Dystonia, facial dysmorphism, intellectual disability and breast cancer associated with a chromosome 13q34 duplication and overexpression of TFDP1: case report

BACKGROUND: Dystonia is a movement disorder characterized by involuntary sustained muscle contractions causing twisting and repetitive movements or abnormal postures. Some cases of primary and neurodegenerative dystonia have been associated with mutations in individual genes critical to the G(1)-S checkpoint pathway (THAP1, ATM, CIZ1 and TAF1). Secondary dystonia is also a relatively common clinical sign in many neurogenetic disorders. However, the contribution of structural variation in the genome to the etiopathogenesis of dystonia remains largely unexplored. CASE PRESENTATION: Cytogenetic analyses with the Affymetrix Genome-Wide Human SNP Array 6.0 identified a chromosome 13q34 duplication in a 36 year-old female with global developmental delay, facial dysmorphism, tall stature, breast cancer and dystonia, and her neurologically-normal father. Dystonia improved with bilateral globus pallidus interna (GPi) deep brain stimulation (DBS). Genomic breakpoint analysis, quantitative PCR (qPCR) and leukocyte gene expression were used to characterize the structural variant. The 218,345 bp duplication was found to include ADPRHL1, DCUN1D2, and TMCO3, and a 69 bp fragment from a long terminal repeat (LTR) located within Intron 3 of TFDP1. The 3' breakpoint was located within Exon 1 of a TFDP1 long non-coding RNA (NR_026580.1). In the affected subject and her father, gene expression was higher for all three genes located within the duplication. However, in comparison to her father, mother and neurologically-normal controls, the affected subject also showed marked overexpression (2×) of the transcription factor TFDP1 (NM_007111.4). Whole-exome sequencing identified an SGCE variant (c.1295G > A, p.Ser432His) that could possibly have contributed to the development of dystonia in the proband. No pathogenic mutations were identified in BRCA1 or BRCA2. CONCLUSION: Overexpression of TFDP1 has been associated with breast cancer and may also be linked to the tall stature, dysmorphism and dystonia seen in our patient.