Duplication 16p11.2 in a child with infantile seizure disorder

Abstract

Submicroscopic recurrent 16p11.2 rearrangements are associated with several neurodevelopmental disorders, including autism, mental retardation, and schizophrenia. The common 16p11.2 region includes 24 known genes, of which 22 are expressed in the developing human fetal nervous system. As yet, the mechanisms leading to neurodevelopmental abnormalities and the broader phenotypes associated with deletion or duplication of 16p11.2 have not been clarified. Here we report a child with spastic quadriparesis, refractory infantile seizures, severe global developmental delay, hypotonia, and microcephaly, and a de novo 598 kb 16p11.2 microduplication. Family history is negative for any of these features in parents and immediate family members. Sequencing analyses showed no mutations in DOC2A, QPRT, and SEZ6L2, genes within the duplicated 16p11.2 region that have been implicated in neuronal function and/or seizure related phenotypes. The child's clinical course is consistent with a rare seizure disorder called malignant migrating partial seizure disorder of infancy, raising the possibility that duplication or disruption of genes in the 16p11.2 interval may contribute to this severe disorder.

Fig. 1

Whole genome 44K oligonucleotide-based microarray analysis. (A) The ~598 Kb duplication at 16p11.2; (B) the segmental duplications and copy number polymorphisms adjacent to the duplicated (597,786 bp) region (between the vertical red lines) as determined using the UCSC Genome Browser (http://genome.ucsc.edu/); and (C) the genes within the ~598 Kb region (within the red rectangle) as determined using the Ensembl Genome Browser (http://www.ensembl.org/).

Fig. 2

16p11.2 Microduplication confirmation by qPCR. Probes for SEZ6L2 and C16orf54 were as reported in Kumar et al. [2008]. Controls A and B are known to have two copies and one copy, respectively, of SEZ6L2 and C16orf54.