However, despite decades of research and hundreds of studies, we do not yet understand the genetic contribution to human NTDs. Mouse studies also show that NTDs may be caused by multigenic influences, as revealed by the differing severities produced when genetic defects are combined ( 7). Studies in mice have described over 200 ( 5) monogenic mutant lines with NTDs and have shown that the genes involved play multiple distinct roles in neurulation ( 1, 6). While environmental factors have been implicated in NTDs, these factors alone fail to explain most cases. These congenital disorders occur with a frequency of 1/1000–1/5000 worldwide and therefore, are among the most common birth defects (together with congenital heart abnormalities and craniofacial anomalies) ( 1– 4). Neural tube defects (NTDs) arise from a failed or disordered closure of the neural tube during embryogenesis. These results implicate GPC5 as a gene required for normal neural tube development. 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. Additionally, glypicans function in the planar cell polarity (PCP) pathway, and several PCP genes have been associated with NTDs. 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. A third heterozygous deletion removed GPC5 and part of GPC6, genes encoding glypicans. A second CNV altered genes ( PGPD8, ZC3H6) for which little is known regarding function or expression. One large heterozygous deletion removed 27 genes, including PAX3, a known spina bifida-associated gene. Among the eight de novo CNVs that we identified, three generated copy number changes of entire genes. We also performed aCGH analysis on the parents of affected individuals with rare CNVs where parental DNA was available (42 sets). 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 tested the hypothesis that rare copy number variants (CNVs), especially de novo germline CNVs, are a significant risk factor for NTDs. However, despite more than three decades of research, the genes involved in human NTDs remain largely unknown. Family and population-based studies have confirmed a genetic component to NTDs. Neural tube defects (NTDs) are common birth defects of complex etiology.
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