9q22 Deletion--first familial case

Abstract

Background: Only 29 cases of constitutional 9q22 deletions have been published and all have been sporadic. Most associate with Gorlin syndrome or nevoid basal cell carcinoma syndrome (NBCCS, MIM #109400) due to haploinsufficiency of the PTCH1 gene (MIM *601309).

Methods and results: We report two mentally retarded female siblings and their cognitively normal father, all carrying a similar 5.3 Mb microdeletion at 9q22.2q22.32, detected by array CGH (244 K). The deletion does not involve the PTCH1 gene, but instead 30 other gene,s including the ROR2 gene (MIM *602337) which causing both brachydactyly type 1 (MIM #113000) and Robinow syndrome (MIM #268310), and the immunologically active SYK gene (MIM *600085). The deletion in the father was de novo and FISH analysis of blood lymphocytes did not suggest mosaicism. All three patients share similar mild dysmorphic features with downslanting palpebral fissures, narrow, high bridged nose with small nares, long, deeply grooved philtrum, ears with broad helix and uplifted lobuli, and small toenails. All have significant dysarthria and suffer from continuous middle ear and upper respiratory infections. The father also has a funnel chest and unilateral hypoplastic kidney but the daughters have no malformations.

Conclusions: This is the first report of a familial constitutional 9q22 deletion and the first deletion studied by array-CGH which does not involve the PTCH1 gene. The phenotype and penetrance are variable and the deletion found in the cognitively normal normal father poses a challenge in genetic counseling.

Figure 1

Pedigree of the family Patients 1, 2, and 3 all have the deletion of 9q22, as indicated by the star. The healthy mother, sister, and paternal grandparents, do not have the deletion, as indicated by N. The healthy brother was not tested for the deletion. Only patients 1 and 2 (P1, P2) have mental retardation.

Figure 2

Facial features of the patients Facial features of patients 1 to 3 from left to right. Note short neck, slight unilateral ptosis, downward slant of the palpebral fissures, narrow nose, small nares, long philtrum with a narrow deep groove, tented upper lip, ears with broad helices and uplifted lobuli.

Figure 3

Hands and feet of the patients Hands and feet of patients 1 to 3 from left to right. Note that patient 1 has small toe nails II-V on both feet and patient 3 has small and deep-set toenails and his 2^nd finger nails are short.

Figure 4

Array CGH results revealed a deletion at 9q22 in all three patients Array CGH results of patients 1, 2 and 3 revealed a 5.3 Mb deletion in all patients at 9q22.2q22.32. The shaded area indicates the deleted area with an average log2-ration of -1, indicating loss of one copy of the genomic segment.

Figure 5

Overlapping deletions at 9q22 The figure depicts the genomic segment deleted in the patients of this study, as displayed in the UCSC Genome Browser (http://genome.ucsc.edu). Reported deletions of 9q22 that overlap the deletion found in this study are marked by black bars; a) Redon et al. [7], patients 1 and 2, b) Shimojima et al. [5], c.1) Fujii et al. [16] patient G5, c.2) Fujii et al. [16] patient G10, d) Nowakowska et al. [17], e) de Ravel et al. [14], f) Boonen et al. [15], g) Kosaki et al. [28]. Arrows on the black bar indicate that the deletion starts or ends outside the area shown in the picture.