Abstract
Chromosome 16 contains multiple copy number variations (CNVs) that predispose to genomic disorders. Here, we differentiate pathogenic duplications of 16p11.2–p12.2 from microscopically similar euchromatic variants of 16p11.2. Patient 1 was a girl of 18 with autism, moderate intellectual disability, behavioural difficulties, dysmorphic features and a 7.71-Mb (megabase pair) duplication (16:21 521 005–29 233 146). Patient 2 had a 7.81-Mb duplication (16:21 382 561–29 191 527), speech delay and obsessional behaviour as a boy and, as an adult, short stature, macrocephaly and mild dysmorphism. The duplications contain 65 coding genes of which Polo-like kinase 1 (PLK1) has the highest likelihood of being haploinsufficient and, by implication, a triplosensitive gene. An additional 1.11-Mb CNV of 10q11.21 in Patient 1 was a possible modifier containing the G-protein-regulated inducer of neurite growth 2 (GPRIN2) gene. In contrast, the euchromatic variants in Patients 3 and 4 were amplifications from a 945-kb region containing non-functional immunoglobulin heavy chain (IGHV), hect domain pseudogene (HERC2P4) and TP53-inducible target gene 3 (TP53TG3) loci in proximal 16p11.2 (16:31 953 353–32 898 635). Paralogous pyrosequencing gave a total copy number of 3–8 in controls and 8 to >10 in Patients 3 and 4. The 16p11.2–p12.2 duplication syndrome is a recurrent genomic disorder with a variable phenotype including developmental delay, dysmorphic features, mild to severe intellectual disability, autism, obsessive or stereotyped behaviour, short stature and anomalies of the hands and fingers. It is important to differentiate pathogenic 16p11.2–p12.2 duplications from harmless, microscopically similar euchromatic variants of proximal 16p11.2, especially at prenatal diagnosis.
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Acknowledgements
We thank all four families concerned as well as Dr Christine Garrett and Dr Kay MacDermot for their clinical input on Patient 1. We are grateful to Dr Petra Muschke (Magdeburg) for the information on Patient 3 and for contacting her for the second blood sampling. We thank Dr Ilona Dietze-Armana for sending information on Patient 4. We are also grateful to Professor Hunt Willard for the D16Z2 centromeric probe. VH, SH and HW were supported by the UK Department of Health as part of the National Genetics Reference Laboratory (Wessex).
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DGV: http://projects.tcag.ca/variation/
DECIPHER v5.0: https://decipher.sanger.ac.uk/
Ensembl Genome Browser: http://www.ensembl.org/Homo_sapiens/Info/Index
UCSC Genome Browser: http://genome.ucsc.edu/
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Barber, J., Hall, V., Maloney, V. et al. 16p11.2–p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2. Eur J Hum Genet 21, 182–189 (2013). https://doi.org/10.1038/ejhg.2012.144
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DOI: https://doi.org/10.1038/ejhg.2012.144
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