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Is the genetic basis of DiGeorge syndrome in HAND?

Nature Genetics volume 21, pages 246–247 (1999)Cite this article

In the late '60s, Angelo DiGeorge described a syndrome characterized by aberrant development of the thymus and parathyroid1. The phenotypic spectrum of DiGeorge syndrome (DGS) has since been extended to include many organs and clinical spheres, including growth retardation, psychiatric disorders and congenital heart disease; the latter being the most dramatic feature and most common cause of death. It has been proposed that the cardiac anomalies arise from defects in the neural crest mesenchyme in pharyngeal arches 3 and 4 (Refs 2,3). Genetically speaking, however, DGS definition has remained ill defined; none of the more than 20 genes isolated from a deleted region described in the early '90s has been shown to be responsible for the disease4. In February, however, Hiroyuki Yamagishi and colleagues reported data in Science that narrow the candidate gene pool dramatically5.

They show that UFD1L, which is deleted in the majority of people with DGS (ref. 6), is down regulated in mice lacking Hand2 (also known as dHand), a gene encoding a bHLH transcription factor essential for normal heart development. Hand2–/– mice die by embryonic day 11 (E11) because of severe abnormalities of the right ventricle and aortic arch arteries. Perhaps most relevant to the DGS phenotype, Hand2–/– mice at E9.5 show hypoplastic pharyngeal arches with extensive apoptosis7,8. Yamagishi et al. also describe a DGS patient with a 20-kb heterozygous de novo deletion, which physically disrupts CDC45L (Refs 9,10) and UFD1L. They propose that the deletion causes the disease in this patient and that the loss of function of one or both of these genes is the genetic basis of the phenotype.

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Figure 1: Expression of Ufd1l in the fourth aortic arch artery at embryonic day 9.5.
Figure 2: A model mechanism.

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  1. Department of Molecular and Human Genetics, Baylor College of Medicine, 1 Baylor Plaza, Houston, 77030, Texas, USA

    Antonio Baldini

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  1. Antonio Baldini
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Baldini, A. Is the genetic basis of DiGeorge syndrome in HAND?. Nat Genet 21, 246–247 (1999). https://doi.org/10.1038/6750

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