Detailed characterization of, and clinical correlations in, 10 patients with distal deletions of chromosome 9p

Abstract

Purpose: Deletions of distal 9p are associated with trigonocephaly, mental retardation, dysmorphic facial features, cardiac anomalies, and abnormal genitalia. Previous studies identified a proposed critical region for the consensus phenotype in band 9p23, between 11.8 Mb and 16 Mb from the 9p telomere. Here we report 10 new patients with 9p deletions; 9 patients have clinical features consistent with 9pϪ syndrome, but possess terminal deletions smaller than most reported cases, whereas one individual lacks the 9pϪ phenotype and shows a 140-kb interstitial telomeric deletion inherited from his mother. Methods: We combined fluorescence in situ hybridization and microarray analyses to delineate the size of each deletion. Results: The deletion sizes vary from 800 kb to 12.4 Mb in our patients with clinically relevant phenotypes. Clinical evaluation and comparison showed little difference in physical features with regard to the deletion sizes. Severe speech and language impairment were observed in all patients with clinically relevant phenotypes. Conclusion: The smallest deleted region common to our patients who demonstrate a phenotype consistent with 9pϪ is Ͻ2 Mb of 9pter, which contains six known genes.These genes may contribute to some of the cardinal features of 9p deletion syndrome. Genet Med 2008:10 (8): 599 -611. Key Words: 9p deletion, FISH, genotype-phenotype correlation, aCGHThe 9p deletion syndrome is characterized by trigonocephaly, moderate to severe mental retardation, low-set, malformed ears, and dysmorphic facial features, such as up-slanting palpebral fissures and a long philtrum. 1,2 Furthermore, abnormal genitalia are found in some 9pϪ patients who have a chromosomal complement of 46, XY, 3 and hypopigmentation has also been described in two independent studies. 4,5 Since the original report of the syndrome in 1973, 6 over 140 cases of 9p deletion have been documented. The breakpoints occur in bands from 9p22 to 9p24, and the large majority of patients have either terminal deletions or translocations involving another chromosome.Previous studies have delineated the size of 9p deletions in an attempt to develop genotype-phenotype correlations. In one large study, Christ et al., 2 characterized the deletion breakpoints in 24 patients with visible 9p deletions and breakpoints at 9p22 or 9p23. Markers D9S274 (14.2 Mb from the telomere) and D9S286 (8 Mb) were absent in all 24 patients with 9pϪ, whereas D9S285 (16 Mb) was present in a subset of these patients. Thus, the minimal deleted segment in this group of patients included 16 Mb of the 9p terminus. Wagstaff and Hemann 4 described a patient with typical features of 9pϪsyndrome and an interstitial deletion between 8 Mb and 19 Mb of 9p. Based on the data of Wagstaff and Hemann, 4 and from their own data, Christ et al., 2 modified their critical region, i.e., the distal 16 Mb of 9p, and concluded that the critical region for the 9pϪsyndrome lies in an ϳ8-Mb region between D9S285 and D9S286, encompassing bands 9p22-9p23.Among a number of recent publicati...

Case Report Familial balanced translocation leading to an offspring with phenotypic manifestations of 9p syndrome

“…Despite the 9p24.3 deletion being microscopic and does not to include the critical region for the consensus phenotype of 9p syndrome (Swinkels et al, 2008), both cousins showed clinical features of this syndrome including neuropsychomotor delay, hypotonia, trigonocephaly, midface hypoplasia, upslanted palpebral fissures, flat nasal bridge, long philtrum, and small and malformed ears, in agreement with previous descriptions for this syndrome (Alfi et al, 1973;Huret et al, 1988;Calvari et al, 2000;Faas et al, 2007;Barbaro et al, 2009), which is in agreement with Hauge et al (2008), who described that the minimal deleted region shared by their patients with clinically relevant phenotypes includes the first 2 Mb of 9pter, region distal to the previously described critical region 9p22.3. Therefore, it is likely that phenotypic features attributed to the 9p-deletion syndrome may be caused by multiple regions on 9p or other modifying factors in the genome (Hauge et al, 2008). Similarly, Barbaro et al (2009) suggested that the mild cranial dysmorphism in patients with deletions distal to Swinkels' critical region could be caused by either misregulation of the candidate gene for trigonocephaly or the deletion of another gene(s) involved in craniofacial development.…”

A Case with Partial 9p Trisomy and Speech Impairment

“…In another report published by de Pater et al, similar findings with Rossi et al were observed in a partial trisomy 9p case whose mother was carrier of t(9;12) [6]. By another study which was reported by Hauge et al with 10 cases of 9p deletion, it was reported that there were genes associated with language and speech development, neurologic development, so language and speech delay may occur as result of copy number variations in these regions [7]. The results of Rossi et al, de Pater et al and Hauge et al, presented that various regions in p arm of the chromosome 9 carry important genes for the development of language and speech and it was understood that the findings of our case were in concordance with the literature reports.…”

“…Trisomy 9p syndrome is defined to clinically and the most significant finding of it's is craniofacial dysmorphism [5]. In addition, it is reported that neurological problems, speech and language disorders are seen in cases with trisomy 9p [6][7][8].…”

Characterization of deletions at 9p affecting the candidate regions for sex reversal and deletion 9p syndrome by MLPA

“…25 Although additional patients with 9p24 deletions and 46,XY gonadal dysgenesis have been identified, 26 -30 at the same time patients with 9p24 deletions and normal male external genitalia and/or very mild gonadal abnormalities have also been described. 6,31,32 We believe that a DMRT defect is involved in the gonadal dysgenesis phenotype, however a more complicated mechanism should be hypothesized, to explain the variable penetrance. One possibility could be that the DMRT haploinsufficiency together with other genetic defects would lead to gonadal dysgenesis through a dosage threshold effect.…”