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Mol Genet Genomic Med. 2019 Feb;7(2):e00507. doi: 10.1002/mgg3.507. Epub 2019 Jan 4.

Atypical nested 22q11.2 duplications between LCR22B and LCR22D are associated with neurodevelopmental phenotypes including autism spectrum disorder with incomplete penetrance.

Author information

1
Diagnostic Genomics, PathWest Laboratory Medicine, Perth, Western Australia, Australia.
2
School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia.
3
The Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia.
4
Centre for Medical Research, University of Western Australia, Nedlands, Western Australia, Australia.
5
Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia.
6
Children's Neuroscience Service, Princess Margaret Hospital, Subiaco, Western Australia, Australia.
7
School of Paediatrics and Child Health, University of Western Australia, Perth, Western Australia, Australia.
8
Rural Health West, Esperance, Western Australia, Australia.
9
State Child Development Centre, West Perth, Western Australia, Australia.
10
Lockridge Child Development Centre, Lockridge, Western Australia, Australia.
11
School of Medicine, Western Sydney University, Penrith South DC, New South Wales, Australia.
12
Genetic Services of Western Australia, Perth, Western Australia, Australia.
13
Department of Health, Office of Population Health Genomics, Public Health and Clinical Services Division, Perth, Western Australia, Australia.
14
Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia, Australia.
15
Western Australian Register of Developmental Anomalies, Perth, Western Australia, Australia.
16
Spatial Sciences, Science and Engineering, Curtin University, Perth, Western Australia, Australia.
17
Curtin Health Innovation Research Institute and Sarich Neuroscience Institute, Curtin University, Crawley, Western Australia, Australia.

Abstract

BACKGROUND:

Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR22A to LCR22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region.

METHODS:

We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR22B and LCR22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR22A and LCR22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues.

RESULTS:

We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder (ASD), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR22B and LCR22D to identify nine genes (ZNF74, KLHL22, MED15, PI4KA, SERPIND1, CRKL, AIFM3, SLC7A4, and BCRP2) with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI4KA is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects.

CONCLUSION:

Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI4KA to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype-phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling.

KEYWORDS:

22q11.2; LCR22B to LCR22D; atypical; autism spectrum disorder; central 22q11.2; duplication

PMID:
30614210
PMCID:
PMC6393688
DOI:
10.1002/mgg3.507
[Indexed for MEDLINE]
Free PMC Article

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