PINK1 p.Leu347Pro mutations in Malays: Prevalence and illustrative cases

Ai Huey Tan; Katja Lohmann; Yi Wen Tay; Jia Lun Lim; Azlina Ahmad-Annuar; Norlisah Ramli; Yen Theng Chin; Ahmad Shahir Mawardi; Khairul Azmi; Zariah Abdul Aziz; Santhi Datuk Puvanarajah; Peter Bauer; Christine Klein; Arndt Rolfs; Shen Yang Lim

doi:10.1016/j.parkreldis.2020.08.015

PINK1 p.Leu347Pro mutations in Malays: Prevalence and illustrative cases

Ai Huey Tan, Katja Lohmann, Yi Wen Tay, Jia Lun Lim, Azlina Ahmad-Annuar, Norlisah Ramli, Yen Theng Chin, Ahmad Shahir Mawardi, Khairul Azmi, Zariah Abdul Aziz, Santhi Datuk Puvanarajah, Peter Bauer, Christine Klein, Arndt Rolfs, Shen Yang Lim^*

^*Corresponding author for this work

24 Citations (Scopus)

Abstract

Background: An improved understanding of the genetic determinants of Parkinson's disease (PD) in underrepresented populations, and better characterization of genotype-phenotype correlations in monogenic PD, are needed. Scarce literature exists regarding the genetic aetiology of PD in Malays, who comprise 200 million individuals in South-East Asia. Phenotypic data regarding PARK-PINK1 are also limited. Methods: A multi-ethnic cohort of PD patients from Malaysia (n = 499, including 185 Malays) were tested using a next-generation sequencing-based PD gene panel. The prevalence and clinico-radiological features of patients with the PINK1 p. Leu347Pro mutation are described. This mutation has previously only been reported in people of Filipino or Chamorro (native Guamanian) ancestry. Results: Homozygous p. Leu347Pro mutations were found in five unrelated Malay patients, yielding a prevalence of 6.9% among Malays with PD onset ≤50 years (2.7% of the Malay group overall). This variant was not detected in the homozygous state in 300 Malay controls, but two were heterozygous carriers (0.67%) indicating a relatively high population frequency in keeping with the high frequency of PARK-PINK1 among Malay patients. Interesting clinical features were observed, e.g., differences in the age at PD onset and clinical progression, despite having the same point mutations. Previously unreported brain MRI abnormalities involving the corticospinal tract and hypothalamus, and “loss of the swallow tail” sign, were documented. Conclusions: This report contributes to the very limited literature on PD genetics in the Malay population, and more broadly to the epidemiological, phenotypic and neuroimaging characterization of PARK-PINK1. It also further supports the pathogenicity of the p. Leu347Pro variant.

Original language	English
Journal	Parkinsonism and Related Disorders
Volume	79
Pages (from-to)	34-39
Number of pages	6
ISSN	1353-8020
DOIs	https://doi.org/10.1016/j.parkreldis.2020.08.015
Publication status	Published - 10.2020

Funding

AHT and SYL are supported by the University of Malaya Parkinson's Disease and Movement Disorder Research Program (PV035-2017). KL and CK are supported by the DFG (FOR2488). AAA is supported by a grant from the Ministry of Education Malaysia (FRGS/1/2018/SKK08/ UM /02/3). The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SYL, KL and CK have received honoraria from the Global Parkinson's Genetics Project (GP2) funded by the Michael J. Fox Foundation (MJFF) and the Aligning Science Across Parkinson's (ASAP) initiative. PB is an employee, and AR the founder and CEO, of Centogene AG. The other authors (AHT, YWT, JLL, AAA, NR, YTC, ASM, KA, ZAA, and SDP) have no conflict of interest.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 5 Gender Equality
SDG 10 Reduced Inequalities

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Research Area: Medical Genetics

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10.1016/j.parkreldis.2020.08.015

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Tan, A. H., Lohmann, K., Tay, Y. W., Lim, J. L., Ahmad-Annuar, A., Ramli, N., Chin, Y. T., Mawardi, A. S., Azmi, K., Aziz, Z. A., Puvanarajah, S. D., Bauer, P., Klein, C., Rolfs, A., & Lim, S. Y. (2020). PINK1 p.Leu347Pro mutations in Malays: Prevalence and illustrative cases. Parkinsonism and Related Disorders, 79, 34-39. https://doi.org/10.1016/j.parkreldis.2020.08.015

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title = "PINK1 p.Leu347Pro mutations in Malays: Prevalence and illustrative cases",

abstract = "Background: An improved understanding of the genetic determinants of Parkinson's disease (PD) in underrepresented populations, and better characterization of genotype-phenotype correlations in monogenic PD, are needed. Scarce literature exists regarding the genetic aetiology of PD in Malays, who comprise 200 million individuals in South-East Asia. Phenotypic data regarding PARK-PINK1 are also limited. Methods: A multi-ethnic cohort of PD patients from Malaysia (n = 499, including 185 Malays) were tested using a next-generation sequencing-based PD gene panel. The prevalence and clinico-radiological features of patients with the PINK1 p. Leu347Pro mutation are described. This mutation has previously only been reported in people of Filipino or Chamorro (native Guamanian) ancestry. Results: Homozygous p. Leu347Pro mutations were found in five unrelated Malay patients, yielding a prevalence of 6.9\% among Malays with PD onset ≤50 years (2.7\% of the Malay group overall). This variant was not detected in the homozygous state in 300 Malay controls, but two were heterozygous carriers (0.67\%) indicating a relatively high population frequency in keeping with the high frequency of PARK-PINK1 among Malay patients. Interesting clinical features were observed, e.g., differences in the age at PD onset and clinical progression, despite having the same point mutations. Previously unreported brain MRI abnormalities involving the corticospinal tract and hypothalamus, and “loss of the swallow tail” sign, were documented. Conclusions: This report contributes to the very limited literature on PD genetics in the Malay population, and more broadly to the epidemiological, phenotypic and neuroimaging characterization of PARK-PINK1. It also further supports the pathogenicity of the p. Leu347Pro variant.",

author = "Tan, \{Ai Huey\} and Katja Lohmann and Tay, \{Yi Wen\} and Lim, \{Jia Lun\} and Azlina Ahmad-Annuar and Norlisah Ramli and Chin, \{Yen Theng\} and Mawardi, \{Ahmad Shahir\} and Khairul Azmi and Aziz, \{Zariah Abdul\} and Puvanarajah, \{Santhi Datuk\} and Peter Bauer and Christine Klein and Arndt Rolfs and Lim, \{Shen Yang\}",

year = "2020",

month = oct,

doi = "10.1016/j.parkreldis.2020.08.015",

language = "English",

volume = "79",

pages = "34--39",

journal = "Parkinsonism and Related Disorders",

issn = "1353-8020",

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TY - JOUR

T1 - PINK1 p.Leu347Pro mutations in Malays: Prevalence and illustrative cases

AU - Tan, Ai Huey

AU - Lohmann, Katja

AU - Tay, Yi Wen

AU - Lim, Jia Lun

AU - Ahmad-Annuar, Azlina

AU - Ramli, Norlisah

AU - Chin, Yen Theng

AU - Mawardi, Ahmad Shahir

AU - Azmi, Khairul

AU - Aziz, Zariah Abdul

AU - Puvanarajah, Santhi Datuk

AU - Bauer, Peter

AU - Klein, Christine

AU - Rolfs, Arndt

AU - Lim, Shen Yang

PY - 2020/10

Y1 - 2020/10

N2 - Background: An improved understanding of the genetic determinants of Parkinson's disease (PD) in underrepresented populations, and better characterization of genotype-phenotype correlations in monogenic PD, are needed. Scarce literature exists regarding the genetic aetiology of PD in Malays, who comprise 200 million individuals in South-East Asia. Phenotypic data regarding PARK-PINK1 are also limited. Methods: A multi-ethnic cohort of PD patients from Malaysia (n = 499, including 185 Malays) were tested using a next-generation sequencing-based PD gene panel. The prevalence and clinico-radiological features of patients with the PINK1 p. Leu347Pro mutation are described. This mutation has previously only been reported in people of Filipino or Chamorro (native Guamanian) ancestry. Results: Homozygous p. Leu347Pro mutations were found in five unrelated Malay patients, yielding a prevalence of 6.9% among Malays with PD onset ≤50 years (2.7% of the Malay group overall). This variant was not detected in the homozygous state in 300 Malay controls, but two were heterozygous carriers (0.67%) indicating a relatively high population frequency in keeping with the high frequency of PARK-PINK1 among Malay patients. Interesting clinical features were observed, e.g., differences in the age at PD onset and clinical progression, despite having the same point mutations. Previously unreported brain MRI abnormalities involving the corticospinal tract and hypothalamus, and “loss of the swallow tail” sign, were documented. Conclusions: This report contributes to the very limited literature on PD genetics in the Malay population, and more broadly to the epidemiological, phenotypic and neuroimaging characterization of PARK-PINK1. It also further supports the pathogenicity of the p. Leu347Pro variant.

AB - Background: An improved understanding of the genetic determinants of Parkinson's disease (PD) in underrepresented populations, and better characterization of genotype-phenotype correlations in monogenic PD, are needed. Scarce literature exists regarding the genetic aetiology of PD in Malays, who comprise 200 million individuals in South-East Asia. Phenotypic data regarding PARK-PINK1 are also limited. Methods: A multi-ethnic cohort of PD patients from Malaysia (n = 499, including 185 Malays) were tested using a next-generation sequencing-based PD gene panel. The prevalence and clinico-radiological features of patients with the PINK1 p. Leu347Pro mutation are described. This mutation has previously only been reported in people of Filipino or Chamorro (native Guamanian) ancestry. Results: Homozygous p. Leu347Pro mutations were found in five unrelated Malay patients, yielding a prevalence of 6.9% among Malays with PD onset ≤50 years (2.7% of the Malay group overall). This variant was not detected in the homozygous state in 300 Malay controls, but two were heterozygous carriers (0.67%) indicating a relatively high population frequency in keeping with the high frequency of PARK-PINK1 among Malay patients. Interesting clinical features were observed, e.g., differences in the age at PD onset and clinical progression, despite having the same point mutations. Previously unreported brain MRI abnormalities involving the corticospinal tract and hypothalamus, and “loss of the swallow tail” sign, were documented. Conclusions: This report contributes to the very limited literature on PD genetics in the Malay population, and more broadly to the epidemiological, phenotypic and neuroimaging characterization of PARK-PINK1. It also further supports the pathogenicity of the p. Leu347Pro variant.

UR - https://www.scopus.com/pages/publications/85089804451

U2 - 10.1016/j.parkreldis.2020.08.015

DO - 10.1016/j.parkreldis.2020.08.015

M3 - Journal articles

C2 - 32861104

AN - SCOPUS:85089804451

SN - 1353-8020

VL - 79

SP - 34

EP - 39

JO - Parkinsonism and Related Disorders

JF - Parkinsonism and Related Disorders

ER -

PINK1 p.Leu347Pro mutations in Malays: Prevalence and illustrative cases

Abstract

Funding

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