Genetic paradoxes in an italian family with PARK2 multiexon duplication

Biallelic mutations in Parkin gene are the commonest cause of autosomal recessive early-onset Parkinson disease (EOPD), with full penetrance and frequency inversely correlated with onset age. Conversely, single heterozygous Parkin mutations are detected both in PD patients and healthy subjects, and are considered as minor susceptibility factors towards the risk of sporadic late-onset PD. We report a 41-year-old male patient presenting a rigid-bradykinetic form of EOPD (onset at 36 years), with slow progression and good levodopa response, who was found to carry three copies of Parkin exons 2 and 3. No further mutations emerged from a comprehensive genetic screening of EOPD genes. To define the allelic distribution of the two exon duplications, mutation analysis was proposed to available relatives, all reportedly healthy. The duplications were excluded in the patient’s mother and brother but, surprisingly, four copies of exons 2 and 3 were identified in the paternal aunt (father was unavailable). Familial segregation demonstrated that the patient was heterozygous for exon 2-3 duplication (in cis on the same allele), while the asymptomatic aunt, aged 71 years, was homozygous for the same duplication. A detailed examination of this lady failed to identify parkinsonian signs, and only disclosed a postural-kinetic tremor and dystonic posturing of her right hand during writing. Conversely, the phenotype of the heterozygous nephew resembled a typical form of EOPD as seen in carriers of biallelic Parkin mutations, while the same heterozygous exon 2-3 duplication has been so far detected in occasional patients with sporadic late-onset PD. This paradox underlines the difficulty in establishing genotype-phenotype correlates, and confirms that monogenic disorders are more complex than previously thought. The identification of genetic, epigenetic or environmental factors able to modify the penetrance and expressivity of single gene mutations represents the great challenge of genetic research.