Spectrum of sequence variation in the FANCG gene

An International Fanconi Anemia Registry (IFAR) study

Arleen D. Auerbach, Jason Greenbaum, Kanan Pujara, Sat Dev Batish, Marco A. Bitencourt, Indira Kokemohr, Hildegard Schneider, Stephan Lobitz, Ricardo Pasquini, Philip F. Giampietro, Helmut Hanenberg, Orna Levran

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive syndrome associated with chromosomal instability, hypersensitivity to DNA cross-linking agents, and predisposition to malignancy. The gene for FA complementation group G (FANCG) was the third FA gene to be cloned, and was found to be identical with human XRCC9, which maps to 9p13. The cDNA is predicted to encode a polypeptide of 622 amino acids, with no sequence similarities to any other known protein or motifs that could point to a molecular function for FANCG/XRCC9. We used single strand conformational polymorphism analysis (SSCP) to screen genomic DNA from a panel of 307 racially and ethnically diverse unrelated FA patients from the International Fanconi Anemia Registry (IFAR) for variants in FANCG. Twenty-seven abnormal SSCP patterns were found; 18 of these variants appear to be pathogenic mutations while nine are likely to be nonpathogenic polymorphisms. Direct sequencing of genomic DNA from seven FA-G probands with one mutant allele not detected in the SSCP study and three additional probands assigned to the FA-G complementation group by retroviral correction with FANCG resulted in the detection of nine additional pathogenic mutations and two common SNPs. Conditions for rapid screening for these mutations by DHPLC for use in a clinical laboratory setting were established. The most common FANCG mutations in the IFAR population were: IVS8-2A>G (seven Portuguese-Brazilian probands), IVS11+1G>C (seven French-Acadian probands), 1794_1803del10 (seven European probands), and IVS3+1G>C (five Korean or Japanese probands). Our data suggest that the Portuguese-Brazilian, French-Acadian, and Korean/Japanese mutations were likely to have been present in a founding member of each of these populations.

Original languageEnglish (US)
Pages (from-to)158-168
Number of pages11
JournalHuman Mutation
Volume21
Issue number2
DOIs
StatePublished - 2003
Externally publishedYes

Fingerprint

Fanconi Anemia
Registries
Genes
Mutation
Chromosomal Instability
Amino Acid Motifs
DNA
DNA Sequence Analysis
Population
Single Nucleotide Polymorphism
Hypersensitivity
Complementary DNA
Alleles
Amino Acids
Peptides

Keywords

  • Cryptic splice site
  • DHPLC
  • FANCG
  • Fanconi anemia
  • French-Acadian
  • Mutation detection
  • Portuguese-Brazilian
  • SSCP

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Auerbach, A. D., Greenbaum, J., Pujara, K., Batish, S. D., Bitencourt, M. A., Kokemohr, I., ... Levran, O. (2003). Spectrum of sequence variation in the FANCG gene: An International Fanconi Anemia Registry (IFAR) study. Human Mutation, 21(2), 158-168. https://doi.org/10.1002/humu.10166

Spectrum of sequence variation in the FANCG gene : An International Fanconi Anemia Registry (IFAR) study. / Auerbach, Arleen D.; Greenbaum, Jason; Pujara, Kanan; Batish, Sat Dev; Bitencourt, Marco A.; Kokemohr, Indira; Schneider, Hildegard; Lobitz, Stephan; Pasquini, Ricardo; Giampietro, Philip F.; Hanenberg, Helmut; Levran, Orna.

In: Human Mutation, Vol. 21, No. 2, 2003, p. 158-168.

Research output: Contribution to journalArticle

Auerbach, AD, Greenbaum, J, Pujara, K, Batish, SD, Bitencourt, MA, Kokemohr, I, Schneider, H, Lobitz, S, Pasquini, R, Giampietro, PF, Hanenberg, H & Levran, O 2003, 'Spectrum of sequence variation in the FANCG gene: An International Fanconi Anemia Registry (IFAR) study', Human Mutation, vol. 21, no. 2, pp. 158-168. https://doi.org/10.1002/humu.10166
Auerbach AD, Greenbaum J, Pujara K, Batish SD, Bitencourt MA, Kokemohr I et al. Spectrum of sequence variation in the FANCG gene: An International Fanconi Anemia Registry (IFAR) study. Human Mutation. 2003;21(2):158-168. https://doi.org/10.1002/humu.10166
Auerbach, Arleen D. ; Greenbaum, Jason ; Pujara, Kanan ; Batish, Sat Dev ; Bitencourt, Marco A. ; Kokemohr, Indira ; Schneider, Hildegard ; Lobitz, Stephan ; Pasquini, Ricardo ; Giampietro, Philip F. ; Hanenberg, Helmut ; Levran, Orna. / Spectrum of sequence variation in the FANCG gene : An International Fanconi Anemia Registry (IFAR) study. In: Human Mutation. 2003 ; Vol. 21, No. 2. pp. 158-168.
@article{f1b387a34e064ede8046ad040c37a3e3,
title = "Spectrum of sequence variation in the FANCG gene: An International Fanconi Anemia Registry (IFAR) study",
abstract = "Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive syndrome associated with chromosomal instability, hypersensitivity to DNA cross-linking agents, and predisposition to malignancy. The gene for FA complementation group G (FANCG) was the third FA gene to be cloned, and was found to be identical with human XRCC9, which maps to 9p13. The cDNA is predicted to encode a polypeptide of 622 amino acids, with no sequence similarities to any other known protein or motifs that could point to a molecular function for FANCG/XRCC9. We used single strand conformational polymorphism analysis (SSCP) to screen genomic DNA from a panel of 307 racially and ethnically diverse unrelated FA patients from the International Fanconi Anemia Registry (IFAR) for variants in FANCG. Twenty-seven abnormal SSCP patterns were found; 18 of these variants appear to be pathogenic mutations while nine are likely to be nonpathogenic polymorphisms. Direct sequencing of genomic DNA from seven FA-G probands with one mutant allele not detected in the SSCP study and three additional probands assigned to the FA-G complementation group by retroviral correction with FANCG resulted in the detection of nine additional pathogenic mutations and two common SNPs. Conditions for rapid screening for these mutations by DHPLC for use in a clinical laboratory setting were established. The most common FANCG mutations in the IFAR population were: IVS8-2A>G (seven Portuguese-Brazilian probands), IVS11+1G>C (seven French-Acadian probands), 1794_1803del10 (seven European probands), and IVS3+1G>C (five Korean or Japanese probands). Our data suggest that the Portuguese-Brazilian, French-Acadian, and Korean/Japanese mutations were likely to have been present in a founding member of each of these populations.",
keywords = "Cryptic splice site, DHPLC, FANCG, Fanconi anemia, French-Acadian, Mutation detection, Portuguese-Brazilian, SSCP",
author = "Auerbach, {Arleen D.} and Jason Greenbaum and Kanan Pujara and Batish, {Sat Dev} and Bitencourt, {Marco A.} and Indira Kokemohr and Hildegard Schneider and Stephan Lobitz and Ricardo Pasquini and Giampietro, {Philip F.} and Helmut Hanenberg and Orna Levran",
year = "2003",
doi = "10.1002/humu.10166",
language = "English (US)",
volume = "21",
pages = "158--168",
journal = "Human Mutation",
issn = "1059-7794",
publisher = "Wiley-Liss Inc.",
number = "2",

}

TY - JOUR

T1 - Spectrum of sequence variation in the FANCG gene

T2 - An International Fanconi Anemia Registry (IFAR) study

AU - Auerbach, Arleen D.

AU - Greenbaum, Jason

AU - Pujara, Kanan

AU - Batish, Sat Dev

AU - Bitencourt, Marco A.

AU - Kokemohr, Indira

AU - Schneider, Hildegard

AU - Lobitz, Stephan

AU - Pasquini, Ricardo

AU - Giampietro, Philip F.

AU - Hanenberg, Helmut

AU - Levran, Orna

PY - 2003

Y1 - 2003

N2 - Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive syndrome associated with chromosomal instability, hypersensitivity to DNA cross-linking agents, and predisposition to malignancy. The gene for FA complementation group G (FANCG) was the third FA gene to be cloned, and was found to be identical with human XRCC9, which maps to 9p13. The cDNA is predicted to encode a polypeptide of 622 amino acids, with no sequence similarities to any other known protein or motifs that could point to a molecular function for FANCG/XRCC9. We used single strand conformational polymorphism analysis (SSCP) to screen genomic DNA from a panel of 307 racially and ethnically diverse unrelated FA patients from the International Fanconi Anemia Registry (IFAR) for variants in FANCG. Twenty-seven abnormal SSCP patterns were found; 18 of these variants appear to be pathogenic mutations while nine are likely to be nonpathogenic polymorphisms. Direct sequencing of genomic DNA from seven FA-G probands with one mutant allele not detected in the SSCP study and three additional probands assigned to the FA-G complementation group by retroviral correction with FANCG resulted in the detection of nine additional pathogenic mutations and two common SNPs. Conditions for rapid screening for these mutations by DHPLC for use in a clinical laboratory setting were established. The most common FANCG mutations in the IFAR population were: IVS8-2A>G (seven Portuguese-Brazilian probands), IVS11+1G>C (seven French-Acadian probands), 1794_1803del10 (seven European probands), and IVS3+1G>C (five Korean or Japanese probands). Our data suggest that the Portuguese-Brazilian, French-Acadian, and Korean/Japanese mutations were likely to have been present in a founding member of each of these populations.

AB - Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive syndrome associated with chromosomal instability, hypersensitivity to DNA cross-linking agents, and predisposition to malignancy. The gene for FA complementation group G (FANCG) was the third FA gene to be cloned, and was found to be identical with human XRCC9, which maps to 9p13. The cDNA is predicted to encode a polypeptide of 622 amino acids, with no sequence similarities to any other known protein or motifs that could point to a molecular function for FANCG/XRCC9. We used single strand conformational polymorphism analysis (SSCP) to screen genomic DNA from a panel of 307 racially and ethnically diverse unrelated FA patients from the International Fanconi Anemia Registry (IFAR) for variants in FANCG. Twenty-seven abnormal SSCP patterns were found; 18 of these variants appear to be pathogenic mutations while nine are likely to be nonpathogenic polymorphisms. Direct sequencing of genomic DNA from seven FA-G probands with one mutant allele not detected in the SSCP study and three additional probands assigned to the FA-G complementation group by retroviral correction with FANCG resulted in the detection of nine additional pathogenic mutations and two common SNPs. Conditions for rapid screening for these mutations by DHPLC for use in a clinical laboratory setting were established. The most common FANCG mutations in the IFAR population were: IVS8-2A>G (seven Portuguese-Brazilian probands), IVS11+1G>C (seven French-Acadian probands), 1794_1803del10 (seven European probands), and IVS3+1G>C (five Korean or Japanese probands). Our data suggest that the Portuguese-Brazilian, French-Acadian, and Korean/Japanese mutations were likely to have been present in a founding member of each of these populations.

KW - Cryptic splice site

KW - DHPLC

KW - FANCG

KW - Fanconi anemia

KW - French-Acadian

KW - Mutation detection

KW - Portuguese-Brazilian

KW - SSCP

UR - http://www.scopus.com/inward/record.url?scp=0037265710&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037265710&partnerID=8YFLogxK

U2 - 10.1002/humu.10166

DO - 10.1002/humu.10166

M3 - Article

VL - 21

SP - 158

EP - 168

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 2

ER -