19. Phase determination and demonstration of parental mosaicism of intragenic PRKN deletions initially identified by chromosomal microarray analysis

Biallelic variants in PRKN are associated with autosomal recessive (AR) juvenile Parkinson disease. Various PRKN mutation types cause disease, however deletions are frequent due to its large size (∼1.4Mb) and its localization within a common fragile site. Here we present a case with biallelic intragenic PRKN deletions identified using chromosomal microarray (CMA) in a newborn. CMA was performed on a six-day old female with a family history of a 17q12 duplication. This maternal 1.5 Mb duplication was observed, along with two non-overlapping intragenic deletions encompassing exons 2 (227 Kb) and 7 (140 Kb) of PRKN. Based on CMA data, it was unclear if these deletions were in cis or trans, so parental CMA studies were performed. The exon 7 deletion was paternally inherited, and the exon 2 deletion appeared to be de novo. CMA SNP genotype data within and surrounding the exon 2 deletion suggested the deletion was maternally derived, and upon closer inspection of the copy number data, the mother appeared to exhibit very low-level mosaicism for the deletion. Therefore, long-range PCR was performed to amplify a product unique to the deleted allele. Sanger sequencing identified the precise breakpoints and confirmed that both proband and mother carry the deletion (c.162142699_162366416delins20). These results demonstrate that the proband's deletions are in trans and consistent with a diagnosis of AR Juvenile Parkinson disease. Confirmation that the mother is mosaic for the exon 2 deletion also has significant recurrence risk implications. When multiple variants are detected in genes associated with AR disorders, it is crucial to determine cis versus trans configuration to establish a diagnosis and determine recurrence risks. Typically, parental studies are sufficient to make this determination. However, this case demonstrates how low-level mosaicism should be considered when an apparently de novo variant is detected, even in the case of an AR disorder.