Syndrome Disintegration: Exome Sequencing Reveals that Fitzsimmons Syndrome is a Co-Occurrence of Multiple Events

被引:18
作者
Armour, Christine M. [1 ,2 ]
Smith, Amanda [1 ,2 ]
Hartley, Taila [2 ]
Chardon, Jodi Warman [1 ,2 ]
Sawyer, Sarah [1 ,2 ]
Schwartzentruber, Jeremy [3 ,4 ]
Hennekam, Raoul [5 ]
Majewski, Jacek [6 ]
Bulman, Dennis E. [2 ]
Suri, Mohnish [7 ]
Boycott, Kym M. [1 ,2 ]
机构
[1] Childrens Hosp Eastern Ontario, Dept Genet, 401 Smyth Rd, Ottawa, ON K1H 8L1, Canada
[2] Univ Ottawa, Childrens Hosp Eastern Ontario, Res Inst, Ottawa, ON, Canada
[3] McGill Univ, Montreal, PQ, Canada
[4] Genome Quebec Innovat Ctr, Montreal, PQ, Canada
[5] Univ Amsterdam, Acad Med Ctr, Dept Pediat, Amsterdam, Netherlands
[6] McGill Univ, Dept Human Genet, Montreal, PQ, Canada
[7] Nottingham Univ Hosp NHS Trust, Nottingham Clin Genet Serv, City Hosp Campus, Nottingham, England
基金
加拿大健康研究院;
关键词
syndrome; exome sequencing; Fitzsimmons syndrome; ARSACS; Trichorhinophalangeal syndrome type 1; concomitant mutations; AUTISM SPECTRUM DISORDERS; CONE-SHAPED EPIPHYSES; SPASTIC PARAPLEGIA; INTELLECTUAL DISABILITY; DELETION; TBL1XR1; DYSARTHRIA; DISCOVERY; GENES;
D O I
10.1002/ajmg.a.37684
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
In 1987 Fitzsimmons and Guilbert described identical male twins with progressive spastic paraplegia, brachydactyly with cone shaped epiphyses, short stature, dysarthria, and "low-normal" intelligence. In subsequent years, four other patients, including one set of female identical twins, a single female child, and a single male individual were described with the same features, and the eponym Fitzsimmons syndrome was adopted (OMIM #270710). We performed exome analysis of the patient described in 2009, and one of the original twins from 1987, the only patients available from the literature. No single genetic etiology exists that explains Fitzsimmons syndrome; however, multiple different genetic causes were identified. Specifically, the twins described by Fitzsimmons had heterozygous mutations in the SACS gene, the gene responsible for autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS), as well as a heterozygous mutation in the TRPS1, the gene responsible in Trichorhinophalangeal syndrome type 1 (TRPS1 type 1) which includes brachydactyly as a feature. A TBL1XR1 mutation was identified in the patient described in 2009 as contributing to his cognitive impairment and autistic features with no genetic cause identified for his spasticity or brachydactyly. The findings show that these individuals have multiple different etiologies giving rise to a similar phenotype, and that "Fitzsimmons syndrome" is in fact not one single syndrome. Over time, we anticipate that continued careful phenotyping with concomitant genome-wide analysis will continue to identify the causes of many rare syndromes, but it will also highlight that previously delineated clinical entities are, in fact, not syndromes at all. (C) 2016 Wiley Periodicals, Inc.
引用
收藏
页码:1820 / 1825
页数:6
相关论文
共 23 条
[1]   Fitzsimmons Syndrome: Spastic Paraplegia, Brachydactyly, and Cognitive Impairment [J].
Armour, Christine M. ;
Humphreys, Peter ;
Hennekam, Raoul C. M. ;
Boycott, Kym M. .
AMERICAN JOURNAL OF MEDICAL GENETICS PART A, 2009, 149A (10) :2254-2257
[2]   A CTNNA3 compound heterozygous deletion implicates a role for αT-catenin in susceptibility to autism spectrum disorder [J].
Bacchelli, Elena ;
Ceroni, Fabiola ;
Pinto, Dalila ;
Lomartire, Silvia ;
Giannandrea, Maila ;
D'Adamo, Patrizia ;
Bonora, Elena ;
Parchi, Piero ;
Tancredi, Raffaella ;
Battaglia, Agatino ;
Maestrini, Elena .
JOURNAL OF NEURODEVELOPMENTAL DISORDERS, 2014, 6
[3]   FORGE Canada Consortium: Outcomes of a 2-Year National Rare-Disease Gene-Discovery Project [J].
Beaulieu, Chandree L. ;
Majewski, Jacek ;
Schwartzentruber, Jeremy ;
Samuels, Mark E. ;
Femandez, Bridget A. ;
Bernier, Francois P. ;
Brudno, Michael ;
Knoppers, Bartha ;
Marcadier, Janet ;
Dyment, David ;
Adam, Shelin ;
Bulman, Dennis E. ;
Jones, Steve J. M. ;
Avard, Denise ;
Minh Thu Nguyen ;
Rousseau, Francois ;
Marshall, Christian ;
Wintle, Richard F. ;
Shen, Yaoqing ;
Scherer, Stephen W. ;
Friedman, Jan M. ;
Michaud, Jacques L. ;
Boycott, Kym M. .
AMERICAN JOURNAL OF HUMAN GENETICS, 2014, 94 (06) :809-817
[4]   Rare-disease genetics in the era of next-generation sequencing: discovery to translation [J].
Boycott, Kym M. ;
Vanstone, Megan R. ;
Bulman, Dennis E. ;
MacKenzie, Alex E. .
NATURE REVIEWS GENETICS, 2013, 14 (10) :681-691
[5]   Whole Exome Sequencing in Females with Autism Implicates Novel and Candidate Genes [J].
Butler, Merlin G. ;
Rafi, Syed K. ;
Hossain, Waheeda ;
Stephan, Dietrich A. ;
Manzardo, Ann M. .
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2015, 16 (01) :1312-1335
[6]   Duplications Involving a Conserved Regulatory Element Downstream of BMP2 Are Associated with Brachydactyly Type A2 [J].
Dathe, Katarina ;
Kjaer, Klaus W. ;
Brehm, Anja ;
Meinecke, Peter ;
Nuernberg, Peter ;
Neto, Jordao C. ;
Brunoni, Decio ;
Tommerup, Nils ;
Ott, Claus E. ;
Klopocki, Eva ;
Seemann, Petra ;
Mundlos, Stefan .
AMERICAN JOURNAL OF HUMAN GENETICS, 2009, 84 (04) :483-492
[7]   SPASTIC PARAPLEGIA ASSOCIATED WITH BRACHYDACTYLY AND CONE SHAPED EPIPHYSES [J].
FITZSIMMONS, JS ;
GUILBERT, PR .
JOURNAL OF MEDICAL GENETICS, 1987, 24 (11) :702-705
[8]   A specific mutation in TBL1XR1 causes Pierpont syndrome [J].
Heinen, Charlotte A. ;
Jongejan, Aldo ;
Watson, Peter J. ;
Redeker, Bert ;
Boelen, Anita ;
Boudzovitch-Surovtseva, Olga ;
Forzano, Francesca ;
Hordijk, Roel ;
Kelley, Richard ;
Olney, Ann H. ;
Pierpont, Mary Ella ;
Schaefer, G. Bradley ;
Stewart, Fiona ;
van Trotsenburg, A. S. Paul ;
Fliers, Eric ;
Schwabe, John W. R. ;
Hennekam, Raoul C. .
JOURNAL OF MEDICAL GENETICS, 2016, 53 (05) :330-337
[9]   SPASTIC PARAPLEGIA, DYSARTHRIA, BRACHYDACTYLY, AND CONE-SHAPED EPIPHYSES - CONFIRMATION OF THE FITZSIMMONS-SYNDROME [J].
HENNEKAM, RCM .
JOURNAL OF MEDICAL GENETICS, 1994, 31 (03) :251-252
[10]  
Lacassie Y, 1999, AM J MED GENET, V84, P90, DOI 10.1002/(SICI)1096-8628(19990521)84:2<90::AID-AJMG2>3.0.CO