Reply to Pragliola et al.

To the Editor:In their letter to the editor, Pragliola et al. (1997 [in this issue])xGoosecoid-like sequences and the smallest region of deletion overlap in DiGeorge and velocardiofacial syndromes. Pragliola, A, Jurecic, V, Chau, CK, Philip, N, and Baldini, A. Am J Hum Genet. 1997; 61: 1456–1458Abstract | Full Text | Full Text PDF | PubMed | Scopus (2)See all ReferencesPragliola et al. (1997 [in this issue]) have noted that in our manuscript (Gottlieb et al. 1997xThe DiGeorge syndrome minimal critical region contains a Goosecoid-like (GSCL) homeobox gene that is expressed early in human development. Gottlieb, S, Emanuel, BS, Driscoll, DA, Sellinger, B, Wang, Z, Roe, B, and Budarf, ML. Am J Hum Genet. 1997; 60: 1194–1201PubMedSee all ReferencesGottlieb et al. 1997) we assume that the GSCL gene is deleted in patient G (Levy et al. 1995xInterstitial 22q11 microdeletion excluding the ADU breakpoint in a patient with DiGeorge syndrome. Levy, A, Demczuk, S, Aurias, A, Depetris, D, Mattei, M, and Philip, N. Hum Mol Genet. 1995; 4: 2417–2419Crossref | PubMed | Scopus (52)See all ReferencesLevy et al. 1995), a patient with DiGeorge syndrome who has an atypical deletion boundary in chromosome 22. Their FISH analysis indicates that GSCL in fact is not deleted in this patient. Since patient G was unavailable to us for analysis, we were unable to verify the deletion status of GSCL. We based our estimate of the deletion boundary in patient G on the information provided in a previous paper published by the same senior investigator (Rizzu et al. 1996xCloning and comparative mapping of a gene from the commonly deleted region of DiGeorge and velocardiofacial syndromes conserved in C. elegans. Rizzu, P, Lindsay, EA, Taylor, C, O'Donnell, H, Levy, A, Scambler, P, and Baldini, A. Mamm Genome. 1996; 7: 639–643Crossref | PubMedSee all ReferencesRizzu et al. 1996): in an article by Rizzu et al. (1996)xCloning and comparative mapping of a gene from the commonly deleted region of DiGeorge and velocardiofacial syndromes conserved in C. elegans. Rizzu, P, Lindsay, EA, Taylor, C, O'Donnell, H, Levy, A, Scambler, P, and Baldini, A. Mamm Genome. 1996; 7: 639–643Crossref | PubMedSee all ReferencesRizzu et al. (1996), the deletion endpoint of patient G is described as 100–150 kb telomeric to the ADU/VDU breakpoint, “close to the 5′ end” of the DGSI/ES2 gene. Since we had the complete sequence of the ∼120-kb region extending from the ADU breakpoint to GSCL, and since we knew that the 5′ end of GSCL is ∼6 kb from DGSI/ES2, we felt that it was reasonable to assume that GSCL was disrupted or deleted in this patient. Pragliola et al. indicate in their letter that, although the deletion endpoint in patient G is within a fosmid containing GSCL, the breakpoint is distal to the 5′ end of the gene. However, as they note—and as we pointed out in our paper—a deletion or translocation breakpoint can easily affect the expression of genes in the vicinity. Therefore, the expression of GSCL could still be affected in patient G. Moreover, as we stated in our paper, the definition of a minimal critical region does not exclude a role for genes outside the region. Thus, although we consider GSCL to be a strong candidate gene for some of the abnormalities associated with DiGeorge syndrome/velocardiofacial syndrome, we have not excluded the possibility that genes outside the regions that we have called the “DiGeorge minimal critical region,” or the smallest region of deletion, play a role in the disease phenotype. We appreciate the additional data from Pragliola et al., clarifying the location of the proximal breakpoint in patient G.