Inverted triplication of 7q11.22 embedded within the 7q11.21q11.23 duplication segment in a child with stigmata dysplastica, developmental and speech delay Hovnik T.1, Kovač J.1, Bertok S.2, Avbelj-Stafanija M.2, Volk M.3, Lovrečič L.3, Neubauer D.4, Battelino T.2 Center for Medical Genetics, University Children’s Hospital, UMC, Ljubljana, Slovenia Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children’s Hospital, UMC, Ljubljana, Slovenia 3 Clinical Institute of medical Genetic, UMC, Ljubljana, Slovenia 4 Department of Child, Adolescent & Developmental Neurology, University Children’s Hospital, UMC, Ljubljana, Slovenia Corresponding Author: dr. Tinka Hovnik (
[email protected]) Authors declare that we have no conflicts of interest in the authorship or publication of this contribution 1
2
BACKGROUND:
The q-arm of human chromosome 7 harbours many copy number variants (CNV) with known pathogenic significance. Chromosome 7q11.23 duplication syndrome (OMIM#609757) is a multisystem developmental disorder with mild craniofacial anomalies and increased incidence of congenital anomalies. On the other hand, Williams-Beuren syndrome (WBS; OMIM#194050) is caused by ~ 1.8-Mb hemizygous deletion on chromosome 7q11.23. WBS triplication syndrome with similar but more severe clinical features has been also described. Figure 1: The result of aCGH indicating complex rearrangement of chromosome 7. The triplicated segment of 7q11.22 is embedded into the duplication of 7q11.21q11.23. The triplicated region contains gene AUTS2, which could contribute to the speech development.
CASE PRESENTATION:
We present a 3-years-old boy with developmental and severe speech delay, dysmorphic signs, bilateral cryptorhidism and hypoplasic corpus callosum. Cytogenetic and molecular analysis revealed a complex de novo chromosomal rearrangement which we characterize as inverted triplication of 7q11.22 segment embedded within larger 7q11.21q11.23 duplication
RESULTS:
A
Although chromosomal imbalances are the major cause of developmental delay, large de novo CNVs are relatively rare events. We have identified a novel complex rearrangement on chromosome 7, duplication with embedded inverted triplication also known as DUP-TRP/INV-DUP structure. Triplication of segment 7q11.22 is probably generated by long range inverted repeats which still need to be identified.
B.2
Figure 2: The result of FISH detecting the triplication of 7q11.22 region (A & B.1). The figure A shows the result of combined FISH for regions 7q11.21 (orange), 7q11.22 (green) and 7q11.23 (orange). The figure B.1 shows the results of FISH on very long chromosomes using only two probes for the region 7q11.21 (orange) and 7q11.22 (green) where the triplication of 7q11.22 region is clearly observed. Additionally, the rearrangement is shown as observed on the G-banded karyotype (figure B.2).
Molecular characterization by array-CGH revealed a 1.93-Mb duplication of segment 7q11.21, 5.27-Mb triplication of segment 7q11.21q11.22 and 1.33-Mb duplication of segment 7q11.23. Further molecular cytogenetic investigation was performed with multiple combinations of specific FISH probes. Metaphase and interphase FISH confirmed the location of triplication 7q11.22 segment within the 7q11.21q11.23 duplication. Additional FISH analysis revealed that triplicated 7q11.22 segment on derivative chromosome 7 was inverted. Parental cytogenetic analysis demonstrated de novo origin of this complex chromosomal rearrangement.
CONCLUSION:
B.1
A
I.
II. Centromere
CEP 7
CEP 7
409J21
409J21
CEP 7
409J21
409J21
CEP 7
CEP 7
CEP 7
409J21
409J21
Figure 3: The result of FISH inversion detection (A). Following the data from the literature, the FISH using distal (RP11-409J21; BlueGnome) and proximal (CEP 7, Agilent) probes for the region 7q11.22 was performed to confirm the presence of the inverted segment. Two different colour patterns were possible describing two possible scenarios: The inversion is not present, if the colour pattern oscillated between red and green (I.). On the other hand the presence of inversion is confirmed if the colour pattern resembles scenario II.
LITERATURE:
Carvalho CM, Ramocki MB, Pehlivan D, Franco LM, Gonzaga-Jauregui C, Fang P, McCall A, Pivnick EK, Hines-Dowell S, Seaver LH, Friehling L, Lee S, Smith R, Del Gaudio D, Withers M, Liu P, Cheung SW, Belmont JW, Zoghbi HY, Hastings PJ, Lupski JR. Inverted genomic segments and complex triplication rearrangements are mediated by inverted repeats in the human genome.Nat Genet. 2011 Oct 2;43(11):1074-81. Dittwald P, Gambin T, Gonzaga-Jauregui C, Carvalho CM, Lupski JR, Stankiewicz P, Gambin A. Inverted low-copy repeats and genome instability--a genome-wide analysis. Hum Mutat. 2013 Jan;34(1):210-20.
