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Current Molecular Medicine


ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Research Article

Novel GLI3 Mutations in Chinese Patients with Non-syndromic Post-axial Polydactyly

Author(s): X. Chen, L. Yuan, H. Xu, P. Hu, Y. Yang, Y. Guo, Z. Guo and H. Deng*

Volume 19, Issue 3, 2019

Page: [228 - 235] Pages: 8

DOI: 10.2174/1566524019666190308110122

Price: $65


Background: Polydactyly, characterized by supernumerary digits in the upper or lower extremities, is the most common congenital digital abnormalities. It derives from the defective patterning of anteroposterior axis of the developing limb, with various etiology and clinical heterogeneity. The patients with post-axial polydactyly type A (PAPA) have the typical symptom of a well-formed supernumerary digit outside the fifth digit.

Objective: The aim of present study was to identify the causative mutations of two unrelated Han Chinese patients with non-syndromic PAPA.

Methods: Two unrelated Han Chinese patients and 100 ethnicity-matched, unrelated normal controls were recruited for this study. BGISEQ-500 exome sequencing was performed in the two patients, followed by validation in the patients and 100 controls by using Sanger sequencing.

Results: Two mutations in the GLI family zinc finger 3 gene (GLI3), including a frameshift mutation c.3437_3453delTCGAGCAGCCCTGCCCC (p.L1146RfsX95) and a nonsense mutation c.3997C>T (p.Q1333X), were identified in two patients but were absent in the 100 healthy controls.

Conclusion: The two GLI3 mutations, p.L1146RfsX95 and p.Q1333X, may account for non-syndromic PAPA in the two patients, respectively. The findings of this study may expand the mutational spectrum of GLI3-PAPA and provide novel insights into the genetic basis of polydactyly.

Keywords: Polydactyly, the GLI3 gene, mutation, exome sequencing, PAPA, gene.

« Previous
Farrugia MC, Calleja-Agius J. Polydactyly: a review. Neonatal Netw 2016; 35(3): 135-42.
Malik S. Polydactyly: phenotypes, genetics and classification. Clin Genet 2014; 85(3): 203-12.
Guo B, Lee SK, Paksima N. Polydactyly: a review. Bull Hosp Jt Dis 2013; 71(1): 17-23.
Wang Z, Wang J, Li Y, et al. Novel frame-shift mutations of GLI3 gene in non-syndromic postaxial polydactyly patients. Clin Chim Acta 2014; 433: 195-9.
Deng H, Tan T, Yuan L. Advances in the molecular genetics of non-syndromic polydactyly. Expert Rev Mol Med 2015; 17e18
Xiang Y, Bian J, Wang Z, Xu Y, Fu Q. Clinical study of 459 polydactyly cases in China, 2010 to 2014. Congenit Anom (Kyoto) 2016; 56(5): 226-32.
Umair M, Shah K, Alhaddad B, et al. Exome sequencing revealed a splice site variant in the IQCE gene underlying post-axial polydactyly type A restricted to lower limb. Eur J Hum Genet 2017; 25(8): 960-5.
Xiang Y, Jiang L, Wang B, et al. Mutational screening of GLI3, SHH, preZRS, and ZRS in 102 Chinese children with nonsyndromic polydactyly. Dev Dyn 2017; 246(5): 392-402.
Crapster JA, Hudgins L, Chen JK, Gomez-Ospina N. A novel missense variant in the GLI3 zinc finger domain in a family with digital anomalies. Am J Med Genet A 2017; 173(12): 3221-5.
Balk K, Biesecker LG. The clinical atlas of Greig cephalopolysyndactyly syndrome. Am J Med Genet A 2008; 146A(5): 548-57.
Xiang Y, Wang Z, Bian J, Xu Y, Fu Q. Exome sequencing reveals a novel nonsense mutation of GLI3 in a Chinese family with ‘non-syndromic’ pre-axial polydactyly. J Hum Genet 2016; 61(10): 907-10.
Deng S, Xu H, Yuan J, et al. Identification of a novel collagen type IV alpha-4 (COL4A4) mutation in a Chinese family with autosomal dominant Alport syndrome using exome sequencing. Indian J Med Res 2016; 144(2): 200-5.
Huang J, Liang X, Xuan Y, et al. A reference human genome dataset of the BGISEQ-500 sequencer. Gigascience 2017; 6(5): 1-9.
Fang C, Zhong H, Lin Y, et al. Assessment of the cPAS-based BGISEQ-500 platform for metagenomic sequencing. Gigascience 2018; 7(3): 1-8.
Patch AM, Nones K, Kazakoff SH, et al. Germline and somatic variant identification using BGISEQ-500 and HiSeq X Ten whole genome sequencing. PLoS One 2018; 13(1)e0190264
Zheng W, Chen H, Deng X, et al. Identification of a novel mutation in the titin gene in a Chinese family with limb-girdle muscular dystrophy 2J. Mol Neurobiol 2016; 53(8): 5097-102.
Lu Q, Yuan L, Xu H, et al. Identification of a missense mutation in the tyrosinase gene in a Chinese family with oculocutaneous albinism type 1. Mol Med Rep 2017; 15(3): 1426-30.
Zheng Y, Wang HL, Li JK, et al. A novel mutation in PRPF31, causative of autosomal dominant retinitis pigmentosa, using the BGISEQ-500 sequencer. Int J Ophthalmol 2018; 11(1): 31-5.
Zheng W, Zhang J, Deng X, et al. Identification of a premature termination mutation in the proline-rich transmembrane protein 2 gene in a Chinese family with febrile seizures. Mol Neurobiol 2016; 53(2): 835-41.
Deng H, Tan T, He Q, et al. Identification of a missense HOXD13 mutation in a Chinese family with syndactyly type I-c using exome sequencing. Mol Med Rep 2017; 16(1): 473-7.
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17(5): 405-24.
Hu P, Wu S, Yuan L, et al. Compound heterozygous POMT1 mutations in a Chinese family with autosomal recessive muscular dystrophy‐dystroglycanopathy C1. J Cell Mol Med 2017; 21(7): 1388-93.
Al-Qattan MM, Shamseldin HE, Salih MA, Alkuraya FS. GLI3-related polydactyly: a review. Clin Genet 2017; 92(5): 457-66.
Verma PK, El-Harouni A. Review of literature: genes related to postaxial polydactyly. Front Pediatr 2015; 3: 8.
Kang S, Rosenberg M, Ko VD, Biesecker LG. Gene structure and allelic expression assay of the human GLI3 gene. Hum Genet 1997; 101(2): 154-7.
Patel R, Singh CB, Bhattacharya V, Singh SK, Ali A. GLI3 mutations in syndromic and non-syndromic polydactyly in two Indian families. Congenit Anom (Kyoto) 2016; 56(2): 94-7.
Jamsheer A, Sowińska A, Trzeciak T, et al. Expanded mutational spectrum of the GLI3 gene substantiates genotype-phenotype correlations. J Appl Genet 2012; 53(4): 415-22.
Kalff-Suske M, Wild A, Topp J, et al. Point mutations through-out the GLI3 gene cause Greig cephalopolysyndactyly syndrome. Hum Mol Genet 1999; 8(9): 1769-77.
Wen X, Lai CK, Evangelista M, et al. Kinetics of hedgehog-dependent full-length Gli3 accumulation in primary cilia and subsequent degradation. Mol Cell Biol 2010; 30(8): 1910-22.
Biesecker LG. What you can learn from one gene: GLI3. J Med Genet 2006; 43(6): 465-9.
Niida Y, Inoue M, Ozaki M, Takase E. Human malformation syndromes of defective GLI: opposite phenotypes of 2q14.2 (GLI2) and 7p14.2 (GLI3) microdeletions and a GLIA/R balance model. Cytogenet Genome Res 2017; 153(2): 56-65.
Naruse I, Ueta E, Sumino Y, Ogawa M, Ishikiriyama S. Birth defects caused by mutations in human GLI3 and mouse Gli3 genes. Congenit Anom (Kyoto) 2010; 50(1): 1-7.
Lopez-Rios J, Speziale D, Robay D, et al. GLI3 constrains digit number by controlling both progenitor proliferation and BMP-dependent exit to chondrogenesis. Dev Cell 2012; 22(4): 837-48.
Fujioka H, Ariga T, Horiuchi K, et al. Molecular analysis of non-syndromic preaxial polydactyly: preaxial polydactyly type-IV and preaxial polydactyly type-I. Clin Genet 2005; 67(5): 429-33.
Furniss D, Critchley P, Giele H, Wilkie AO. Nonsense-mediated decay and the molecular pathogenesis of mutations in SALL1 and GLI3. Am J Med Genet A 2007; 143A(24): 3150-60.
Johnston JJ, Olivos-Glander I, Killoran C, et al. Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: robust phenotype prediction from the type and position of GLI3 mutations. Am J Hum Genet 2005; 76(4): 609-22.
Debeer P, Peeters H, Driess S, et al. Variable phenotype in Greig cephalopolysyndactyly syndrome: clinical and radiological findings in 4 independent families and 3 sporadic cases with identified GLI3 mutations. Am J Med Genet A 2003; 120A(1): 49-58.
Volodarsky M, Langer Y, Birk OS. A novel GLI3 mutation affecting the zinc finger domain leads to preaxial-postaxial polydactyly-syndactyly complex. BMC Med Genet 2014; 15: 110.
Radhakrishna U, Bornholdt D, Scott HS, et al. The phenotypic spectrum of GLI3 morphopathies includes autosomal dominant preaxial polydactyly type-IV and postaxial polydactyly type-A/B; No phenotype prediction from the position of GLI3 mutations. Am J Hum Genet 1999; 65(3): 645-55.
Baraitser M, Winter RM, Brett EM. Greig cephalopolysyndactyly: report of 13 affected individuals in three families. Clin Genet 1983; 24(4): 257-65.
Gu S, Yang H, Qi Y, et al. Novel ATPase Cu(2+) transporting beta polypeptide mutations in Chinese families with Wilson’s disease. PLoS One 2013; 8(7)e66526
Démurger F, Ichkou A, Mougou-Zerelli S, et al. New insights into genotype-phenotype correlation for GLI3 mutations. Eur J Hum Genet 2015; 23(1): 92-102.
McPherson E, Cold C. Severe Pallister-Hall syndrome with persistent urogenital sinus, renal agenesis, imperforate anus, bilateral hypothalamic hamartomas, and severe skeletal anomalies. Am J Med Genet A 2013; 161A(10): 2666-9.
Johnston JJ, Sapp JC, Turner JT, et al. Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations. Hum Mutat 2010; 31(10): 1142-54.
Freese K, Driess S, Bornholdt D, et al. Gene symbol: GLI3. Disease: Pallister-Hall syndrome. Hum Genet 2003; 112(1): 103.
Narumi Y, Kosho T, Tsuruta G, et al. Genital abnormalities in Pallister-Hall syndrome: Report of two patients and review of the literature. Am J Med Genet A 2010; 152A(12): 3143-7.
Ng D, Johnston JJ, Turner JT, et al. Gonadal mosaicism in severe Pallister-Hall syndrome. Am J Med Genet A 2004; 124A(3): 296-302.
Turner C, Killoran C, Thomas NS, et al. Human genetic disease caused by de novo mitochondrial-nuclear DNA transfer. Hum Genet 2003; 112(3): 303-9.
Galasso C, Scirè G, Fabbri F, et al. Long-term treatment with growth hormone improves final height in a patient with Pallister-Hall syndrome. Am J Med Genet 2001; 99(2): 128-31.
Kang S, Graham JM Jr, Olney AH, Biesecker LG. GLI3 frameshift mutations cause autosomal dominant Pallister-Hall syndrome. Nat Genet 1997; 15(3): 266-8.
Kalff-Suske M, Paparidis Z, Bornholdt D, et al. Gene symbol: GLI3. Disease: Pallister-Hall syndrome. Hum Genet 2004; 114(4): 403.
Killoran CE, Abbott M, McKusick VA, Biesecker LG. Overlap of PIV syndrome, VACTERL and Pallister-Hall syndrome: clinical and molecular analysis. Clin Genet 2000; 58(1): 28-30.
Biesecker LG, Graham JM Jr. Pallister-Hall syndrome. J Med Genet 1996; 33(7): 585-9.
Kang S, Allen J, Graham JM Jr, et al. Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome. J Med Genet 1997; 34(6): 441-6.
Saitsu H, Sonoda M, Higashijima T, et al. Somatic mutations in GLI3 and OFD1 involved in sonic hedgehog signaling cause hypothalamic hamartoma. Ann Clin Transl Neurol 2016; 3(5): 356-65.
Shin SH, Kogerman P, Lindstrom E, Toftgard R, Biesecker LG. GLI3 mutations in human disorders mimic Drosophila cubitus interruptus protein functions and localization. Proc Natl Acad Sci USA 1999; 96(6): 2880-4.

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