Likely Underrecognized Mosaicism in Genetic Disease: High Frequency of Mosaic Mutations in ADCY5-Related Dyskinesia (P5.398)

Objective: To investigate the genetic spectrum of adenylate cyclase-5 (ADCY5)-related dyskinesia and phenotype-genotype relationship and effect of mosaicism Background: We recently identified mutations in ADCY5 as the cause of an autosomal dominant movement disorder with various forms of dyskinesia. To date, four mutations in six unrelated families have been published. Methods: A patient panel with choreiform/dystonic dyskinesia was examined for ADCY5 mutations by exome sequencing, Sanger sequencing of ADCY5 or molecular inversion probe (MIP) capture and sequencing. Mosaicism was identified or confirmed by allele-specific PCR amplification. Clinical features were evaluated in these patients. The genotype-phenotype correlation, with particular attention to mosaicism will be discussed. Results: Six missense mutations and one in-frame insertion were found in 21 unrelated families and sporadic cases, including recurrent mutations 418Q and 418W in 15 cases. Mosaicism was detected in six sporadic cases and two progenitors in familiar cases. In general, the patients with mosaicism display milder phenotypes and remain ambulant. Most exhibit paroxysmal episodes. In one progenitor, the childhood onset episodic chorea almost disappeared in adulthood. To detect mosaicism, careful review of the chromatograph in Sanger sequencing revealed five cases. MIPs detected one that was missed by sanger sequencing, however it failed detection in three cases. Allele-specific PCR confirmed all mosaicism and identified two cases that were missed by other methods. Buccal mucosa or skin biopsy were obtained in two patients and mosaicism was detected in all examined tissues. Conclusions: Mutations in ADCY5 cause a wide range of movement disorders with childhood onset and slow progression of dystonia, chorea, myoclonus, hypotonia and tremor, paroxysmal in some cases. Mosaicism contributes to the phenotypic variability. Low levels and/or tissue-limited mosaicism will be challenging for clinical diagnosis. We suggest that mosaicism may be a frequent mechanism in sporadic cases of inherited diseases. Disclosure: Dr. Chen has received license fee payments from Athena Diagnostics. Dr. Friedman has nothing to disclose. Dr. Meneret has nothing to disclose. Dr. Bonkowski has nothing to disclose. Dr. Hisama has received personal compensation for activities with Familion, Inc, and with the University of Washington for her lectures on cardiac genetics. Dr. Davis has nothing to disclose. Dr. Swanson has nothing to disclose. Dr. Bernes has nothing to disclose. Dr. Vidailhet has nothing to disclose. Dr. Roze has nothing to disclose. Dr. Bird has received licensing fees payments from Athena Diagnostics Inc. Dr Wendy Raskind received licensing fees from Athena Diagnostics.