TY - JOUR
T1 - Low prevalence of known pathogenic mutations in dominant PD genes
T2 - A Swedish multicenter study
AU - Puschmann, Andreas
AU - Jiménez-Ferrer, Itzia
AU - Lundblad-Andersson, Elin
AU - Mårtensson, Emma
AU - Hansson, Oskar
AU - Odin, Per
AU - Widner, Håkan
AU - Brolin, Kajsa
AU - Mzezewa, Ropafadzo
AU - Kristensen, Jonas
AU - Soller, Maria
AU - Rödström, Emil Ygland
AU - Ross, Owen A.
AU - Toft, Mathias
AU - Breedveld, Guido J.
AU - Bonifati, Vincenzo
AU - Brodin, Lovisa
AU - Zettergren, Anna
AU - Sydow, Olof
AU - Linder, Jan
AU - Wirdefeldt, Karin
AU - Svenningsson, Per
AU - Nissbrandt, Hans
AU - Belin, Andrea Carmine
AU - Forsgren, Lars
AU - Swanberg, Maria
N1 - Publisher Copyright:
© 2019 The Authors
PY - 2019/9
Y1 - 2019/9
N2 - Objective: To determine the frequency of mutations known to cause autosomal dominant Parkinson disease (PD) in a series with more than 10% of Sweden's estimated number of PD patients. Methods: The Swedish Parkinson Disease Genetics Network was formed as a national multicenter consortium of clinical researchers who together have access to DNA from a total of 2,206 PD patients; 85.4% were from population-based studies. Samples were analyzed centrally for known pathogenic mutations in SNCA (duplications/triplications, p.Ala30Pro, p.Ala53Thr) and LRRK2 (p.Asn1437His, p.Arg1441His, p.Tyr1699Cys, p.Gly2019Ser, p.Ile2020Thr). We compared the frequency of these mutations in Swedish patients with published PD series and the gnomAD database. Results: A family history of PD in first- and/or second-degree relatives was reported by 21.6% of participants. Twelve patients (0.54%) carried LRRK2 p.(Gly2019Ser) mutations, one patient (0.045%) an SNCA duplication. The frequency of LRRK2 p.(Gly2019Ser) carriers was 0.11% in a matched Swedish control cohort and a similar 0.098% in total gnomAD, but there was a marked difference between ethnicities in gnomAD, with 42-fold higher frequency among Ashkenazi Jews than all others combined. Conclusions: In relative terms, the LRRK2 p.(Gly2019Ser) variant is the most frequent mutation among Swedish or international PD patients, and in gnomAD. SNCA duplications were the second most common of the mutations examined. In absolute terms, however, these known pathogenic variants in dominant PD genes are generally very rare and can only explain a minute fraction of familial aggregation of PD. Additional genetic and environmental mechanisms may explain the frequent co-occurrence of PD in close relatives.
AB - Objective: To determine the frequency of mutations known to cause autosomal dominant Parkinson disease (PD) in a series with more than 10% of Sweden's estimated number of PD patients. Methods: The Swedish Parkinson Disease Genetics Network was formed as a national multicenter consortium of clinical researchers who together have access to DNA from a total of 2,206 PD patients; 85.4% were from population-based studies. Samples were analyzed centrally for known pathogenic mutations in SNCA (duplications/triplications, p.Ala30Pro, p.Ala53Thr) and LRRK2 (p.Asn1437His, p.Arg1441His, p.Tyr1699Cys, p.Gly2019Ser, p.Ile2020Thr). We compared the frequency of these mutations in Swedish patients with published PD series and the gnomAD database. Results: A family history of PD in first- and/or second-degree relatives was reported by 21.6% of participants. Twelve patients (0.54%) carried LRRK2 p.(Gly2019Ser) mutations, one patient (0.045%) an SNCA duplication. The frequency of LRRK2 p.(Gly2019Ser) carriers was 0.11% in a matched Swedish control cohort and a similar 0.098% in total gnomAD, but there was a marked difference between ethnicities in gnomAD, with 42-fold higher frequency among Ashkenazi Jews than all others combined. Conclusions: In relative terms, the LRRK2 p.(Gly2019Ser) variant is the most frequent mutation among Swedish or international PD patients, and in gnomAD. SNCA duplications were the second most common of the mutations examined. In absolute terms, however, these known pathogenic variants in dominant PD genes are generally very rare and can only explain a minute fraction of familial aggregation of PD. Additional genetic and environmental mechanisms may explain the frequent co-occurrence of PD in close relatives.
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U2 - 10.1016/j.parkreldis.2019.07.032
DO - 10.1016/j.parkreldis.2019.07.032
M3 - Article
C2 - 31422003
AN - SCOPUS:85070555795
SN - 1353-8020
VL - 66
SP - 158
EP - 165
JO - Parkinsonism and Related Disorders
JF - Parkinsonism and Related Disorders
ER -