016/j.ajhg.2019.09.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817532PMC
October 2019

NOVEL MUTATIONS IN PATIENTS WITH VITAMIN D-DEPENDENT RICKETS TYPE 2A: A MILD DISEASE PHENOTYPE CAUSED BY A NOVEL CANONICAL SPLICE-SITE MUTATION.

Endocr Pract 2020 Jan 26;26(1):72-81. Epub 2019 Sep 26.

Vitamin D-dependent rickets type 2A (VDDR2A) is a rare autosomal recessive disorder caused by mutations in the vitamin D receptor gene (), leading to end-organ resistance to 1,25-dihydroxyvitamin D (1,25[OH]D). The objective of this study was to investigate VDR mutations in 11 patients from 8 Turkish-Arab families. All coding exons and intron-exon boundaries of the gene were amplified by polymerase chain reaction from peripheral leukocyte DNA and sequenced. The effect of splice-site mutations on mRNA splicing was evaluated by a customized mini-gene assay. Homozygous mutations were found in all the patients, including four novel mutations: c.473G>T (p.R158L), c.1-4A>G (IVS3-2A>G), c.755+1G>T, and c.352_356delGACAG (p.D118Sfs*7). The c.1-4A>G mutation was located in the canonical splice acceptor site and 4 base pairs from the original ATG start codon. The mutation resulted in both complete (60% of transcripts) and partial exon 4 skipping (15% of transcripts). The latter was due to activation of a cryptic splice acceptor site and did not disrupt the open reading frame. Both c.755+1G>T and c.352_356delGACAG resulted in frameshifts and a premature stop codon. Clinically, all the patients required continued treatment, except for patient IV-3, who presented with alopecia, hypocalcemia, and increased 1,25(OH)D at 1.5 years of age as a result of the c.1-4A>G mutation. He stopped taking medication at 6 years of age and still maintained normal height and biochemical profile. We have identified four novel mutations. Although canonical splice-site mutations cause premRNA splicing errors that usually lead to a severe disease phenotype, mild disease can also occur due to activation of a cryptic splice site. = 1,25-dihydroxyvitamin D (calcitriol); = 25-hydroxyvitamin D; = polymerase chain reaction; = parathyroid hormone; = vitamin D-dependent rickets type 2A; = vitamin D receptor.
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http://dx.doi.org/10.4158/EP-2019-0295DOI Listing
January 2020

Immune response and reactogenicity of an unadjuvanted intradermally delivered human papillomavirus vaccine using a first generation Nanopatch™ in rhesus macaques: An exploratory, pre-clinical feasibility assessment.

Vaccine X 2019 Aug 20;2:100030. Epub 2019 Jun 20.

New Technologies, Vaccine Drug Product Development, Vaccine Process Research and Development, MRL, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA.

The human papillomavirus (HPV) 9-valent, recombinant vaccine (Gardasil™9) helps protect young adults (males and females) against anogenital cancers and genital warts caused by certain HPV genotypes (ref. Gardasil™9 insert). This vaccine is administered intramuscularly (IM). The aim of this study was to determine preclinically whether intradermal (ID) vaccination with an unadjuvanted 9-valent recombinant HPV vaccine using a first-generation ID delivery device, the Nanopatch™, could enhance vaccine immunogenicity compared with the traditional ID route (Mantoux technique). IM injection of HPV VLPs formulated with Merck & Co., Inc., Kenilworth, NJ, USA Alum Adjuvant (MAA) were included in the rhesus study for comparison. The Nanopatch™ prototype contains a high-density array comprised of 10,000 microprojections/cm, each 250 µm long. It was hypothesized the higher density array with shallower ID delivery may be superior to the Mantoux technique. To test this hypothesis, HPV VLPs without adjuvant were coated on the Nanopatch™, stability of the Nanopatch™ with unadjuvanted HPV VLPs were evaluated under accelerated conditions, skin delivery was verified using radiolabelled VLPs or FluoSpheres®, and the immune response and skin site reaction with the Nanopatch™ was evaluated in rhesus macaques. The immune response induced by Nanopatch™ administration, measured as HPV-specific binding antibodies, was similar to that induced using the Mantoux technique. It was also observed that a lower dose of unadjuvanted HPV VLPs delivered with the first-generation Nanopatch™ and applicator or Mantoux technique resulted in an immune response that was significantly lower compared to a higher-dose of alum adjuvanted HPV VLPs delivered IM in rhesus macaques. The study also indicated unadjuvanted HPV VLPs could be delivered with the first-generation Nanopatch™ and applicator to the skin in 15 s with a transfer efficiency of approximately 20%. This study is the first demonstration of patch administration in non-human primates with a vaccine composed of HPV VLPs.
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http://dx.doi.org/10.1016/j.jvacx.2019.100030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668242PMC
August 2019

A novel mutation in a family with expanded syndrome of piebaldism.

JAAD Case Rep 2019 Jul 13;5(7):627-631. Epub 2019 Jul 13.

Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

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http://dx.doi.org/10.1016/j.jdcr.2019.01.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6630042PMC
July 2019

Pathology in Practice.

J Am Vet Med Assoc 2019 07;255(2):177-180

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http://dx.doi.org/10.2460/javma.255.2.177DOI Listing
July 2019

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

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

Am J Hum Genet 2019 06 23;104(6):1182-1201. Epub 2019 May 23.

Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia. Electronic address:

We report the results of clinical exome sequencing (CES) on >2,200 previously unpublished Saudi families as a first-tier test. The predominance of autosomal-recessive causes allowed us to make several key observations. We highlight 155 genes that we propose to be recessive, disease-related candidates. We report additional mutational events in 64 previously reported candidates (40 recessive), and these events support their candidacy. We report recessive forms of genes that were previously associated only with dominant disorders and that have phenotypes ranging from consistent with to conspicuously distinct from the known dominant phenotypes. We also report homozygous loss-of-function events that can inform the genetics of complex diseases. We were also able to deduce the likely causal variant in most couples who presented after the loss of one or more children, but we lack samples from those children. Although a similar pattern of mostly recessive causes was observed in the prenatal setting, the higher proportion of loss-of-function events in these cases was notable. The allelic series presented by the wealth of recessive variants greatly expanded the phenotypic expression of the respective genes. We also make important observations about dominant disorders; these observations include the pattern of de novo variants, the identification of 74 candidate dominant, disease-related genes, and the potential confirmation of 21 previously reported candidates. Finally, we describe the influence of a predominantly autosomal-recessive landscape on the clinical utility of rapid sequencing (Flash Exome). Our cohort's genotypic and phenotypic data represent a unique resource that can contribute to improved variant interpretation through data sharing.
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http://dx.doi.org/10.1016/j.ajhg.2019.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562004PMC
June 2019

Functional analysis of 22 splice-site mutations in the PHEX, the causative gene in X-linked dominant hypophosphatemic rickets.

Bone 2019 08 15;125:186-193. Epub 2019 May 15.

Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia. Electronic address:

Context: X-linked hypophosphatemic rickets (XLH) is caused by inactivating mutations in the PHEX gene and is the most common form of hereditary rickets. The splice-site mutations account for 17% of all reported PHEX mutations. The functional consequence of these splice-site mutations has not been systemically investigated.

Objective: The current study was undertaken to functionally annotate previously reported 22 splice-site mutations in the PHEX gene.

Methods: PHEX mini-genes with different splice-site mutations were created by site-directed mutagenesis and expressed in HEK293 cells. The mRNA transcripts were analyzed by RT-PCR, cloning, and sequencing.

Results: These splicing mutations led to a variety of consequences, including exon skipping, intron retention, and activation of cryptic splice sites. Among 22 splice-site mutations, exon skipping was the most common event accounting for 73% (16/22). Non-canonical splice-site mutations could result in splicing errors to the same extent as canonical splice-site mutations such as c.436+3G>C, c.436+4A>C, c.436+6T>C, c.437-3C>G, c.850-3C>G, c.1080-3C>A, c.1482+5G>C, c.1586+6T>C, c.1645+5G>A, c.1645+6T>C, c.1701-16T>A, c.1768+5G>A, and c.1899+5G>A. Interestingly, non-canonical (c.436+6T>C and c.1586+6T>C) and canonical splice-site mutations (c.1769-1G>C) could generate partial splicing errors (both wild-type and mutant transcripts were detected), resulting in incomplete inactivation of PHEX gene, which may explain the mild disease phenotype reported previously, providing evidence of genotype-phenotype correlation. c.1645C>T (p.R549*) had no impact on pre-mRNA splicing although it is located next to canonical splice donor site GT.

Conclusions: Exon skipping is the most common outcome due to splice-site mutations. Both canonical and non-canonical splice-site mutations can result in either severe or mild RNA splicing defects, contributing to phenotype heterogeneity. Non-canonical splice-site mutations should not be overlooked in genetic screening especially those located within 50 bp from canonical splice site.
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http://dx.doi.org/10.1016/j.bone.2019.05.017DOI Listing
August 2019

An atypical pulmonary fibrosis is associated with co-inheritance of mutations in the calcium binding protein genes and .

Eur Respir J 2019 07 18;54(1). Epub 2019 Jul 18.

Dept of Cell Biology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Background: Pulmonary fibrosis is one of the leading indications for lung transplantation. The disease, which is of unknown aetiology, can be progressive, resulting in distortion of the extracellular matrix (ECM), inflammation, fibrosis and eventual death.

Methods: 13 patients born to consanguineous parents from two unrelated families presenting with interstitial lung disease were clinically investigated. Nine patients developed respiratory failure and subsequently died. Molecular genetic investigations were performed on patients' whole blood or archived tissues, and cell biological investigations were performed on patient-derived fibroblasts.

Results: The combination of a unique pattern of early-onset lung fibrosis (at 12-15 years old) with distinctive radiological findings, including 1) traction bronchiectasis, 2) intralobular septal thickening, 3) shrinkage of the secondary pulmonary lobules mainly around the bronchovascular bundles and 4) early type 2 respiratory failure (elevated blood carbon dioxide levels), represents a novel clinical subtype of familial pulmonary fibrosis. Molecular genetic investigation of families revealed a hypomorphic variant in and a novel truncating mutation in , both segregating with the disease in an autosomal recessive manner. Family members that were either heterozygous carriers or wild-type normal for both variants were unaffected. Analysis of patient-derived fibroblasts demonstrated significantly reduced S100A3 and S100A13 expression. Further analysis demonstrated aberrant intracellular calcium homeostasis, mitochondrial dysregulation and differential expression of ECM components.

Conclusion: Our data demonstrate that digenic inheritance of mutations in and underlie the pathophysiology of pulmonary fibrosis associated with a significant reduction of both proteins, which suggests a calcium-dependent therapeutic approach for management of the disease.
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http://dx.doi.org/10.1183/13993003.02041-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637284PMC
July 2019

Autosomal recessive ADCY5-Related dystonia and myoclonus: Expanding the genetic spectrum of ADCY5-Related movement disorders.

Parkinsonism Relat Disord 2019 07 28;64:145-149. Epub 2019 Feb 28.

Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; Department of Biomedical Research, King Fahad Specialist Hospital, Dammam, Saudi Arabia.

Introduction: ADCY5-related hyperkinesia encompasses a heterogeneous group of phenotypes, including paroxysmal chorea, myoclonus, and dystonia. The disease is attributed to mutations of ADCY5, which encodes an adenylate cyclase enzyme. The disease can occur in a sporadic or familial pattern. With exception of one study, all reports on familial ADCY5-related hyperkinesia were associated with an autosomal dominant inheritance. Herein, we describe a native Arabian Bedouin family with an autosomal recessive ADCY5-related disorder and expand the genotypic and phenotypic spectrum of this disorder.

Methods: The pedigree included 4 generations of a family with 6 affected individuals. The patients were examined clinically and radiologically. Homozygosity mapping and Whole Exome Sequencing (WES) were used to identify a variant, predicted to be pathogenic, which segregated with disease in this family.

Results: All patients presented with early-onset dystonia and myoclonus. The patients had delayed motor and language milestones, axial hypotonia, severe anxiety, social phobia, and isolation. One patient had dilated cardiomyopathy. WES of one affected individual revealed a novel homozygous missense mutation (c.1762G > A, p.D588N) of ADCY5, that segregated with disease in an autosomal recessive manner, and was absent in more than 1000 ethnically-matched chromosomes. The mutation replaces a highly conserved nucleotide and is predicted to be deleterious.

Conclusion: This study reports the second family with autosomal recessive childhood-onset ADCY5-related disorder and expands our understanding of phenotype/genotype correlations of this disorder.
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http://dx.doi.org/10.1016/j.parkreldis.2019.02.039DOI Listing
July 2019

LGMD1D myopathy with cytoplasmic and nuclear inclusions in a Saudi family due to DNAJB6 mutation.

Acta Myol 2018 Sep 1;37(3):221-226. Epub 2018 Sep 1.

Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.

Autosomal dominant LGMD1D has been described in multiple families in Asia, Europe, and USA. However, to the best of our knowledge, no cases of LGMD1D have been reported among native Bedouin Saudi families. Fifty Saudi families with LGMD were analyzed and the causative underlying genes were studied utilizing genome wide linkage, homozygosity mapping, and neurological gene panel. We identified one family of a Bedouin origin with LGMD1D. Two patients had progressive proximal and distal weakness, dysphagia, and respiratory symptoms. Creatinine kinase was normal. Muscle biopsy showed marked variation in myofibers size with scattered angular atrophic fiber, necrotic fibers, and myophagocytosis, with red-rimmed vacuoles depicting a sarcoplasmic body. Heterozygous c.C287T (p.P96L) variant in exon 5 of DNAJB6 (NM_005494) gene was found. This change is localized within glycine and phenylalanine rich domain and alter an amino acid residue. Our findings will expand on the existing genotypic and phenotypic spectrum of this disorder and aid in elucidating hidden mechanisms implicated in LGMD1D.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390114PMC
September 2018

Pattern Recognition Receptor Polymorphisms as Predictors of Oxaliplatin Benefit in Colorectal Cancer.

J Natl Cancer Inst 2019 08;111(8):828-836

See the Notes section for the full list of authors' affiliations.

Background: Constitutional loss of function (LOF) single nucleotide polymorphisms (SNPs) in pattern recognition receptors FPR1, TLR3, and TLR4 have previously been reported to predict oxaliplatin benefit in colorectal cancer. Confirmation of this association could substantially improve patient stratification.

Methods: We performed a retrospective biomarker analysis of the Short Course in Oncology Therapy (SCOT) and COIN/COIN-B trials. Participant status for LOF variants in FPR1 (rs867228), TLR3 (rs3775291), and TLR4 (rs4986790/rs4986791) was determined by genotyping array or genotype imputation. Associations between LOF variants and disease-free survival (DFS) and overall survival (OS) were analyzed by Cox regression, adjusted for confounders, using additive, dominant, and recessive genetic models. All statistical tests were two-sided.

Results: Our validation study populations included 2929 and 1948 patients in the SCOT and COIN/COIN-B cohorts, respectively, of whom 2728 and 1672 patients had functional status of all three SNPs determined. We found no evidence of an association between any SNP and DFS in the SCOT cohort, or with OS in either cohort, irrespective of the type of model used. This included models for which an association was previously reported for rs867228 (recessive model, multivariable-adjusted hazard ratio [HR] for DFS in SCOT = 1.19, 95% confidence interval [CI] = 0.99 to 1.45, P = .07; HR for OS in COIN/COIN-B = 0.92, 95% CI = 0.63 to 1.34, P = .66), and rs4986790 (dominant model, multivariable-adjusted HR for DFS in SCOT = 0.86, 95% CI = 0.65 to 1.13, P = .27; HR for OS in COIN/COIN-B = 1.08, 95% CI = 0.90 to 1.31, P = .40).

Conclusion: In this prespecified analysis of two large clinical trials, we found no evidence that constitutional LOF SNPs in FPR1, TLR3, or TLR4 are associated with differential benefit from oxaliplatin. Our results suggest these SNPs are unlikely to be clinically useful biomarkers.
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http://dx.doi.org/10.1093/jnci/djy215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695319PMC
August 2019

Exome Sequencing: Mutilating Sensory Neuropathy with Spastic Paraplegia due to a Mutation in FAM134B Gene.

Case Rep Genet 2018 12;2018:9468049. Epub 2018 Dec 12.

Department of Neurology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Hereditary sensory and autonomic neuropathies (HSANs) are a clinically and genetically heterogeneous group of disorders involving various sensory and autonomic dysfunctions. The most common symptoms of HSANs include loss of sensations of pain and temperature that frequently lead to chronic ulcerations in the feet and hands of the patient. In this case study, we present the clinical features and genetic characteristics of two affected individuals from two unrelated Saudi families presenting mutilating sensory loss and spastic paraplegia. We employed homozygosity mapping and exome sequencing which is an efficient strategy to characterize the recessive genes, thus obtaining a rapid molecular diagnosis for genetically heterogeneous disorders like HSAN. Subsequently, a nonsense mutation (c.926 C>G; p.S309⁎) in was identified. In addition, we confirmed that the mutant FAM134B transcripts were reduced in these patients presumably disrupting the receptors of the degradative endoplasmic reticulum pathways that facilitate the autophagy processes.
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http://dx.doi.org/10.1155/2018/9468049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311306PMC
December 2018

Autozygome and high throughput confirmation of disease genes candidacy.

Genet Med 2019 03 21;21(3):736-742. Epub 2018 Sep 21.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Purpose: Establishing links between Mendelian phenotypes and genes enables the proper interpretation of variants therein. Autozygome, a rich source of homozygous variants, has been successfully utilized for the high throughput identification of novel autosomal recessive disease genes. Here, we highlight the utility of the autozygome for the high throughput confirmation of previously published tentative links to diseases.

Methods: Autozygome and exome analysis of patients with suspected Mendelian phenotypes. All variants were classified according to the American College of Medical Genetics and Genomics guidelines.

Results: We highlight 30 published candidate genes (ACTL6B, ADAM22, AGTPBP1, APC, C12orf4, C3orf17 (NEPRO), CENPF, CNPY3, COL27A1, DMBX1, FUT8, GOLGA2, KIAA0556, LENG8, MCIDAS, MTMR9, MYH11, QRSL1, RUBCN, SLC25A42, SLC9A1, TBXT, TFG, THUMPD1, TRAF3IP2, UFC1, UFM1, WDR81, XRCC2, ZAK) in which we identified homozygous likely deleterious variants in patients with compatible phenotypes. We also identified homozygous likely deleterious variants in 18 published candidate genes (ABCA2, ARL6IP1, ATP8A2, CDK9, CNKSR1, DGAT1, DMXL2, GEMIN4, HCN2, HCRT, MYO9A, PARS2, PLOD3, PREPL, SCLT1, STX3, TXNRD2, WIPI2) although the associated phenotypes are sufficiently different from the original reports that they represent phenotypic expansion or potentially distinct allelic disorders.

Conclusions: Our results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.
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http://dx.doi.org/10.1038/s41436-018-0138-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752307PMC
March 2019

Phenotype heterogeneity of congenital adrenal hyperplasia due to genetic mosaicism and concomitant nephrogenic diabetes insipidus in a sibling.

BMC Med Genet 2018 07 11;19(1):115. Epub 2018 Jul 11.

Department of Genetics (MBC-03), King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh, 11211, Saudi Arabia.

Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder caused by mutations in the CYP21A2. Congenital nephrogenic diabetes insipidus (NDI) is a rare X-linked recessive or autosomal recessive disorder caused by mutations in either AVPR2 or AQP2. Genotype-phenotype discordance caused by genetic mosaicism in CAH patients has not been reported, nor the concomitant CAH and NDI.

Case Presentation: We investigated a patient with concomitant CAH and NDI from a consanguineous family. She (S-1) presented with clitoromegaly at 3 month of age, and polydipsia and polyuria at 13 month of age. Her parents and two elder sisters (S-2 and S-3) were clinically normal, but elevated levels of serum 17-hydroxyprogesterone (17-OHP) were observed in the mother and S-2. The coding region of CYP21A2 and AQP2 were analyzed by PCR-sequencing analysis to identify genetic defects. Two homozygous CYP21A2 mutations (p.R357W and p.P454S) were identified in the proband and her mother and S-2. The apparent genotype-phenotype discordance was due to presence of small amount of wild-type CYP21A2 alleles in S-1, S-2, and their mother's genome, thus protecting them from development of classic form of 21OHD (C21OHD). A homozygous AQP2 mutation (p.A147T) was also found in the patient. The patient was treated with hydrocortisone and hydrochlorothiazide. Her symptoms were improved with normal laboratory findings. The clitoromegaly is persisted.

Conclusions: Genetic mosaicism is a novel mechanism contributing to the genotype-phenotype discordance in 21OHD and small percentage of wild-type CYP21A2 alleles may be sufficient to prevent phenotype development. This is a first report of concurrent 21OHD and NDI caused by simultaneous homozygous CYP21A2 and AQP2 mutations.
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http://dx.doi.org/10.1186/s12881-018-0629-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042323PMC
July 2018

De novo truncating variants in WHSC1 recapitulate the Wolf-Hirschhorn (4p16.3 microdeletion) syndrome phenotype.

Genet Med 2019 01 11;21(1):185-188. Epub 2018 Jun 11.

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Purpose: Wolf-Hirschhorn syndrome (WHS) is a genomic disorder with a recognizable dysmorphology profile caused by hemizygosity at 4p16.3. Previous attempts have failed to map the minimal critical locus to a single gene, leaving open the possibility that the core phenotypic components of the syndrome are caused by the combined haploinsufficiency of multiple genes.

Methods: Clinical exome sequencing and "reverse" phenotyping.

Results: We identified two patients with de novo truncating variants in WHSC1, which maps to the WHS critical locus. The phenotype of these two individuals is consistent with WHS, which suggests that haploinsufficiency of WHSC1 is sufficient to recapitulate the core phenotype (characteristic facies, and growth and developmental delay) of this classic microdeletion syndrome.

Conclusion: Our study expands the list of microdeletion syndromes that are solved at the single-gene level, and establishes WHSC1 as a disease gene in humans. Given the severe nature of the reported variants, the full phenotypic expression of WHSC1 may be further expanded by future reports of milder variants.
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http://dx.doi.org/10.1038/s41436-018-0014-8DOI Listing
January 2019

Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development.

Brain 2018 07;141(7):1934-1945

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

The post-translational modification of proteins through the addition of UFM1, also known as ufmylation, plays a critical developmental role as revealed by studies in animal models. The recent finding that biallelic mutations in UBA5 (the E1-like enzyme for ufmylation) cause severe early-onset encephalopathy with progressive microcephaly implicates ufmylation in human brain development. More recently, a homozygous UFM1 variant was proposed as a candidate aetiology of severe early-onset encephalopathy with progressive microcephaly. Here, we establish a locus for severe early-onset encephalopathy with progressive microcephaly based on two families, and map the phenotype to a novel homozygous UFM1 mutation. This mutation has a significantly diminished capacity to form thioester intermediates with UBA5 and with UFC1 (the E2-like enzyme for ufmylation), with resulting impaired ufmylation of cellular proteins. Remarkably, in four additional families where eight children have severe early-onset encephalopathy with progressive microcephaly, we identified two biallelic UFC1 mutations, which impair UFM1-UFC1 intermediate formation with resulting widespread reduction of cellular ufmylation, a pattern similar to that observed with UFM1 mutation. The striking resemblance between UFM1- and UFC1-related clinical phenotype and biochemical derangements strongly argues for an essential role for ufmylation in human brain development. The hypomorphic nature of UFM1 and UFC1 mutations and the conspicuous depletion of biallelic null mutations in the components of this pathway in human genome databases suggest that it is necessary for embryonic survival, which is consistent with the embryonic lethal nature of knockout models for the orthologous genes.
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http://dx.doi.org/10.1093/brain/awy135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6022668PMC
July 2018

High Incidence of Severe Combined Immunodeficiency Disease in Saudi Arabia Detected Through Combined T Cell Receptor Excision Circle and Next Generation Sequencing of Newborn Dried Blood Spots.

Front Immunol 2018 16;9:782. Epub 2018 Apr 16.

Department of Genetics, Research Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.

Severe combined immunodeficiency disease (SCID) is the most severe form of primary immunodeficiency disorders (PID). T-cell receptor excision circle (TREC) copy number analysis is an efficient tool for population-based newborn screening (NBS) for SCID and other T cell lymphopenias. We sought to assess the incidence of SCID among Saudi newborn population and examine the feasibility of using targeted next generation sequencing PID gene panel (T-NGS PID) on DNA isolated from dried blood spots (DBSs) in routine NBS programs as a mutation screening tool for samples with low TREC count. Punches from 8,718 DBS collected on Guthrie cards were processed anonymously for the TREC assay. DNA was extracted from samples with confirmed low TREC count, then screened for 22q11.2 deletion syndrome by real-time polymerase chain reaction and for mutations in PID-related genes by T-NGS PID panel. Detected mutations were confirmed by Sanger sequencing. Sixteen out of the 8,718 samples were confirmed to have low TREC copy number. Autosomal recessive mutations in were confirmed in three samples. Two additional samples were positive for the 22q11.2 deletion syndrome. In this study, we provide evidence for high incidence of SCID among Saudi population (1/2,906 live births) and demonstrate the feasibility of using T-NGS PID panel on DNA extracted from DBSs as a new reliable, rapid, and cost-effective mutation screening method for newborns with low TREC assay, which can be implemented as part of NBS programs for SCID.
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http://dx.doi.org/10.3389/fimmu.2018.00782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911483PMC
June 2019

Molecular Analysis of Congenital Hypothyroidism in Saudi Arabia: SLC26A7 Mutation Is a Novel Defect in Thyroid Dyshormonogenesis.

J Clin Endocrinol Metab 2018 05;103(5):1889-1898

Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

Context: Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder, affecting one in 3000 to 4000 newborns. Since the introduction of a newborn screening program in 1988, more than 300 cases have been identified. The underlying genetic defects have not been systematically studied.

Objective: To identify the mutation spectrum of CH-causing genes.

Methods: Fifty-five patients from 47 families were studied by next-generation exome sequencing.

Results: Mutations were identified in 52.7% of patients (29 of 55) in the following 11 genes: TG, TPO, DUOX2, SLC26A4, SLC26A7, TSHB, TSHR, NKX2-1, PAX8, CDCA8, and HOXB3. Among 30 patients with thyroid dyshormonogenesis, biallelic TG mutations were found in 12 patients (40%), followed by biallelic mutations in TPO (6.7%), SLC26A7 (6.7%), and DUOX2 (3.3%). Monoallelic SLC26A4 mutations were found in two patients, one of them coexisting with two tandem biallelic deletions in SLC26A7. In 25 patients with thyroid dysgenesis, biallelic mutations in TSHR were found in six patients (24%). Biallelic mutations in TSHB, PAX 8, NKX2-1, or HOXB3 were found once in four different patients. A monoallelic CDCA8 mutation was found in one patient. Most mutations were novel, including three TG, two TSHR, and one each in DUOX2, TPO, SLC26A7, TSHB, NKX2-1, PAX8, CDCA8, and HOXB3. SLC26A7 and HOXB3 were novel genes associated with thyroid dyshormonogenesis and dysgenesis, respectively.

Conclusions: TG and TSHR mutations are the most common genetic defects in Saudi patients with CH. The prevalence of other disease-causing mutations is low, reflecting the consanguineous nature of the population. SLC26A7 mutations appear to be associated with thyroid dyshormonogenesis.
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http://dx.doi.org/10.1210/jc.2017-02202DOI Listing
May 2018

Clinical and genetic characteristics of 15 families with hereditary hypophosphatemia: Novel Mutations in PHEX and SLC34A3.

PLoS One 2018 5;13(3):e0193388. Epub 2018 Mar 5.

Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.

Background: Hereditary hypophosphatemia is a group of rare renal phosphate wasting disorders. The diagnosis is based on clinical, radiological, and biochemical features, and may require genetic testing to be confirmed.

Methodology: Clinical features and mutation spectrum were investigated in patients with hereditary hypophosphatemia. Genomic DNA of 23 patients from 15 unrelated families were screened sequentially by PCR-sequencing analysis for mutations in the following genes: PHEX, FGF23, DMP1, ENPP1, CLCN5, SLC34A3 and SLC34A1. CytoScan HD Array was used to identify large deletions.

Results: Genetic evaluation resulted in the identification of an additional asymptomatic but intermittent hypophosphatemic subject. Mutations were detected in 21 patients and an asymptomatic sibling from 13 families (86.6%, 13/15). PHEX mutations were identified in 20 patients from 12 families. Six of them were novel mutations present in 9 patients: c.983_987dupCTACC, c.1586+2T>G, c.1206delA, c.436+1G>T, c.1217G>T, and g.22,215,887-22,395,767del (179880 bp deletion including exon 16-22 and ZNF645). Six previously reported mutations were found in 11 patients. Among 12 different PHEX mutations, 6 were de novo mutations. Patients with de novo PHEX mutations often had delayed diagnosis and significantly shorter in height than those who had inherited PHEX mutations. Novel compound heterozygous mutations in SLC34A3 were found in one patient and his asymptomatic sister: c.1335+2T>A and c.1639_1652del14. No mutation was detected in two families.

Conclusions: This is the largest familial study on Turkish patients with hereditary hypophosphatemia. PHEX mutations, including various novel and de novo variants, are the most common genetic defect. More attention should be paid to hypophosphatemia by clinicians since some cases remain undiagnosed both during childhood and adulthood.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193388PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837132PMC
July 2018

Replication of Type 2 diabetes-associated variants in a Saudi Arabian population.

Physiol Genomics 2018 04 16;50(4):296-297. Epub 2018 Feb 16.

Department of Clinical Epidemiology, Leiden University Medical Center , Leiden , the Netherlands.

Over 120 Type 2 diabetes (T2D) loci have been identified from genome-wide association studies (GWAS), mainly from Caucasian populations. Very limited knowledge is available on the Saudi Arabian population. In this study, 122 previously reported T2D-related variants from 84 loci were examined in a Saudi Arabian cohort of 1,578 individuals (659 T2D cases and 919 controls). Eleven single nucleotide polymorphisms (SNPs) corresponding to nine independent loci had a P value <0.05. If a more stringent Bonferroni threshold of P = 4.1 × 10 ( = 0.05/122) were applied, none of the SNPs would have reached the significance level. Nine of the SNPs with a P value <0.05 showed similar odds ratios as previously described, but rs11605924 ( CRY2) and rs9470794 ( ZFAND3) were in the opposite direction. This study demonstrates the importance of large-scale GWAS in the Saudi Arabian population to identify ethnicity-specific disease-associated variants.
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http://dx.doi.org/10.1152/physiolgenomics.00100.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966803PMC
April 2018

Further delineation of Temtamy syndrome of corpus callosum and ocular abnormalities.

Am J Med Genet A 2018 03 31;176(3):715-721. Epub 2018 Jan 31.

Department of Genetics, King Faisal Specialist Hospital Research Center, Riyadh, Saudi Arabia.

Temtamy syndrome is a syndromic form of intellectual disability characterized by ocular involvement, epilepsy and dysgenesis of the corpus callosum. After we initially mapped the disease to C12orf57, we noted a high carrier frequency of an ancient startloss founder mutation [c.1A>G; p.M1?] in our population, and variable phenotypic expressivity in newly identified cases. This study aims to combine 33 previously published patients with 23 who are described here for the first time to further delineate the phenotype of this syndrome. In addition to the known p.M1? founder, we describe four novel homozygous variants, thus increasing the number of Temtamy syndrome-related C12orf57 variants to seven, all but one predicted to be loss of function. While all patients presented with intellectual disability/developmental delay, the frequency of other phenotypic features was variable: 73.2% (41/56) had epilepsy, 63% (34/54) had corpus callosal abnormalities, 14.5% (8/55) had coloboma, and 16.4% (9/55) had microphthalmia. Our analysis also revealed a high frequency of less recognized features such as congenital heart disease (51.4%), and brain white matter abnormalities (38%, 19/50). We conclude that C12orf57 variants should be considered in the etiology of developmental delay/intellectual disability, even when typical syndromic features are lacking, especially in those who trace their ancestry to Saudi Arabia where a founder C12orf57 mutation is among the most common recessive causes of intellectual disability.
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http://dx.doi.org/10.1002/ajmg.a.38615DOI Listing
March 2018

Correction to: Recessive VARS2 mutation underlies a novel syndrome with epilepsy, mental retardation, short stature, growth hormone deficiency, and hypogonadism.

Hum Genomics 2017 12 8;11(1):33. Epub 2017 Dec 8.

Department of Genetics, King Faisal Specialist Hospital and Research Centre, MBC 03, PO Box 3354, Riyadh, 11211, Saudi Arabia.

Correction: After publication of the article [1], it has been brought to our attention that there is a nomenclature issue with this article. At the time of acceptance, the VARS2 mutation was considered equivalent to the VARS2 mutation. However, this has changed so that VARS now only refers to shorter mitochondrial sequence of valyl-tRNA synthesase containing 1093 amino acids. "Therefore, in the context of this article, every usage of "VARS2" should be replaced with "VARS" when referring to the causative variant".
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http://dx.doi.org/10.1186/s40246-017-0130-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723066PMC
December 2017

Recessive VARS2 mutation underlies a novel syndrome with epilepsy, mental retardation, short stature, growth hormone deficiency, and hypogonadism.

Hum Genomics 2017 Nov 14;11(1):28. Epub 2017 Nov 14.

Department of Genetics, King Faisal Specialist Hospital and Research Centre, MBC 03, PO Box 3354, Riyadh, 11211, Saudi Arabia.

Background: Most mitochondrial and cytoplasmic aminoacyl-tRNA synthetases (aaRSs) are encoded by nuclear genes. Syndromic disorders resulting from mutation of aaRSs genes display significant phenotypic heterogeneity. We expand aaRSs-related phenotypes through characterization of the clinical and molecular basis of a novel autosomal-recessive syndrome manifesting severe mental retardation, ataxia, speech impairment, epilepsy, short stature, microcephaly, hypogonadism, and growth hormone deficiency.

Results: A G>A variant in exon 29 of VARS2 (c.3650G>A) (NM_006295) was identified in the index case. This homozygous variant was confirmed by Sanger sequencing and segregated with disease in the family studied. The c.3650G>A change results in alteration of arginine to histidine at residue 1217 (R1217H) of the mature protein and is predicted to be pathogenic.

Conclusions: These findings contribute to a growing list of aaRSs disorders, broadens the spectrum of phenotypes attributable to VARS2 mutations, and provides new insight into genotype-phenotype correlations among the mitochondrial synthetase genes.
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http://dx.doi.org/10.1186/s40246-017-0124-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686820PMC
November 2017