Molecular characterization of deletion breakpoints in adults with 22q11 deletion syndrome

Abstract

22q11 Deletion syndrome (22q11DS) is a common microdeletion syndrome with variable expression, including congenital and later onset conditions such as schizophrenia. Most studies indicate that expression does not appear to be related to length of the deletion but there is limited information on the endpoints of even the common deletion breakpoint regions in adults. We used a real-time quantitative PCR (qPCR) approach to fine map 22q11.2 deletions in 44 adults with 22q11DS, 22 with schizophrenia (SZ; 12 M, 10 F; mean age 35.7 SD 8.0 years) and 22 with no history of psychosis (NP; 8 M, 14 F; mean age 27.1 SD 8.6 years). QPCR data were consistent with clinical FISH results using the TUPLE1 or N25 probes. Two subjects (one SZ, one NP) negative for clinical FISH had atypical 22q11.2 deletions confirmed by FISH using the RP11-138C22 probe. Most (n = 34; 18 SZ, 16 NP) subjects shared a common 3 Mb hemizygous 22q11.2 deletion. However, eight subjects showed breakpoint variability: a more telomeric proximal breakpoint (n = 2), or more centromeric (n = 3) or more telomeric distal breakpoint (n = 3). One NP subject had a proximal nested 1.4 Mb deletion. COMT and TBX1 were deleted in all 44 subjects, and PRODH in 40 subjects (19 SZ, 21 NP). The results delineate proximal and distal breakpoint variants in 22q11DS. Neither deletion extent nor PRODH haploinsufficiency appeared to explain the clinical expression of schizophrenia in the present study. Further studies are needed to elucidate the molecular basis of schizophrenia and clinical heterogeneity in 22q11DS.

Schizophrenia and 22q11.2 deletion syndrome

“…Proximally, the deletion did not include the PRODH gene in three individuals [4]. In contrast, the telomeric 22q11.2 deletion region was not included in case reports of other deletions with schizophrenia [4]. Thus, no evidence indicates that the length or position of the 22q11.2 deletion predicts schizophrenia expression in 22qDS.…”

“…For example, 22 adults with schizophrenia in one study had 22q11.2 deletions that included most of the telomeric half of the 3-Mb common deletion. Proximally, the deletion did not include the PRODH gene in three individuals [4]. In contrast, the telomeric 22q11.2 deletion region was not included in case reports of other deletions with schizophrenia [4].…”

“…The molecular cytogenetic method, fluorescence in situ hybridization (FISH), which detects the commonly associated 22q11.2 deletions, became available to clinical laboratories in the mid-1990s. Some variability exists in the length and genomic extent of the 22q11.2 deletions, which are most commonly 3 million bases (Mb) long, but most are clinically detectable using FISH and a standard probe (eg, TUPLE1) from the typically deleted region [4]. The deletion is most commonly a spontaneous (de novo) mutation that occurs during gametogenesis (egg or sperm formation).…”

“…The relatively few studies reporting on the extent of 22q11.2 deletions in 22qDS and schizophrenia are consistent with this (Table 2). A typical 3-Mb hemizygous 22q11.2 deletion is most commonly associated with schizophrenia [4]. However, deletions of various extents have been reported, and no region of 22q11.2 hemizygosity is shared by all individuals with 22qDS and schizophrenia [4] (Table 2).…”

“…A typical 3-Mb hemizygous 22q11.2 deletion is most commonly associated with schizophrenia [4]. However, deletions of various extents have been reported, and no region of 22q11.2 hemizygosity is shared by all individuals with 22qDS and schizophrenia [4] (Table 2). For example, 22 adults with schizophrenia in one study had 22q11.2 deletions that included most of the telomeric half of the 3-Mb common deletion.…”