Low prevalence of known pathogenic mutations in dominant PD genes: A Swedish multicenter study

Andreas Puschmann, Itzia Jiménez-Ferrer, Elin Lundblad-Andersson, Emma Mårtensson, Oskar Hansson, Per Odin, Håkan Widner, Kajsa Brolin, Ropafadzo Mzezewa, Jonas Kristensen, Maria Soller, Emil Ygland Rödström, Owen A. Ross, Mathias Toft, Guido J. Breedveld, Vincenzo Bonifati, Lovisa Brodin, Anna Zettergren, Olof Sydow, Jan LinderKarin Wirdefeldt, Per Svenningsson, Hans Nissbrandt, Andrea Carmine Belin, Lars Forsgren, Maria Swanberg

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)158-165
Number of pages8
JournalParkinsonism and Related Disorders
Volume66
DOIs
StatePublished - Sep 2019

Fingerprint

Multicenter Studies
Parkinson Disease
Mutation
Genes
Mutation Rate
Jews
Sweden
Research Personnel
Databases
DNA
Population

ASJC Scopus subject areas

  • Neurology
  • Geriatrics and Gerontology
  • Clinical Neurology

Cite this

Puschmann, A., Jiménez-Ferrer, I., Lundblad-Andersson, E., Mårtensson, E., Hansson, O., Odin, P., ... Swanberg, M. (2019). Low prevalence of known pathogenic mutations in dominant PD genes: A Swedish multicenter study. Parkinsonism and Related Disorders, 66, 158-165. https://doi.org/10.1016/j.parkreldis.2019.07.032

Low prevalence of known pathogenic mutations in dominant PD genes : A Swedish multicenter study. / Puschmann, Andreas; Jiménez-Ferrer, Itzia; Lundblad-Andersson, Elin; Mårtensson, Emma; Hansson, Oskar; Odin, Per; Widner, Håkan; Brolin, Kajsa; Mzezewa, Ropafadzo; Kristensen, Jonas; Soller, Maria; Rödström, Emil Ygland; Ross, Owen A.; Toft, Mathias; Breedveld, Guido J.; Bonifati, Vincenzo; Brodin, Lovisa; Zettergren, Anna; Sydow, Olof; Linder, Jan; Wirdefeldt, Karin; Svenningsson, Per; Nissbrandt, Hans; Belin, Andrea Carmine; Forsgren, Lars; Swanberg, Maria.

In: Parkinsonism and Related Disorders, Vol. 66, 09.2019, p. 158-165.

Research output: Contribution to journalArticle

Puschmann, A, Jiménez-Ferrer, I, Lundblad-Andersson, E, Mårtensson, E, Hansson, O, Odin, P, Widner, H, Brolin, K, Mzezewa, R, Kristensen, J, Soller, M, Rödström, EY, Ross, OA, Toft, M, Breedveld, GJ, Bonifati, V, Brodin, L, Zettergren, A, Sydow, O, Linder, J, Wirdefeldt, K, Svenningsson, P, Nissbrandt, H, Belin, AC, Forsgren, L & Swanberg, M 2019, 'Low prevalence of known pathogenic mutations in dominant PD genes: A Swedish multicenter study', Parkinsonism and Related Disorders, vol. 66, pp. 158-165. https://doi.org/10.1016/j.parkreldis.2019.07.032
Puschmann A, Jiménez-Ferrer I, Lundblad-Andersson E, Mårtensson E, Hansson O, Odin P et al. Low prevalence of known pathogenic mutations in dominant PD genes: A Swedish multicenter study. Parkinsonism and Related Disorders. 2019 Sep;66:158-165. https://doi.org/10.1016/j.parkreldis.2019.07.032
Puschmann, Andreas ; Jiménez-Ferrer, Itzia ; Lundblad-Andersson, Elin ; Mårtensson, Emma ; Hansson, Oskar ; Odin, Per ; Widner, Håkan ; Brolin, Kajsa ; Mzezewa, Ropafadzo ; Kristensen, Jonas ; Soller, Maria ; Rödström, Emil Ygland ; Ross, Owen A. ; Toft, Mathias ; Breedveld, Guido J. ; Bonifati, Vincenzo ; Brodin, Lovisa ; Zettergren, Anna ; Sydow, Olof ; Linder, Jan ; Wirdefeldt, Karin ; Svenningsson, Per ; Nissbrandt, Hans ; Belin, Andrea Carmine ; Forsgren, Lars ; Swanberg, Maria. / Low prevalence of known pathogenic mutations in dominant PD genes : A Swedish multicenter study. In: Parkinsonism and Related Disorders. 2019 ; Vol. 66. pp. 158-165.
@article{40c72a06ad66491d8d5af2bcb623ccb6,
title = "Low prevalence of known pathogenic mutations in dominant PD genes: A Swedish multicenter study",
abstract = "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.",
author = "Andreas Puschmann and Itzia Jim{\'e}nez-Ferrer and Elin Lundblad-Andersson and Emma M{\aa}rtensson and Oskar Hansson and Per Odin and H{\aa}kan Widner and Kajsa Brolin and Ropafadzo Mzezewa and Jonas Kristensen and Maria Soller and R{\"o}dstr{\"o}m, {Emil Ygland} and Ross, {Owen A.} and Mathias Toft and Breedveld, {Guido J.} and Vincenzo Bonifati and Lovisa Brodin and Anna Zettergren and Olof Sydow and Jan Linder and Karin Wirdefeldt and Per Svenningsson and Hans Nissbrandt and Belin, {Andrea Carmine} and Lars Forsgren and Maria Swanberg",
year = "2019",
month = "9",
doi = "10.1016/j.parkreldis.2019.07.032",
language = "English (US)",
volume = "66",
pages = "158--165",
journal = "Parkinsonism and Related Disorders",
issn = "1353-8020",
publisher = "Elsevier BV",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=85070555795&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070555795&partnerID=8YFLogxK

U2 - 10.1016/j.parkreldis.2019.07.032

DO - 10.1016/j.parkreldis.2019.07.032

M3 - Article

C2 - 31422003

AN - SCOPUS:85070555795

VL - 66

SP - 158

EP - 165

JO - Parkinsonism and Related Disorders

JF - Parkinsonism and Related Disorders

SN - 1353-8020

ER -