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Expanded mutational spectrum of the GLI3 gene substantiates genotype-phenotype correlations.
J Appl Genet. 2012 Nov; 53(4):415-22.JA

Abstract

Greig cephalopolysyndactyly syndrome (GCPS) and isolated preaxial polydactyly type IV (PPD-IV) are rare autosomal dominant disorders, both caused by mutations in the GLI3 gene. GCPS is mainly characterised by craniofacial abnormalities (macrocephaly/prominent forehead, hypertelorism) and limb malformations, such as PPD-IV, syndactyly and postaxial polydactyly type A or B (PAPA/B). Mutations in the GLI3 gene can also lead to Pallister-Hall syndrome (PHS) and isolated PAPA/B. In this study, we investigated 16 unrelated probands with the clinical diagnosis of GCPS/PPD-IV and found GLI3 mutations in 12 (75%) of them (nine familial and three sporadic cases). We also performed a detailed clinical evaluation of all 12 GLI3-positive families, with a total of 27 patients. The hallmark triad of GCPS (preaxial polydactyly, macrocephaly/prominent forehead, hypertelorism) was present in 14 cases (52%), whereas at least one typical dysmorphic feature was manifested in 17 patients (63%). Upon sequencing of the GLI3 gene, we demonstrated eight novel and two previously reported heterozygous point mutations. We also performed multiplex ligation-dependent probe amplification (MLPA) to screen for intragenic copy number changes and identified heterozygous deletions in the two remaining cases (16.7%). Our findings fully support previous genotype-phenotype correlations, showing that exonic deletions, missense mutations, as well as truncating variants localised out of the middle third of the GLI3 gene result in GCPS/PPD-IV and not PHS. Additionally, our study shows that intragenic GLI3 deletions may account for a significant proportion of GCPS/PPD-IV causative mutations. Therefore, we propose that MLPA or quantitative polymerase chain reaction (qPCR) should be implemented into routine molecular diagnostic of the GLI3 gene.

Authors+Show Affiliations

Department of Medical Genetics, University of Medical Sciences, ul. Grunwaldzka 55 paw. 15, 60-352 Poznań, Poland. jamsheer@wp.plNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22903559

Citation

Jamsheer, Aleksander, et al. "Expanded Mutational Spectrum of the GLI3 Gene Substantiates Genotype-phenotype Correlations." Journal of Applied Genetics, vol. 53, no. 4, 2012, pp. 415-22.
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.
Jamsheer, A., Sowińska, A., Trzeciak, T., Jamsheer-Bratkowska, M., Geppert, A., & Latos-Bieleńska, A. (2012). Expanded mutational spectrum of the GLI3 gene substantiates genotype-phenotype correlations. Journal of Applied Genetics, 53(4), 415-22. https://doi.org/10.1007/s13353-012-0109-x
Jamsheer A, et al. Expanded Mutational Spectrum of the GLI3 Gene Substantiates Genotype-phenotype Correlations. J Appl Genet. 2012;53(4):415-22. PubMed PMID: 22903559.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Expanded mutational spectrum of the GLI3 gene substantiates genotype-phenotype correlations. AU - Jamsheer,Aleksander, AU - Sowińska,Anna, AU - Trzeciak,Tomasz, AU - Jamsheer-Bratkowska,Małgorzata, AU - Geppert,Anita, AU - Latos-Bieleńska,Anna, Y1 - 2012/08/18/ PY - 2012/06/11/received PY - 2012/07/30/accepted PY - 2012/07/18/revised PY - 2012/8/21/entrez PY - 2012/8/21/pubmed PY - 2013/3/23/medline SP - 415 EP - 22 JF - Journal of applied genetics JO - J Appl Genet VL - 53 IS - 4 N2 - Greig cephalopolysyndactyly syndrome (GCPS) and isolated preaxial polydactyly type IV (PPD-IV) are rare autosomal dominant disorders, both caused by mutations in the GLI3 gene. GCPS is mainly characterised by craniofacial abnormalities (macrocephaly/prominent forehead, hypertelorism) and limb malformations, such as PPD-IV, syndactyly and postaxial polydactyly type A or B (PAPA/B). Mutations in the GLI3 gene can also lead to Pallister-Hall syndrome (PHS) and isolated PAPA/B. In this study, we investigated 16 unrelated probands with the clinical diagnosis of GCPS/PPD-IV and found GLI3 mutations in 12 (75%) of them (nine familial and three sporadic cases). We also performed a detailed clinical evaluation of all 12 GLI3-positive families, with a total of 27 patients. The hallmark triad of GCPS (preaxial polydactyly, macrocephaly/prominent forehead, hypertelorism) was present in 14 cases (52%), whereas at least one typical dysmorphic feature was manifested in 17 patients (63%). Upon sequencing of the GLI3 gene, we demonstrated eight novel and two previously reported heterozygous point mutations. We also performed multiplex ligation-dependent probe amplification (MLPA) to screen for intragenic copy number changes and identified heterozygous deletions in the two remaining cases (16.7%). Our findings fully support previous genotype-phenotype correlations, showing that exonic deletions, missense mutations, as well as truncating variants localised out of the middle third of the GLI3 gene result in GCPS/PPD-IV and not PHS. Additionally, our study shows that intragenic GLI3 deletions may account for a significant proportion of GCPS/PPD-IV causative mutations. Therefore, we propose that MLPA or quantitative polymerase chain reaction (qPCR) should be implemented into routine molecular diagnostic of the GLI3 gene. SN - 2190-3883 UR - https://www.unboundmedicine.com/medline/citation/22903559/Expanded_mutational_spectrum_of_the_GLI3_gene_substantiates_genotype_phenotype_correlations_ L2 - https://dx.doi.org/10.1007/s13353-012-0109-x DB - PRIME DP - Unbound Medicine ER -