A partial trisomy 1q patient with a deletion 1q22 and an insertion 1(q42q44) into 1q22

We report on a patient whose karyotype was defined to be 46,XY,der(1). ish del (q22) ins (q22q44q42) dup (q42q44), by combining G banding, aCGH, and FISH studies. As a child the patient had distinctive features, with a broad flattened nasal bridge, slight hypertelorism, downward slanted eyes, bushy eyebrows, divergent strabismus, trigonocephaly with a prominent forehead, short stubby nose, triangular mouth, high palate, long prominent philtrum and hypognathia (Fig. 1a). Birth weight is not known. He started to walk late and speech was delayed and difficult to understand. As a grown-up he has a long narrow face, is friendly and pleasant with a slurred pronunciation, functioning at about IQ 50–60. He has low hemoglobin with high transferrin values, but no known heart defects. Otherwise he is healthy with normal stature. He is now 53 years old, he lives in an institution and he is sociable. G-banding detected an abnormal chromosome 1 (Fig. 1b), which apparently contained a duplicated region in 1q24. aCGH (44K oligo array, Agilent Technologies, Santa Clara, CA; data analysis by BlueFuse, BlueGnome, Cambridge, UK) detected three aberrations: (1) 1p36.13 deletion (chr1:16686959–16794038 bp), (2) 1q22 deletion (chr1:152396245–152647439 bp), (3) 1q42–q44 duplication (chr1:221209415–245422360 bp) (supporting information Table I may be found in the online version of this article). The positions of the aberrations refer to the NCBI Build 35. The deletion in 1p36.13 is a well known copy number variation, detected in several independent studies (http://projects.tcag.variation), and it does not overlap with the region previously reported to be involved in the 1p36 microdeletion syndrome [Heilstedt et al., 2003]. This deletion was not verified by FISH because we assume that it does not contribute to the pathological phenotype in our patient. The 250 kb deletion in chromosome 1q22 was confirmed by FISH using the BAC clones RP11-586I23 and RP11-243J18 which gave signal on chromosome 1, but not on der(1) (Fig. 2a,b and Table I). This region includes six genes: one gene encoding a hypothetical protein in addition to the genes; ASH1L, MSTO1, YY1AP1, DAP3, and GON4L. Because of the limited information about the function of these genes, we are not able to hypothesize the contribution of this deletion to the clinical phenotype of the patient. The third aberration detected by aCGH is a 23 Mb duplication. Even though the G-banding result indicated a duplication in chromosome 1q24, the duplication detected by aCGH maps in chromosome 1q42.1! q44. FISH experiments revealed that (1) the duplicated segment (from RP11-55A11 to RP11-103M14, see Table I) is inserted in 1q in a proximal region and (2) it has inverted orientation compared to its original location (Fig. 2c). We then hypothesized that the duplicated 1q42.1! q44-segment is inserted in 1q22, in connection with the deletion. The FISH results confirmed this hypothesis, since the two clones flanking the deletion (RP11-313J15 and RP11-1141E12) are located at the borders of the duplicated region in this patient (Fig. 2d,e). No close relatives are available for investigations, and there is no family history suggesting the presence of inherited chromosome abnormalities. The 1q22 deletion has a nearly perfect overlap with the SD1q22 region [Kuryshev et al., 2006], consisting of two segmental duplications head-tail oriented, spanning about 240 kb originated from an Alu-Alu mediated recombination about 37 million of years ago. The region contains approximately 40% Alu sequences, which is an enrichment compared to the genome average of 10.6% [Human genome consortium, 2001]. The abundance of Alu elements could facilitate the double crossover event resulting in the der(1) detected