Paroxysmal Cranial Dyskinesia And Nail-Patella Syndrome Caused By A Novel Variant In Thelmx1bgene

Background In a Danish family, multiple individuals in five generations present with early-onset paroxysmal cranial dyskinesia, musculoskeletal abnormalities, and kidney dysfunction. Objective To demonstrate linkage and to identify the underlying genetic cause of disease. Methods Genome-wide single-nucleotide polymorphisms analysis, Sequence-Tagged-Site marker analyses, exome sequencing, and Sanger sequencing were performed. Results Linkage analyses identified a candidate locus on chromosome 9. Exome sequencing revealed a novel variant inLMX1Bpresent in all affected individuals, logarithm of the odds (LOD) score ofz= 6.54, predicted to be damaging. Nail-patella syndrome (NPS) is caused by pathogenic variants inLMX1Bencoding a transcription factor essential to cytoskeletal and kidney growth and dopaminergic and serotonergic network development. NPS is characterized by abnormal musculoskeletal features and kidney dysfunction. Movement disorders have not previously been associated with NPS. Conclusions Paroxysmal dyskinesia is a heretofore unrecognized feature of the NPS spectrum. The pathogenic mechanism might relate to aberrant dopaminergic circuits. (c) 2020 International Parkinson and Movement Disorder Society