Comparative genomic hybridization solves a 14‐year‐old PARKIN mystery

In 2001, we and our colleagues reported on two families with PARKIN mutations, one of which (family Ph) presented with only one PARKIN mutation. Mutations in the PARKIN (PARK2) gene cause early-onset autosomal-recessive parkinsonism. At that time, we concluded: “. . .a hemizygous mutation may confer increased susceptibility to typical Parkinson’s disease”, and further speculated: “. . .either the hemizygous deletion makes these individuals more susceptible to parkinsonism/ dystonia or there are multiple other, as yet undetected parkin mutations. . . .” Two follow-up publications came to similar conclusions. Here, we present new data using microarray comparative genomic hybridization (array CGH) to reanalyze the PARKIN gene in family Ph, which resolve these questions. In our original publication in Annals of Neurology, semiquantitative polymerase chain reaction (PCR) was performed for assessment of PARKIN copy number variants (CNVs). This method was introduced by L€ ucking et al. in a seminal publication for PARKIN gene characterization. Under the premise that we might have missed the second mutation in the PARKIN gene, we recently reanalyzed all available DNA samples of family Ph for CNVs using array CGH, a method now commonly utilized in clinical settings for the detection of submicroscopic genomic rearrangements. The experiments were performed on a 1M Agilent CGH array (Agilent Technologies, Santa Clara, CA). Data were processed at Population Diagnostics, Inc. (Oxford, UK). Patient genomic DNA was prepared from brain (Ph1 and Ph15) and whole blood (Ph6 and Ph13). We detected a second mutation in the PARKIN gene (Figure 1). The unaffected mother (Ph6) is a carrier of a 118kb duplication including exon 6 of the PARKIN gene, which was not previously identified with semiquantitative PCR. Thus, the early onset of symptoms in the three affected brothers