Familial adenomatous polyposis (FAP) is a dominantly inherited syndrome leading to the development of multiple intestinal polyps and colorectal cancer. FAP is associated with germline defects of
APC
...tumor suppressor gene; although truncating mutations account for the majority of cases, large
APC
deletions represent a common disease-causing defect. While a number of intragenic deletions have been well-characterized, sequencing data of breakpoints involved in large
APC
rearrangements are extremely scanty. We characterized six deletions identified by multiplex ligation-dependent probe amplification (three intragenic and three larger deletions encompassing the
APC
locus): in each case, we precisely mapped the breakpoints by array-comparative genomic hybridization and/or long-range PCR followed by sequencing. All rearrangements were novel and no rearrangements proved to be recurrent or clustered. The three intragenic deletions involved exons 4, 9 and 14, respectively; larger deletions (30,444, 265,471 and 921,295 bp in length) involved
APC
as well as adjacent genes. Nine out of 12 breakpoints fell within repetitive elements (5 Alu, 2 LINE, 1 Tigger and 1 MIR), while the remaining 3 fell within unique sequences. In five out of six patients, non-allelic homologous recombination or non-homologous end joining appear as the most likely mechanisms behind
APC
rearrangements. Although a certain variability of clinical features was detectable both between and within families with deletions, all deletion carriers were classifiable as FAP patients showing colonic and extracolonic manifestations that belong to the spectrum of the syndrome. Therefore, different sized deletions, variable breakpoint localizations and haploinsufficiency for other genes besides
APC
, resulted in the same FAP clinical phenotype.
Objective
DNAJC6
mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age < 11), prominent atypical signs, poor or absent response to levodopa, and ...rapid progression (wheelchair‐bound within ∼10 years from onset). Here, for the first time, we report
DNAJC6
mutations in early‐onset Parkinson's disease (PD).
Methods
The
DNAJC6
open reading frame was analyzed in 274 patients with early‐onset sporadic or familial PD. Selected variants were followed up by cosegregation, homozygosity mapping, linkage analysis, whole‐exome sequencing, and protein studies.
Results
We identified two families with different novel homozygous
DNAJC6
mutations segregating with PD. In each family, the
DNAJC6
mutation was flanked by long runs of homozygosity within highest linkage peaks. Exome sequencing did not detect additional pathogenic variants within the linkage regions. In both families, patients showed severely decreased steady‐state levels of the auxilin protein in fibroblasts. We also identified a sporadic patient carrying two rare noncoding
DNAJC6
variants possibly effecting RNA splicing. All these cases fulfilled the criteria for a clinical diagnosis of early‐onset PD, had symptoms onset in the third‐to‐fifth decade, and slow disease progression. Response to dopaminergic therapies was prominent, but, in some patients, limited by psychiatric side effects. The phenotype overlaps that of other monogenic forms of early‐onset PD.
Interpretation
Our findings delineate a novel form of hereditary early‐onset PD. Screening of
DNAJC6
is warranted in all patients with early‐onset PD compatible with autosomal recessive inheritance. Our data provide further evidence for the involvement of synaptic vesicles endocytosis and trafficking in PD pathogenesis. Ann Neurol 2016;79:244–256
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