Mosaic 22q13 deletions: evidence for concurrent mosaic segmental isodisomy and gene conversion

Abstract

Although 22q terminal deletions are well documented, very few patients with mosaicism have been reported. We describe two new cases with mosaic 22q13.2-qter deletion, detected by karyotype analysis, showing the neurological phenotype of 22q13.3 deletion syndrome. Case 1 represents an exceptional case of mosaicism for maternal 22q13.2-qter deletion (45% of cells) and 22q13.2-qter paternal segmental isodisomy (55% of cells). This complex situation was suspected because cytogenetic, FISH and array-CGH analyses showed the presence of an 8.8 Mb mosaic 22q13.2-qter deletion, whereas microsatellite marker analysis was consistent with maternal deletion without any evidence of mosaic deletion. Molecular analysis led to the definition of very close, but not coincident, deletion and uniparental disomy (UPD) break points. Furthermore, we demonstrated that the segmental UPD arose by gene conversion in the same region. In Case 2, mosaicism for a paternal 8.9 Mb 22q13.2-qter deletion (73% of cells) was detected. In both patients, the level of mosaicism was also verified in saliva samples. We propose possible causative mechanisms for both rearrangements. Although the size of the deletions was quite similar, the phenotype was more severe in Case 2 than in Case 1. As maternal UPD 22 has not been generally associated with any defects and as the size of the deletion is very similar in the two cases, phenotype severity is likely to depend entirely on the degree of mosaicism in each individual.

Analysis of relative gene dosage and expression differences of the paralogs RABL2A and RABL2B by Pyrosequencing

“…Although clearly indicating a RABL2B deficiency, the value is different from the expected ratio of 0.5. Whether this reflects a mosaic 22q13 deletion known to occur (Bonaglia et al, 2009) remains to be elucidated. Data are summarized in Table 1.…”

Phelan McDermid Syndrome

“…PMS is typically caused by the loss of the distal segment of the long arm of chromosome 22, as the consequence of terminal or interstitial (subtelomeric) deletions, balanced or unbalanced translocations, ring chromosomes (the chromosome arms are fused together to form a ring), and mosaicisms of these anomalies (Bonaglia et al, 2009; Bonaglia et al, 2011; Dhar et al, 2010; Jeffries et al, 2005; Luciani et al, 2003; Phelan and McDermid, 2012; Sarasua et al, 2014a; Soorya et al, 2013; Wilson et al, 2003). Microscopically visible rearrangements, including large deletions, translocations and ring chromosomes, can be detected with G-banding karyotyping (Bonaglia et al, 2011; Soorya et al, 2013), while cryptic translocations can be revealed using fluorescence in situ hybridization (FISH) (Bonaglia et al, 2001).…”

Association between deletion size and important phenotypes expands the genomic region of interest in Phelan-McDermid syndrome (22q13 deletion syndrome)

“…Simple terminal deletions account for approximately 75% of PMS cases 10. The other cases have been comprised of translocations in the 22q13 region,2 11–13 ring chromosome 221 2 14–16 and mosaics 17 18…”