Digeorge Syndrome/velocardiofacial Syndrome Complex 2

The DiGeorge syndrome (DGS; 188400) and velocardiofacial syndrome (VCFS; 192430) may present many clinical problems, including cardiac defects, hypoparathyroidism, T-cell immunodeficiency, and facial dysmorphism. They are frequently associated with deletions within 22q11.2 (accounting in part for the designation CATCH22), but a number of cases have no detectable molecular defect of this region. Daw et al. (1996) stated that a number of single case reports with deletions of 10p suggested genetic heterogeneity of DGS. They compared the regions of hemizygosity in 4 patients with terminal deletions of 10p (1 patient with hypoparathyroidism and 3 with DGS) and 1 patient with VCFS and a large interstitial deletion. Fluorescence in situ hybridization (FISH) analysis demonstrated that these patients had overlapping deletions at the 10p13/10p14 boundary. A YAC contig spanning the shortest region of deletion overlap (SRO) was assembled and allowed the size of the SRO to be approximated to 2 Mb. As with deletions of 22q11, phenotypes varied considerably between affected patients. Daw et al. (1996) concluded that the results strongly support the hypothesis that haploinsufficiency of a gene or genes within 10p (DGS2 locus) can cause the DGS/VCFS spectrum of malformations.

Schuffenhauer et al. (1998) performed FISH and PCR analyses in 12 patients with 10p deletions, 9 of them with features of DGS, and in a familial translocation 10p;14q associated with midline defects. The critical DGS2 region was defined by 2 DGS patients and mapped within a 1-cM interval including D10S547 and D10S585. The other 7 DGS patients were hemizygous for both loci. The breakpoint of the reciprocal translocation 10p;14q mapped at a distance of at least 12 cM distal to the critical DGS2 region. Interstitial and terminal deletions described in these patients were in the range of 10 to 50 cM and enabled the tentative mapping of loci for ptosis and hearing loss, features that are not part of the DGS clinical spectrum.

Bartsch et al. (1999) sought evidence for chromosomal microdeletions at 10p14-p13 in patients with the DGS/VCFS phenotype. In a series of patients studied in Dresden, all with normal karyotypes, 22q11 microdeletions were found in 12, and no patient was found to have a deletion of the critical region of 10p. Another series studied in Munich included 22 patients with an unequivocal diagnosis of DGS and no detectable deletion of 22q11. These patients had at least 2 of the 3 major DGS signs: conotruncal heart defect, T-cell deficiency, and hypocalcemia/hypoparathyroidism. FISH analysis showed a dizygous pattern in all of the patients, indicating no deletions at the 10p critical region. On the basis of this study, Bartsch et al. (1999) suggested that FISH service laboratories need not implement a screen for 10p microdeletions among DGS/VCFS patients.

Lichtner et al. (2000) reported clinical and molecular deletion analysis of a patient described by Hasegawa et al. (1997) and a new case, both with the HDR phenotype: hypoparathyroidism, deafness, and renal dysplasia (146255). They were found to have partial monosomy for 10p due to terminal deletions with breakpoints between D10S585 and D10S1720. By comparison with data previously published on patients with DiGeorge/velocardiofacial syndrome associated with 10p monosomy, Lichtner et al. (2000) concluded that this is a contiguous gene syndrome. Hemizygosity for a proximal region can cause cardiac defects and T cell deficiency; hemizygosity for a more distal region can cause hypoparathyroidism, sensorineural deafness, and renal dysplasia.

Villanueva et al. (2002) determined that a genomic sequence including the nebulette gene (NEBL; 605491) was heterozygously deleted in cell lines derived from 2 female DGS2 patients with the proximal deletion of chromosome 10p14-p13, which is associated with cardiac and craniofacial abnormalities. One patient showed a cardiac defect, immune deficiency, cleft palate, facial dysmorphia, and developmental delay. The other showed microcephaly, microphthalmia, and hypotelorism. The NEBL gene was not deleted in cell lines derived from 2 patients with the more distal deletion of 10p14-p13, which is associated with HDR syndrome.