A frameshift mutation in the gene for PAX3 in a girl with spina bifida and mild signs of Waardenburg syndrome.

Hol, F.A.; Hamel, B.C.J.; Geurds, M.P.A.; Mullaart, R.A.; Barr, Frederic G.; Macina, Roberto A.; Mariman, E.C.M.

doi:10.1136/jmg.32.1.52

Cited by 53 publications

(31 citation statements)

References 22 publications

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“…In these 1976 CNVs, a total of 2269 genes were affected. Interestingly, a subset of such CNV-altered genes have previously been implicated in neural tube formation; for instance, JMJD5 ('jumonji' domain containing 5 (37), HES1 and HES3 (84); PAX3 (27,85); and both BRD3 and BRD4 (bromodomain-containing 3 and 4) (86).…”

Section: Rare Copy Number Variationsmentioning

confidence: 99%

“…Our groups and others have described NTDs in chromosomal and inherited syndromes, including trisomy 13 (13)(14)(15)(16), trisomy 18 (16 -19), trisomy 21, and 22q11.2 and 13q deletion syndromes (20)(21)(22)(23). In rare cases, syndromes that variably present with NTDs have been associated with a mutation in a single gene (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). Using traditional linkage disequilibrium, patient studies of individual (non-folate-related) candidate genes, including jumonji (JMJ) (37), apolipoprotein E (ApoE), apolipoprotein B (ApoB) (38), bone morphogenetic protein-4 (BMP4) (39), CITED2 (40), transcription factor AP2 (TFAP2) (41), multiple sequence homeobox-2 (MSX2) (41), PAX3 (42) and noggin (NOG) (43), have only rarely succeeded in ascribing attributable risk for NTDs to specific genes.…”

Section: Introductionmentioning

confidence: 99%

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Copy number variation analysis implicates the cell polarity gene glypican 5 as a human spina bifida candidate gene

Bassuk

Muthuswamy

Boland³

et al. 2012

Human Molecular Genetics

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Neural tube defects (NTDs) are common birth defects of complex etiology. Family and population-based studies have confirmed a genetic component to NTDs. However, despite more than three decades of research, the genes involved in human NTDs remain largely unknown. We tested the hypothesis that rare copy number variants (CNVs), especially de novo germline CNVs, are a significant risk factor for NTDs. We used array-based comparative genomic hybridization (aCGH) to identify rare CNVs in 128 Caucasian and 61 Hispanic patients with non-syndromic lumbar-sacral myelomeningocele. We also performed aCGH analysis on the parents of affected individuals with rare CNVs where parental DNA was available (42 sets). Among the eight de novo CNVs that we identified, three generated copy number changes of entire genes. One large heterozygous deletion removed 27 genes, including PAX3, a known spina bifida-associated gene. A second CNV altered genes (PGPD8, ZC3H6) for which little is known regarding function or expression. A third heterozygous deletion removed GPC5 and part of GPC6, genes encoding glypicans. Glypicans are proteoglycans that modulate the activity of morphogens such as Sonic Hedgehog (SHH) and bone morphogenetic proteins (BMPs), both of which have been implicated in NTDs. Additionally, glypicans function in the planar cell polarity (PCP) pathway, and several PCP genes have been associated with NTDs. Here, we show that GPC5 orthologs are expressed in the neural tube, and that inhibiting their expression in frog and fish embryos results in NTDs. These results implicate GPC5 as a gene required for normal neural tube development.

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Section: Rare Copy Number Variationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Copy number variation analysis implicates the cell polarity gene glypican 5 as a human spina bifida candidate gene

Bassuk

Muthuswamy

Boland³

et al. 2012

Human Molecular Genetics

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“…Mutations have been identified and described in the PAX3 gene of individuals with Waardenburg syndrome [87, 88, 89]. Splotch mice homozygous for mutations in the PAX3 gene have spina bifida, exencephaly and other neural crest abnormalities [86, 89, 90]. However, Splotch mice heterozygous for the PAX3 mutation do not typically have an NTD, but do have features resembling Waardenburg syndrome [89].…”

Section: Approaches To Identifying Genes Predisposing To Ntdsmentioning

confidence: 99%

“…Digenic inheritance has been suggested for some cases of myelomeningocele occurrence in patients also showing signs of WS-III [51]. Mutations have been identified and described in the PAX3 gene of individuals with Waardenburg syndrome [87, 88, 89]. Splotch mice homozygous for mutations in the PAX3 gene have spina bifida, exencephaly and other neural crest abnormalities [86, 89, 90].…”

Section: Approaches To Identifying Genes Predisposing To Ntdsmentioning

confidence: 99%

Genetic Studies in Neural Tube Defects

et al. 2000

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Neural tube defects (NTD) are one of the most common birth defects and are caused by both environmental and genetic factors. The approach to identifying the genes predisposing to NTD, through linkage analysis and candidate gene analysis, is reviewed along with characteristics of a large, nationally ascertained cohort of families. Results from specific assessments of p53, PAX3 and MTHFR failed to suggest that these genes play a major role in NTD development in these families. Advances in genetic laboratory and statistical techniques have made this a prime opportunity for investigation into the causes of complex disorders, such as NTD. However, traditional approaches may prove to be challenging due to the difficulty of ascertaining samplable multiplex families.

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“…Heterozygous splotch mice display pigmentary abnormalities while homozygotes die during gestation with spina bifida or exencephaly (Vogan et al, 1993;Auerbach, 1954). Mutations within the human PAX3 gene have been associated with Waardenburg syndrome, a condition occasionally associated with NTDs (Baldwin et al, 1992;Hoth et al, 1993;Hol et al, 1995). In 1995, Hol and colleagues identified a 5-bp deletion in exon 5 of the PAX3 gene in a patient with spina bifida and mild manifestations of Waardenburg syndrome.…”

Section: Introductionmentioning

confidence: 99%

Screening for novel PAX3 polymorphisms and risks of spina bifida

Lü

Zhu

Wen

et al. 2006

Birth Defects Research

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BACKGROUND: PAX3 plays an important role in mammalian embryonic development. Known mutations in PAX3 are etiologically associated with Waardenburg syndrome and syndromic neural tube defects (NTDs). Mutations in the murine homologue, pax3, are responsible for the phenotype of splotch mice, in which nullizygotes are 100% penetrant for NTDs. METHODS: The study sample included 74 infants with spina bifida (cases) and 87 nonmalformed infant controls. The conserved paired-box domain as well as the upstream genomic region of PAX3 were subjected to resequencing and those identified SNPs were evaluated as haplotypes. The associations of haplotypes for selected gene regions and the risks of spina bifida were further studied. RESULTS: Nineteen SNPs were observed; 15 observed in controls had been submitted to the National Center for Biotechnology Information (NCBI) database with allele frequencies. The PAX3 gene variant T-1186C (rs16863657) and its related haplotype, TCTCCGCCC of nine SNPs, were found to be associated with an increased risk of spina bifida, with an OR of 3.5 (95% CI: 1.2-10.0) among Hispanic Whites. CONCLUSIONS: Our analyses indicated that PAX3 SNPs were not strong risk factors for human spina bifida. However, additional follow-up of the PAX3 gene variant T-1186C (rs16863657) and its related haplotype, TCTCCGCCC, may be important in other populations.

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A frameshift mutation in the gene for PAX3 in a girl with spina bifida and mild signs of Waardenburg syndrome.

Cited by 53 publications

References 22 publications

Copy number variation analysis implicates the cell polarity gene glypican 5 as a human spina bifida candidate gene

Copy number variation analysis implicates the cell polarity gene glypican 5 as a human spina bifida candidate gene

Genetic Studies in Neural Tube Defects

Screening for novel PAX3 polymorphisms and risks of spina bifida

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