To describe a patient with de novo duplication of 16p12.1-p12.2 associated with severe action tremor and developmental delay, and genetic analysis of candidate genes within the duplicated chromosomal segment.

A family history of essential tremor (ET) can be found in 30-80% of all affected patients, suggesting a strong genetic contribution to its etiology. However, discovery of disease-causing genes has been largely elusive. Candidate genes can be identified using linkage analysis, whole exome or genome sequencing, and genetic association studies. Detection of genomic rearrangements with gene dosage changes in tremor patients provides another unique opportunity to identify additional candidate genes.

Case report and genetic analysis of the candidate chromosomal region. Chromosomal microarray analysis was performed in patient and both parents. We designed PCR primers for all coding exons of selected candidate genes. We included 75 unrelated probands from kindreds with familiar ET. Candidate genes were sequenced in all ET controls.

The proband is a 20-year-old female with significant developmental delay who developed progressive tremor at age of 15 years. Her tremor was a moderate to severe 4-5 Hz postural and action distal tremor, not present at rest, minimally responsive to propranolol. Additional examination revealed diffusely brisk reflexes with positive Hoffman and cross adductor sign, and upgoing toes. MRI brain did not show evidence of hypomyelination. She underwent chromosomal microarray analysis that identified duplications 12p13.33 and 16p12.2-p12.1. Chromosome 12p duplication was also detected in her father. Duplication of 12p was considered nonpathogenic and duplication 16p was de novo. The duplicated segment on chromosome 16p contained eight genes and six were considered possible candidate for tremor: UQCRC2, CDR2, EEF2K, POLR3A, LOG23117, and c16orf65. No putative deleterious mutations have been identified in ET controls.

We report identification and genetic analysis of six novel candidate genes on chromosome 16p12.1-p12.2 that may be associated with ET.