Holly Napret, Dean Grimmond, Artur Darmanian and Dale Wright
1Sydney Genome Diagnostics, The Children’s Hospital at Westmead, Hawkesbury Rd, Westmead NSW 2145
Background: The 22q11.2 region is complex with well-defined segmental duplications, or low copy repeats (LCR), which predispose to genomic instability. Eight LCRs (A-H) can be found in the region. Heterogeneous copy number abnormalities (CNA) and structural rearrangements arise typically via non-homologous allelic recombination (NHAR). Four centromeric LCRs (A-D) are associated with a proximal deletion and Velocardiofacial/Di George syndrome (VCFS/DGS), whereas telomeric LCRs (D-H) are associated with various distal microdeletions and reciprocal microduplications. We describe a family with a distal 22q11.2 deletion.
Methodology: A male presented with preauricular skin tags, short stature and abnormal behaviour. The sister was overweight with ADHD. His uncle had moderate development delay. The mother and grandmother appeared phenotypically normal. All had an 8x60K ISCA microarray (Agilent Technologies), analysed using the ADM-2 algorithm with CNA called based on 5 consecutive probes (Cytogenomics v22.214.171.124). UCSC genome browser [hg19] was used to evaluate Development Delay CNAs and segmental duplications >1kb.
Results: All individuals showed a heterozygous deletion [~0.59Mb] within chromosome 22 bands q11.22q11.23, extending from coordinates 23.01 to 2365Mb. This included five genes, from MIR650 to part of BCR, of which only BCR is OMIM-disease listed. However, the uncle showed an additional deletion within [2.85Mb] chromosome 14 band q24.2. Chromosome 22 LCRs flanked the deletion.
Conclusion: The inherited 22q11.2 deletion here is rare but found enriched in Development Delay cases vs. controls. It is flanked by LCRs with 90-98% sequence homology, suggesting a mechanism of NHAR. The function of genes involved is poorly understood. Clinical features of 22q11.2 distal deletion described include development delay, microcephaly, low birthweight, short stature; including preaurical skin tags. The deletion may contribute to the uncle’s phenotype but more likely explained by the 14q24.2 deletion. The different clinical features and asymptomatic carriers in this family are consistent with a variably expressed and penetrant phenotype.
Holly Napret is a trainee Hospital Scientist who is currently learning chromosome microarray