DiGeorge (DGS, MIM 188400) and velocardiofacial (VCFS, MIM 192430) syndromes may present many clinical problems including cardiac defects, hypoparathyroidism, T-cell immunodeficiency and facial dysmorphism. They are frequently associated with deletions within 22q11.2, but a number of cases have no detectable molecular defect of this region. A number of single case reports with deletions of 10p suggest genetic heterogeneity of DGS. Here we compare the regions of hemizygosity in four patients with terminal deletions of 10p (one patient diagnosed as having hypoparathyroidism and three as DGS) and one patient with a large interstitial deletion (diagnosed as VCFS). Fluorescence in situ hybridization (FISH) analysis demonstrates that these patients have overlapping deletions at the 10p13/10p14 boundary. A YAC contig spanning the shortest region of deletion overlap (SRO) has been assembled, and allows the size of SRO to be approximated to 2 Mb. As with deletions of 22q11, phenotypes vary considerably between affected patients. These results strongly support the hypothesis that haploinsufficiency of a gene or genes within 10p (the DGSII locus) can cause the DGS/VCFS spectrum of malformation.

A wide spectrum of birth defects are caused by deletions of the DiGeorge syndrome critical region (DGCR) at human chromosome 22q11. Over one hundred such deletions have now been examined and a minimally deleted region of 300kb defined. Within these sequences we have identified a gene expressed during human and murine embryogenesis. The gene, named TUPLE1, and its murine homologue, encodes a protein containing repeated motifs similar to the WD40 domains found in the beta-transducin/enhancer of split (TLE) family. The TUPLE1 product has several features typical of transcriptional control proteins and in particular has homology with the yeast Tup1 transcriptional regulator. We propose that haploinsufficiency for TUPLE1 is at least partly responsible for DiGeorge syndrome and related abnormalities.

Deletions within human chromosome 22q11 cause a wide variety of birth defects including the DiGeorge syndrome and velo-cardio-facial (Shprintzen) syndrome. Despite the positional cloning of several genes from the critical region, it is still not possible to state whether the phenotype is secondary to haploinsufficiency of one or more than one gene. In embryological studies phenocopies of these abnormalities are produced by a variety of actions which disrupt the contribution made by the cranial and cardiac neural crest to development. The TUPLE1/HIRA gene is related to WD40 domain transcriptional regulators and maps within the DiGeorge critical region. We have cloned the chick homologue of HIRA and conducted in situ expression analysis in early chick embryos. Hira is expressed in the developing neural plate, the neural tube, neural crest and the mesenchyme of the head and branchial arch structures. HIRA may therefore have a role in the haploinsufficiency syndromes caused by deletion of 22q11.

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We describe 2 patients with a partial DiGeorge syndrome (facial dysmorphism, hypoparathyroidism, renal agenesis, mental retardation) and a rearrangement of chromosome 10p. The first patient carries a complex chromosomal rearrangement, with a reciprocal insertional translocation between the short arm of chromosome 10 and the long arm of chromosome 8, with karyotype 46, XY ins(8;10) (8pter 8q13::10p15-->10p14::8q24.1-->8qter) ins(10:8) (10pter--> 10p15::8q24.1-->8q13::10p14-->10qter). The karyotype of the second patient shows a terminal deletion of the short arm of chromosome 10. In both patients, the breakpoints on chromosome 10p reside outside the previously determined DiGeorge critical region II (DGCRII). This is in agreement with previous reports of patients with a terminal deletion of 10p with breakpoints distal to the DGCRII and renal malformations/hypoparathyroidism, and thus adds to evidence that these features may be caused by haploinsufficiency of one or more genes distal to the DGCRII.