Pathogenic variants in CDC45 on the remaining allele in patients with a chromosome 22q11.2 deletion result in a novel autosomal recessive condition.
22q11.2 deletion syndrome
CDC45 gene
craniosynostosis
next-generation sequencing
rare nonsynonymous variants
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
31
01
2019
accepted:
15
08
2019
pubmed:
3
9
2019
medline:
12
1
2021
entrez:
3
9
2019
Statut:
ppublish
Résumé
The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion in humans, with highly variable phenotypic expression. Whereas congenital heart defects, palatal anomalies, immunodeficiency, hypoparathyroidism, and neuropsychiatric conditions are observed in over 50% of patients with 22q11DS, a subset of patients present with additional "atypical" findings such as craniosynostosis and anorectal malformations. Recently, pathogenic variants in the CDC45 (Cell Division Cycle protein 45) gene, located within the LCR22A-LCR22B region of chromosome 22q11.2, were noted to be involved in the pathogenesis of craniosynostosis. We performed next-generation sequencing on DNA from 15 patients with 22q11.2DS and atypical phenotypic features such as craniosynostosis, short stature, skeletal differences, and anorectal malformations. We identified four novel rare nonsynonymous variants in CDC45 in 5/15 patients with 22q11.2DS and craniosynostosis and/or other atypical findings. This study supports CDC45 as a causative gene in craniosynostosis, as well as a number of other anomalies. We suggest that this association results in a condition independent of Meier-Gorlin syndrome, perhaps representing a novel condition and/or a cause of features associated with Baller-Gerold syndrome. In addition, this work confirms that the phenotypic variability observed in a subset of patients with 22q11.2DS is due to pathogenic variants on the nondeleted chromosome.
Identifiants
pubmed: 31474763
doi: 10.1038/s41436-019-0645-4
pii: S1098-3600(21)01284-3
pmc: PMC7197230
mid: NIHMS1580777
doi:
Substances chimiques
CDC45 protein, human
0
Cell Cycle Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
326-335Subventions
Organisme : NICHD NIH HHS
ID : P01 HD070454
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH119737
Pays : United States
Organisme : NIMH NIH HHS
ID : U01 MH101719
Pays : United States
Références
McDonald-McGinn DM, Sullivan KE, Marino B, et al. 22q11.2 deletion syndrome. Nat Rev Dis Primers. 2015;1:15071.
doi: 10.1038/nrdp.2015.71
Saitta SC, Harris SE, Gaeth AP, et al. Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion. Hum Mol Genet. 2004;13:417–428.
doi: 10.1093/hmg/ddh041
McDonald-McGinn DM, Fahiminiya S, Revil T, et al. Hemizygous mutations in SNAP29 unmask autosomal recessive conditions and contribute to atypical findings in patients with 22q11.2DS. J Med Genet. 2013;50:80–90.
doi: 10.1136/jmedgenet-2012-101320
Kunishima S, Imai T, Kobayashi R, Kato M, Ogawa S, Saito H. Bernard–Soulier syndrome caused by a hemizygous GPIbβ mutation and 22q11.2 deletion. Pediatr Int. 2013;55:434–437.
doi: 10.1111/ped.12105
Fenwick AL, Kliszczak M, Cooper F, et al. Mutations in CDC45, encoding an essential component of the pre-initiation complex, cause Meier–Gorlin syndrome and craniosynostosis. Am J Hum Genet. 2016;99:125–138.
doi: 10.1016/j.ajhg.2016.05.019
Miller KA, Twigg SR, McGowan SJ, et al. Diagnostic value of exome and whole genome sequencing in craniosynostosis. J Med Genet. 2017;54:260–268.
doi: 10.1136/jmedgenet-2016-104215
de Munnik SA, Hoefsloot EH, Roukema J, et al. Meier–Gorlin syndrome. Orphanet J Rare Dis. 2015;10:114-015–0322-x.
doi: 10.1186/s13023-015-0322-x
Saha P, Thome KC, Yamaguchi R, Hou Z, Weremowicz S, Dutta A. The human homolog of Saccharomyces cerevisiae CDC45. J Biol Chem. 1998;273:18205–18209.
doi: 10.1074/jbc.273.29.18205
Al-Hertani W, Hastings VA, McGowan-Jordan J, Hurteau J, Graham GE. Severe craniosynostosis in an infant with deletion 22q11.2 syndrome. Am J Med Genet A. 2013;161A:153–157.
doi: 10.1002/ajmg.a.35491
Rojnueangnit K, Robin NH. Craniosynostosis and radial ray defect: a rare presentation of 22q11.2 deletion syndrome. Am J Med Genet A. 2013;161A:2024–2026.
doi: 10.1002/ajmg.a.36004
Yamamoto T, Sameshima K, Sekido K, et al. Trigonocephaly in a boy with paternally inherited deletion 22q11.2 syndrome. Am J Med Genet A. 2006;140:1302–1304.
doi: 10.1002/ajmg.a.31297
McDonald-McGinn DM, Gripp KW, Kirschner RE, et al. Craniosynostosis: another feature of the 22q11.2 deletion syndrome. Am J Med Genet A. 2005;136A:358–362.
doi: 10.1002/ajmg.a.30746
Ardeshirdavani A, Souche E, Dehaspe L, Van Houdt J, Vermeesch JR, Moreau Y. NGS-Logistics: federated analysis of NGS sequence variants across multiple locations. Genome Med. 2014;6:71–014-0071-9. eCollection 2014
pubmed: 25328540
pmcid: 4198698
Unolt M, DiCairano L, Schlechtweg K, et al. Congenital diaphragmatic hernia in 22q11.2 deletion syndrome. Am J Med Genet A. 2017;173:135–142.
doi: 10.1002/ajmg.a.37980
Yang N, Wu N, Zhang L, et al. TBX6 compound inheritance leads to congenital vertebral malformations in humans and mice. Hum Mol Genet. 2019;28:539–547.
doi: 10.1093/hmg/ddy358
Zernant J, Lee W, Nagasaki T, et al. Extremely hypomorphic and severe deep intronic variants in the ABCA4 locus result in varying Stargardt disease phenotypes. Cold Spring Harb Mol Case Stud. 2018;4:a002733.
doi: 10.1101/mcs.a002733
Devanna P, van de Vorst M, Pfundt R, Gilissen C, Vernes SC. Genome-wide investigation of an ID cohort reveals de novo 3’UTR variants affecting gene expression. Hum Genet. 2018;137:717–721.
doi: 10.1007/s00439-018-1925-9
Dusl M, Senderek J, Muller JS, et al. A 3’-UTR mutation creates a microRNA target site in the GFPT1 gene of patients with congenital myasthenic syndrome. Hum Mol Genet. 2015;24:3418–3426.
doi: 10.1093/hmg/ddv090
Makarova KS, Koonin EV, Kelman Z. TheCMG (CDC45/RecJ, MCM, GINS) complex is a conserved component of the DNA replication system in all archaea and eukaryotes. Biol Direct. 2012;7:7–6150-7-7.
doi: 10.1186/1745-6150-7-7
Shaikh TH, Gottlieb S, Sellinger B, et al. Characterization of CDC45L: a gene in the 22q11.2 deletion region expressed during murine and human development. Mamm Genome. 1999;10:322–326.
doi: 10.1007/s003359900996
Pacek M, Walter JC. A requirement for MCM7 and Cdc45 in chromosome unwinding during eukaryotic DNA replication. EMBO J. 2004;23:3667–3676.
doi: 10.1038/sj.emboj.7600369
Gerhardt J, Guler GD, Fanning E. Human DNA helicase B interacts with the replication initiation protein Cdc45 and facilitates Cdc45 binding onto chromatin. Exp Cell Res. 2015;334:283–293.
doi: 10.1016/j.yexcr.2015.04.014
Kohler C, Koalick D, Fabricius A, et al. Cdc45 is limiting for replication initiation in humans. Cell Cycle. 2016;15:974–985.
doi: 10.1080/15384101.2016.1152424
Szambowska A, Tessmer I, Kursula P, et al. DNA binding properties of human Cdc45 suggest a function as molecular wedge for DNA unwinding. Nucleic Acids Res. 2014;42:2308–2319.
doi: 10.1093/nar/gkt1217
Hestand MS, Nowakowska BA, Vergaelen E, et al. A catalog of hemizygous variation in 127 22q11 deletion patients. Hum Genome Var. 2016;3:15065.
doi: 10.1038/hgv.2015.65
Yoshida K, Kuo F, George EL, Sharpe AH, Dutta A. Requirement of CDC45 for postimplantation mouse development. Mol Cell Biol. 2001;21:4598–4603.
doi: 10.1128/MCB.21.14.4598-4603.2001
Van Maldergem L, Siitonen HA, Jalkh N, et al. Revisiting the craniosynostosis-radial ray hypoplasia association: Baller–Gerold syndrome caused by mutations in the RECQL4 gene. J Med Genet. 2006;43:148–152.
doi: 10.1136/jmg.2005.031781
Siitonen HA, Sotkasiira J, Biervliet M, et al. The mutation spectrum in RECQL4 diseases. Eur J Hum Genet. 2009;17:151–158.
doi: 10.1038/ejhg.2008.154
Piard J, Aral B, Vabres P, et al. Search for ReCQL4 mutations in 39 patients genotyped for suspected Rothmund-Thomson/Baller–Gerold syndromes. Clin Genet. 2015;87:244–251.
doi: 10.1111/cge.12361
Sangrithi MN, Bernal JA, Madine M, et al. Initiation of DNA replication requires the RECQL4 protein mutated in Rothmund-Thomson syndrome. Cell. 2005;121:887–898.
doi: 10.1016/j.cell.2005.05.015
Van Maldergem L, Piard J, Larizza L, Wang LL. Baller–Gerold syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews. Seattle (WA): University of Washington; 1993.
Pollok S, Bauerschmidt C, Sanger J, Nasheuer HP, Grosse F. Human Cdc45 is a proliferation-associated antigen. FEBS J. 2007;274:3669–3684.
doi: 10.1111/j.1742-4658.2007.05900.x
Tomita Y, Imai K, Senju S, et al. A novel tumor-associated antigen, cell division cycle 45-like can induce cytotoxic T-lymphocytes reactive to tumor cells. Cancer Sci. 2011;102:697–705.
doi: 10.1111/j.1349-7006.2011.01865.x
Colnaghi R, Carpenter G, Volker M, O’Driscoll M. The consequences of structural genomic alterations in humans: genomic disorders, genomic instability and cancer. Semin Cell Dev Biol. 2011;22:875–885.
doi: 10.1016/j.semcdb.2011.07.010