Mutations of UFD1L Are Not Responsible for the Majority of Cases of DiGeorge Syndrome/Velocardiofacial Syndrome without Deletions within Chromosome 22q11

Abstract

Mutations of UFD1L Are Not Responsible for the Majority of Cases of DiGeorge Syndrome/ Velocardiofacial Syndrome without Deletions within Chromosome 22q11 To the Editor: Deletions of chromosome 22q11 are associated with a wide spectrum of congenital malformation, encompassed by the acronym "CATCH22" (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia on chromosome 22), including velocardiofacial syndrome (VCFS; MIM 192430), DiGeorge syndrome (DGS; MIM 188400), and conotruncal-anomaly face (Emanuel et al. 1998). The major anomalies include outflow-tract congenital heart defects, hypoplasia of the parathyroids and thymus, craniofacial dysmorphism, and learning/behavioral problems (Ryan et al. 1997). Many of these are thought to be due to a defective neural-crest contribution during development. The DiGeorge chromosomal region (DGCR) is entirely cloned (Carlson et al. 1997) and sequenced, and several genes have been reported mapping to the region. Mutation screens of genes mapping to the proximal end of this region, termed the "minimal DiGeorge chromosomal region" (MDGCR; Gong et al. 1996), have been negative (Wadey et al. 1995; Gong et al. 1997; Gottlieb et al. 1997; Lindsay et al. 1998). Attention therefore has turned to the regions adjacent and distal to the MDGCR. Recently, the gene UFD1L was proposed as the major gene haploinsufficient in this group of syndromes (Yamagishi et al. 1999). UFD1L is downstream of dHAND, a gene known to be involved in control of the development of structures affected in DGS, and Ufd1l is expressed in the branchial arches, frontonasal mass, and outflow tract. In addition, a single patient has been reported with a de novo deletion affecting UFD1L and the neighboring gene, CDC45L2 (Yamagishi et al. 1999). CDC45 is required for initiation of DNA replication in yeast, and CDC45 mutants are nonviable. However, CDC45L2 expression is not altered in d-HAND Ϫ/Ϫ embryos. On the basis of these findings, Yamagishi and colleagues concluded that UFD1L hap-conditions can be obtained at the e-mail addresses that follow:

Prenatal diagnosis of the 22q11.2 deletion syndrome

“…41 At the present time, no laboratory has identified point mutations in any other gene in the region in nondeleted patients with DGS/VCFS. 42 The etiology of congenital heart defects (CHD) is heterogeneous; in addition to the 22q11.2 deletion, other causes must be considered, including aneuploidy, other single gene defects, maternal disease states such as diabetes, and exposure to teratogens. The detection rate for the 22q11.2 deletion in a fetus with a conotruncal cardiac defect depends on the type of lesion and the accuracy of the fetal echocardiogram.…”

Molecular determinants of neural crest migration

“…UFD1l is expressed in the pharyngeal pouches and fourth arch artery and is a downstream target of dHAND, a transcription factor required for normal development of the out¯ow tract [Yamagishi et al, 1999]. Although one patient has been found to have a deletion of UDF1l and its neighbor gene CDC45L, extensive mutation screening of these genes has not shown an association of this gene with most cases of DiGeorge syndrome [Saitta et al, 1999;Wadey et al, 1999]. Furthermore, UDF1l /À mice do not have cardiac defects, suggesting that disruption of this gene alone does not cause the 22q11 DS phenotype [Lindsay et al, 1999].…”

Recent advances in the understanding of genetic causes of congenital heart defects

“…Analysis of 21 patients with DGS/VCFS without 22q11 deletions detected by D22S75 revealed one individual with a lesion deleting exons 1-3 of UFD1L, leading the authors to conclude that UFD1L might be the DGS/VCFS gene (47). Analysis of 42 additional DGS/VCFS patients lacking 22q11 deletions by a consortium of laboratories, however, failed to reveal any deletions or point mutations of UFD1L (48). Thus, the apparent involvement of UFD1L in a pathway relevant to neural crest development makes it an excellent positional candidate for DGS/VCFS, but additional studies are needed prior to concluding whether or not it plays a central role in disease pathogenesis.…”