A 600 kb triplication in the cat eye syndrome critical region causes anorectal, renal and preauricular anomalies in a three-generation family

Abstract

Cat eye syndrome (CES) is caused by a gain of the proximal part of chromosome 22. Usually, a supernumerary marker chromosome is present, containing two extra copies of the chromosome 22q11.1q11.21 region. More sporadically, the gain is present intrachromosomally. The critical region for CES is currently estimated to be about 2.1 Mb and to contain at least 14 RefSeq genes. Gain of this region may cause ocular coloboma, preauricular, anorectal, urogenital and congenital heart malformations. We describe a family in which a 600 kb intrachromosomal triplication is present in at least three generations. The copy number alteration was detected using MLPA and further characterized with interphase and metaphase FISH and SNP-array. The amplified fragment is located in the distal part of the CES region. The family members show anal atresia and preauricular tags or pits, matching part of the phenotype of this syndrome. This finding suggests that amplification of the genes CECR2, SLC25A18 and ATP6V1E1, mapping within the critical region for CES, may be responsible for anorectal, renal and preauricular anomalies in patients with CES.

Incomplete penetrance, variable expressivity, or dosage insensitivity in four families with directly transmitted unbalanced chromosome abnormalities

“…This large deletion covers most of a region that is likely to be dosage insensitive despite containing the CECR6 gene which is thought to be haploinsufficient. The deletions in Family 4 and that of Damatova et al () imply that the CESCR can be reduced to the ∼1 Mb between CECR2 and the LCR22A repeat (Figure b) which contains the ∼600 kb directly transmitted triplication found by Knijnenburg et al () in a three generation family with many of the features of CES. These results support the idea that CES can result from the increased dosage of just the three genes CECR2 , SLC25A18 , and ATP6V1E1 (Figure b).…”

“…(a) An idiogram of chromosome 13 with 63–76.1 Mb from bands 13q21.31‐q22.1 in the oblong box; solid black horizontal bars and vertical dashed lines represent the minimum extent of the interstitial duplication in Family 3 and other relevant duplications and deletions from the literature with arrows indicating those that extend beyond the screenshot. (b) An idiogram of chromosome 22 with the 2.8 Mb euchromatic segment of band 22q11.21 from 16 to 18.8 Mb in the oblong box; the solid black horizontal bars and vertical dashed lines illustrate the minimum extent of the interstitial deletion in Family 4 and a similar deletion from the literature (Damatova et al, ); solid black horizontal bars and vertical dashed lines underneath the screenshot represent the minimum extent of the interstitial deletion in patient 648 from the DECIPHER database, the 600 kb interstitial duplication in the family of Knijnenburg et al (), the triplo‐ and tetra‐dosage insensitive region identified by Liehr () and the CES type 1 interval from the centromere to the chromosome 22 Low Copy Repeat A (LCR22A)…”

A de novo sSMC(22) Characterized by High-Resolution Arrays in a Girl with Cat-Eye Syndrome without Coloboma

“…This fact suggests that other unknown factors beside CECR2 amplification are required to generate a coloboma. In line, a 600-kb intrachromosomal triplication spanning only CECR2 , SLC25A18 and ATP6V1E1 genes was described in patients with 3 CES traits but neither coloboma nor mental disability [Knijnenburg et al, 2012].…”

Hemifacial microsomia in cat‐eye syndrome: 22q11.1–q11.21 as candidate loci for facial symmetry

“…Recently, a 600 kb intrachromosomal 22q11.1q11.21 triplication involving six of the genes affected in our patient, CECR2 , SLC25A18 , ATP6V1E1 , BCL2L13 , BID , and MICAL3 , was reported in family members of at least three generations with features overlapping with CES: anal atresia and/or preauricular tags or pits. Interestingly, the maternal granduncle of the proposita was diagnosed with Goldenhar syndrome with deafness, facial asymmetry, microtia, and absence of one auditory canal, but unfortunately he declined genetics testing [Knijnenburg et al, ]. Mutations in the gene Cecr2 trigger misregulation of mesenchymal or ectodermal transcription factors and the protein contributes to neurogenesis and inner ear development [Fairbridge et al, ; Dawe et al, ].…”

“…The co‐localization of the breakpoints in these different syndromes, plus the presence of low‐copy repeats (LCR‐22) adjacent to each interval, suggested the existence of several specific regions of chromosomal instability in 22q11 that are involved in the production of both deletions and duplications [McTaggart et al, ; McDermid and Morrow, ]. Furthermore, patients with intrachromosomal duplication and triplication of 22q11.1–q11.2 (three and four copies total, respectively), have overlapping features of CES ranging from eye coloboma to anal atresia to craniofacial defects [Reiss et al, ; Knoll et al, ; Lindsay et al, ; Meins et al, ; Knijnenburg et al, ], indicating that partial trisomy is sufficient to cause the major and minor features of CES.…”