Chambers, Chelsea

AbstractBackgroundMutations in the parkin gene (PRKN) are the most commonly identified genetic factors in early onset Parkinson disease (EOPD), with biallelic mutations, resulting in a clinical phenotype. However, normal variation is also common in PRKN, particularly in the form of copy number variation (CNV), challenging interpretation of genetic testing results. Here we report a case of a 29‐year‐old male with EOPD and two deletions in PRKN detected by chromosomal microarray (CMA).MethodsThe proband was clinically examined by a neurologist for postural instability with frequent falls, bradykinesia, gait freezing with festination, and hypophonia. Chromosomal microarray analysis (CMA) was performed on the proband and his parents using the Affymetrix CytoScan HD microarray. Subsequent fluorescence in situ hybridization (FISH) was performed on the proband and both parents.ResultsChromosomal microarray detected the presence of two deletions of PRKN in the proband. Parental CMA analysis was performed to determine the clinical significance of this finding, as well as to demonstrate phase of these deletions. Parental CMA revealed that one deletion was paternally inherited and one deletion was de novo. A custom FISH approach was then successfully used to phase the deletions.ConclusionChromosomal microarray and fluorescence in situ hybridization analysis of this trio identified two deletions in PRKN occurring in trans, providing a genetic etiology for the clinical diagnosis of EOPD. The determination of inheritance and phase of the deletions was critical to the proper interpretation of these results. These findings highlight the utility of CMA in the detection of clinically relevant CNVs in cases of EOPD, and also serve to emphasize the importance of follow‐up FISH and parental testing.

The differential diagnosis of fever-induced movement disorders in childhood is broad. Whole exome sequencing has yielded new insights into those cases with a suspected genetic basis. We report the case of an 8-year-old boy with a history of neonatal seizures who presented with near-continuous hyperkinetic movements of his limbs during a febrile illness. Initial diagnostic testing did not explain his abnormalities; however, given the suspicion for a channelopathy, whole exome sequencing was performed and it demonstrated a de novo pathogenic heterozygous variant in KCNQ2. There is an expanding phenotypic spectrum of heterozygous alterations in KCNQ2; however, this report provides the first description of a pathogenic KCNQ2 variant fever-induced hyperkinetic movement disorder in childhood. We also review the literature of cases previously published with the same pathogenic variant.