Mutations in KIF27, GNAS and IFT140 genes in a patient with VACTERL association

Siti Aishah Sulaiman, Nor Azian Abdul Murad, Yock Ping Chow, Zam Zureena Mohd Rani, Salwati Shuib, Dayang Anita A. Aziz, Hana Azhari, Sharifah Azween Syed Omar, Zarina Abdul Latiff, Rahman Jamal

Abstract


VACTERL association is a rare genetic disorder involving at least three of the following congenital malformations: vertebral defects (V), anal atresia (A), cardiac defects (C), trachea-oesophageal fistula with or without oesophageal atresia (TE), renal anomalies (R) and limb abnormalities (L). Until now, the aetiology of VACTERL association is unknown, particularly at the molecular level. Here, we performed whole exome sequencing (WES) of an infant with VACTERL association. The patient was delivered prematurely at 30 weeks and had 4/6 of the VACTERL malformations. Trio-WES analysis was performed using Torrent Suite and ANNOVAR. Polymorphisms with allele frequency of >0.01 were excluded and the remaining variants were filtered based on de novo mutations, autosomal recessive, X-linked and di-genic inheritance traits. In this patient, no homozygous, compound heterozygous or X-linked mutations was associated with VACTERL. However, we identified two heterozygous mutations; KIF27 (ENST00000297814: c.3004A> C:p.N1002H) and GNAS (ENST00000371098: c.205C>A:p.H69N) genes that were inherited from her father and mother respectively. A de novo, IFT140 gene mutation (ENST00000426508: c.683C>G:p.S228C) was also identified in this patient. The VACTERL phenotype in this patient may due to heterozygous mutations affecting KIF27 and GNAS genes, inherited via autosomal recessive trait. In addition, the IFT140 gene mutation may also be involved. These genes are known to be directly or non-directly involved in the sonic hedgehog signalling that is known to be implicated in VACTERL. This is the first report of these genetic mutations in association with VACTERL.


Full Text:

PDF

References


Solomon BD. VACTERL/VATER Association. Orphanet Journal of Rare Diseases. 2011;6(1):56.

Solomon BD, Bear KA, Kimonis V, de Klein A, Scott DA, Shaw-Smith C, et al. Clinical Geneticists’ Views of VACTERL/VATER Association. American journal of medical genetics Part A. 2012;158A(12):3087-100.

Brosens E, Eussen H, van Bever Y, van der Helm RM, Ijsselstijn H, Zaveri HP, et al. VACTERL Association Etiology: The Impact of de novo and Rare Copy Number Variations. Molecular Syndromology. 2013;4(1-2):20-6.

Garcia-Barceló M-M, Wong KK-y, Lui VC-h, Yuan Z-w, So M-t, Ngan ES-w, et al. Identification of a HOXD13 mutation in a VACTERL patient. American Journal of Medical Genetics Part A. 2008;146A(24):3181-5.

Wessels MW, Kuchinka B, Heydanus R, Smit BJ, Dooijes D, de Krijger RR, et al. Polyalanine expansion in the ZIC3 gene leading to X-linked heterotaxy with VACTERL association: A new polyalanine disorder? Journal of Medical Genetics. 2010;47(5):351-5.

Reardon W, Zhou X, Eng C. A novel germline mutation of the PTEN gene in a patient with macrocephaly, ventricular dilatation, and features of VATER association. Journal of Medical Genetics. 2001;38(12):820-3.

McCauley J, Masand N, McGowan R, Rajagopalan S, Hunter A, Michaud JL, et al. X-linked VACTERL with hydrocephalus syndrome: Further delineation of the phenotype caused by FANCB mutations. American Journal of Medical Genetics Part A. 2011;155(10):2370-80.

Stankiewicz P, Sen P, Bhatt SS, Storer M, Xia Z, Bejjani BA, et al. Genomic and Genic Deletions of the FOX Gene Cluster on 16q24.1 and Inactivating Mutations of FOXF1 Cause Alveolar Capillary Dysplasia and Other Malformations. American Journal of Human Genetics. 2009;84(6):780-91.

Nakamura Y, Kikugawa S, Seki S, Takahata M, Iwasaki N, Terai H, et al. PCSK5 mutation in a patient with the VACTERL association. BMC Research Notes. 2015;8:228.

Saisawat P, Kohl S, Hilger AC, Hwang D-Y, Gee HY, Dworschak GC, et al. Whole exome resequencing reveals recessive mutations in TRAP1 in individuals with CAKUT and VACTERL association. Kidney international. 2014;85(6):1310-7.

Lubinsky M. Sonic Hedgehog, VACTERL, and Fanconi anemia: Pathogenetic connections and therapeutic implications. American Journal of Medical Genetics Part A. 2015;167(11):2594-8.

Friedland-Little JM, Hoffmann AD, Ocbina PJR, Peterson MA, Bosman JD, Chen Y, et al. A novel murine allele of Intraflagellar Transport Protein 172 causes a syndrome including VACTERL-like features with hydrocephalus. Human Molecular Genetics. 2011;20(19):3725-37.

Ocbina PJR, Anderson KV. Intraflagellar Transport, Cilia and Mammalian Hedgehog Signaling: Analysis in Mouse Embryonic Fibroblasts. Developmental dynamics : an official publication of the American Association of Anatomists. 2008;237(8):2030-8.

Siebel S, Solomon BD. Mitochondrial Factors and VACTERL Association-Related Congenital Malformations. Molecular Syndromology. 2013;4(1-2):63-73.

Rabbani B, Tekin M, Mahdieh N. The promise of whole-exome sequencing in medical genetics. J Hum Genet. 2014;59(1):5-15.

Cingolani P, Platts A, Wang LL, Coon M, Nguyen T, Wang L, et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w(1118); iso-2; iso-3. Fly. 2012;6(2):80-92.

Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Research. 2010;38(16):e164-e.

Robinson JT, Thorvaldsdóttir H, Winckler W, Guttman M, Lander ES, Getz G, et al. Integrative Genomics Viewer. Nature biotechnology. 2011;29(1):24-6.

Thorvaldsdóttir H, Robinson JT, Mesirov JP. Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Briefings in Bioinformatics. 2013;14(2):178-92.

Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protocols. 2009;4(8):1073-81.

Adzhubei I, Jordan DM, Sunyaev SR. Predicting Functional Effect of Human Missense Mutations Using PolyPhen-2. Curr Protoc Hum Genet. 2013;0 7:Unit7.20-Unit7.

Schwarz JM, Rodelsperger C, Schuelke M, Seelow D. MutationTaster evaluates disease-causing potential of sequence alterations. Nat Meth. 2010;7(8):575-6.

Shihab HA, Gough J, Cooper DN, Stenson PD, Barker GLA, Edwards KJ, et al. Predicting the Functional, Molecular, and Phenotypic Consequences of Amino Acid Substitutions using Hidden Markov Models. Human Mutation. 2013;34(1):57-65.

Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nature genetics. 2014;46(3):310-5.

Choi Y, Sims GE, Murphy S, Miller JR, Chan AP. Predicting the Functional Effect of Amino Acid Substitutions and Indels. PLOS ONE. 2012;7(10):e46688.

Quang D, Chen Y, Xie X. DANN: a deep learning approach for annotating the pathogenicity of genetic variants. Bioinformatics. 2015;31(5):761-3.

Kanehisa M, Goto S. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Research. 2000;28(1):27-30.

Mi H, Huang X, Muruganujan A, Tang H, Mills C, Kang D, et al. PANTHER version 11: Expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements. Nucleic Acids Research. 2017;45(D1):D183-D9.

Belinky F, Nativ N, Stelzer G, Zimmerman S, Iny Stein T, Safran M, et al. PathCards: multi-source consolidation of human biological pathways. Database. 2015;2015:bav006-bav.

Klejnot M, Kozielski F. Structural insights into human Kif7, a kinesin involved in Hedgehog signalling. Acta Crystallographica Section D: Biological Crystallography. 2012;68(Pt 2):154-9.

Endo T. Molecular mechanisms of skeletal muscle development, regeneration, and osteogenic conversion. Bone.80:2-13.

Kim PCW, Mo R, Hui C-c. Murine models of VACTERL syndrome: Role of sonic hedgehog signaling pathway. Journal of Pediatric Surgery. 2001;36(2):381-4.

Weinstein LS, Yu S, Warner DR, Liu J. Endocrine Manifestations of Stimulatory G Protein α-Subunit Mutations and the Role of Genomic Imprinting. Endocrine Reviews. 2001;22(5):675-705.

He X, Zhang L, Chen Y, Remke M, Shih D, Lu F, et al. The G-protein Alpha Subunit Gsα Is A Tumor Suppressor In Sonic Hedgehog-driven Medulloblastoma. Nature medicine. 2014;20(9):1035-42.

Wei Q, Zhang Y, Li Y, Zhang Q, Ling K, Hu J. The BBSome controls IFT assembly and turnaround in cilia. Nat Cell Biol. 2012;14(9):950-7.

Yuan X, Serra RA, Yang S. Function and regulation of primary cilia and intraflagellar transport proteins in the skeleton. Annals of the New York Academy of Sciences. 2015;1335(1):78-99.

Liem KF, Ashe A, He M, Satir P, Moran J, Beier D, et al. The IFT-A complex regulates Shh signaling through cilia structure and membrane protein trafficking. The Journal of Cell Biology. 2012;197(6):789-800.

Haycraft CJ, Banizs B, Aydin-Son Y, Zhang Q, Michaud EJ, Yoder BK. Gli2 and Gli3 Localize to Cilia and Require the Intraflagellar Transport Protein Polaris for Processing and Function. PLoS Genetics. 2005;1(4):e53.

Wang Z, Liu X, Yang B-Z, Gelernter J. The Role and Challenges of Exome Sequencing in Studies of Human Diseases. Frontiers in Genetics. 2013;4:160.

Linderman MD, Brandt T, Edelmann L, Jabado O, Kasai Y, Kornreich R, et al. Analytical validation of whole exome and whole genome sequencing for clinical applications. BMC Medical Genomics. 2014;7:20-.

Castori M. Diabetic Embryopathy: A Developmental Perspective from Fertilization to Adulthood. Molecular Syndromology. 2013;4(1-2):74-86.

Stevenson RE, Hunter AGW. Considering the Embryopathogenesis of VACTERL Association. Molecular Syndromology. 2013;4(1-2):7-15.

Husain M, Dutra-Clarke M, Lemieux B, Wencel M, Solomon BD, Kimonis V. Phenotypic diversity of patients diagnosed with VACTERL association. American Journal of Medical Genetics Part A. 2018;doi:10.1002/ajmg.a.40363.


Refbacks

  • There are currently no refbacks.


http://www.ukm.my http://www.ppukm.ukm.my/
Asia-Pacific Journal of Molecular Medicine (APJMM),
C/o: Level 8, UKM Medical Molecular Biology Institute (UMBI), UKM Medical Centre,
Jalan Ya’acob Latiff, Bandar Tun Razak,
56000 Cheras, Kuala Lumpur, MALAYSIA
Tel: +6 03 9145 6321/9239
Fax: +6 03 9171 7185
Email: hui-min@ppukm.ukm.edu.my