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Detection of a 4p16.3 Deletion nearby the Wolf-Hirschhorn Critical Region in a Young Female with Sei

Aaron Williams

University of Texas Medical Branch

Our patient is a Hispanic 4 year old female born at 38 weeks with past medical history of multiple types of seizures, global developmental delay, and microcephaly. The mother reported an uncomplicated pregnancy with no environmental exposures. Chromosomal microarray (CMA) showed a 1,009 kbp deletion at 4p16.3. Deletions of 4p16.3 are causative Wolf-Hirschhorn Syndrome (WHS), which presents with a characteristic facial appearance, delayed growth and development, intellectual disability, and seizures. WHS affects approximately 1 in 20,000 to 1 in 50,000 live births (Bi et al., 2016). Our patient’s deletion is small and distal to the known Wolf-Hirschhorn Syndrome critical regions 1 and 2 (WHSCR1 and 2). Deletions in our patient’s region have been interpreted as variants of unknown significance (VUS) (e.g., ClinVar RCV000512414, RCV000054035, RCV000054036;, and are of unknown pathogenicity in patients with symptoms including intellectual disability, global developmental delay, and seizures (Patients 256886, 255712, 291456, 256885; However, this region includes a newly defined seizure candidate region just distal to the WHSCR2 (Bi et al., 2016). The deleted region contains 4 genes involved in normal brain function that, when mutated or lost, have been shown to cause developmental delay and seizure susceptibility: complexin 1 (CPLX1), cyclin G-associated kinase (GAK), polycomb group ring finger 3 (PCGF3), and PIGG (Reim et al., 2001; Glynn et al., 2007; Kielar et al., 2012; Makrythanasis et al., 2016, Bi et al. 2016). Given our patient’s clinical presentation, her symptoms are likely a result of a pathogenic 4p16.3 deletion caused by haploinsufficiency of genes involved in neurological development and function. The results of this case may be helpful in future determinations of pathogenicity for patients with 4p16.3 deletions distal to and not including the WHSCR1 and 2, and, furthermore, may provide a possible etiology for children born with idiopathic seizures, global developmental delay, and microcephaly.

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