A new genomic duplication syndrome complementary to the velocardiofacial (22q11 deletion) syndrome

Abstract

Fluorescence in situ hybridization (FISH) analysis can reveal undetected chromosomal rearrangements. We report a patient with cleft palate, hydronephrosis, and minor dysmorphic features, including low-set posteriorly rotated ears, down-slanting palpebral fissures, mandibular micrognathia, and brachymesophalangia. Routine chromosome analysis identified no abnormality of chromosome 22; FISH analysis with the TUPLE1 probe disclosed an interstitial duplication of 22q11.2. FISH analysis did not reveal the duplication on the initial testing of metaphase chromosomes, although, on review, the area was brighter on one chromosome in each metaphase spread. FISH analysis of interphase cells showed three TUPLE1-probe sites with two chromosome-specific identification probes in each cell. Family history showed two older full siblings, a brother with behavior problems, oppositional defiant disorder, and learning problems and a sister with hydronephrosis and mild delays. The father and both siblings had similar facial features, and all three had the same interstitial duplication of the TUPLE1 probe. This family illustrates the novel complementary duplication syndrome of the velocardiofacial syndrome, which adds it to the expanding list of genomic deletion/duplication syndromes. The laboratory results further show the utility and need for careful analysis of interphase cells even in samples where good quality metaphases are available.

Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes

“…Importantly, in patients for whom parental samples were available we observed a high frequency of familial duplications (two of the five probands with common ϳ3-Mb and proximal "nested" ϳ1.5-Mb duplications, and both of the probands with smaller distal atypical duplications for whom parental samples were available), consistent with what has been observed by others. 9,23,24 These results emphasize the importance of investigating other family members for the microduplication.…”

“…There is some degree of overlap with features seen in VCFS/DGS but to a lesser extent than the first reports of 22q11.2 microduplications indicated, which were limited by ascertainment bias. 9,23,24 Our study avoids this bias to the extent that clinical samples were received for a variety of indications (including developmental delay, dysmorphic features, congenital anomalies, autism, and others), although it is not a truly population-based survey. Four of the five probands with ϳ3-Mb and ϳ1.5-Mb proximal nested microduplications in our cohort were referred for testing because of developmental or speech delay and dysmorphic features.…”

“…3 Additional case reports led to the further characterization of the duplication 22q11.2 syndrome as a new genomic disorder that is complementary to, but distinct from, the 22q11.2 deletion syndrome. 9,[23][24][25] Molecular analyses have revealed that individuals with 22q11.2 microduplication typically carry a ϳ3-Mb duplication that is the reciprocal of the common ϳ3-Mb deletion found in DGS/VCFS, although larger duplications of ϳ4-Mb and ϳ6-Mb that include the DGS/VCFS region were also reported. 9 The phenotypes previously associated with microduplications of 22q11.2 include cardiovascular anomalies, velopharyngeal insufficiency with or without cleft palate, hearing loss, growth and developmental delay, learning disabilities, behavioral problems, and various dysmorphic features.…”

“…9 The phenotypes previously associated with microduplications of 22q11.2 include cardiovascular anomalies, velopharyngeal insufficiency with or without cleft palate, hearing loss, growth and developmental delay, learning disabilities, behavioral problems, and various dysmorphic features. Based on the current literature, the phenotypes in patients with microduplication of 22q11.2 may have partial overlap with DGS/ VCFS 9,23,24 ; however, this degree of overlap is almost certainly the result of ascertainment bias, because the patients thus far reported to harbor 22q11.2 microduplications were generally selected on the basis of clinical features that prompted referral to rule out VCFS/DGS microdeletion. 9,25 Despite the frequency with which 22q11.2 microdeletion occurs, only a small number of patients with microduplication of this region have been described to date; this may be, in part, owing to a highly variable and mild phenotype such that many individuals with microduplications within 22q11.2 may not undergo testing.…”

Orofacial clefting: recent insights into a complex trait

“…Genetic variants that result in a phenotype including clefting and that are found segregating with a genomic rearrangement in multiple members are best represented by the 22q deletion syndrome. Duplications of this same region have been associated with cleft palate [32], suggesting that genome-wide searches using comparative genomic hybridization (CGH; see Glossary), quantitative-PCR (see Glossary) or allele-loss might reveal additional clefting loci.…”