Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis

X Jia, L Madireddy, S Caillier, A Santaniello, F Esposito, G Comi, O Stuve, Y Zhou, B Taylor, T Kilpatrick, F Martinelli-Boneschi, BAC Cree, JR Oksenberg, SL Hauser, SE Baranzini

Research output: Contribution to journalArticle

Abstract

Objective: Primary progressive multiple sclerosis (PPMS) causes accumulation of neurological disability from disease onset without clinical attacks typical of relapsing multiple sclerosis (RMS). However, whether genetic variation influences the disease course remains unclear. We aimed to determine whether mutations causative of neurological disorders that share features with multiple sclerosis (MS) contribute to risk for developing PPMS. Methods: We examined whole-genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects of European ancestry. We selected pathogenic variants exclusively found in PPMS patients that cause monogenic neurological disorders and performed two rounds of replication genotyping in 746 PPMS, 3,049 RMS, and 1,000 healthy subjects. To refine our findings, we examined the burden of rare, potentially pathogenic mutations in 41 genes that cause hereditary spastic paraplegias (HSPs) in PPMS (n = 314), secondary progressive multiple sclerosis (SPMS; n = 587), RMS (n = 2,248), and healthy subjects (n = 987) genotyped using the MS replication chip. Results: WGS and replication studies identified three pathogenic variants in PPMS patients that cause neurological disorders sharing features with MS: KIF5A p.Ala361Val in spastic paraplegia 10; MLC1 p.Pro92Ser in megalencephalic leukodystrophy with subcortical cysts, and REEP1 c.606 + 43G>T in Spastic Paraplegia 31. Moreover, we detected a significant enrichment of HSP-related mutations in PPMS patients compared to controls (risk ratio [RR] = 1.95; 95% confidence interval [CI], 1.27–2.98; p = 0.002), as well as in SPMS patients compared to controls (RR = 1.57; 95% CI, 1.18–2.10; p = 0.002). Importantly, this enrichment was not detected in RMS. Interpretation: This study provides evidence to support the hypothesis that rare Mendelian genetic variants contribute to the risk for developing progressive forms of MS. Ann Neurol 2018;83:51–63. © 2018 American Neurological Association
Original languageEnglish
Pages (from-to)51-63
Number of pages13
JournalAnnals of Neurology
Volume84
Issue number1
DOIs
Publication statusPublished - 2018

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Chronic Progressive Multiple Sclerosis
Multiple Sclerosis
Genome
Nervous System Diseases
Hereditary Spastic Paraplegia
Healthy Volunteers
Paraplegia
Mutation
Odds Ratio
Confidence Intervals
Cysts

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Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis. / Jia, X; Madireddy, L; Caillier, S; Santaniello, A; Esposito, F; Comi, G; Stuve, O; Zhou, Y; Taylor, B; Kilpatrick, T; Martinelli-Boneschi, F; Cree, BAC; Oksenberg, JR; Hauser, SL; Baranzini, SE.

In: Annals of Neurology, Vol. 84, No. 1, 2018, p. 51-63.

Research output: Contribution to journalArticle

Jia, X, Madireddy, L, Caillier, S, Santaniello, A, Esposito, F, Comi, G, Stuve, O, Zhou, Y, Taylor, B, Kilpatrick, T, Martinelli-Boneschi, F, Cree, BAC, Oksenberg, JR, Hauser, SL & Baranzini, SE 2018, 'Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis', Annals of Neurology, vol. 84, no. 1, pp. 51-63. https://doi.org/10.1002/ana.25263
Jia, X ; Madireddy, L ; Caillier, S ; Santaniello, A ; Esposito, F ; Comi, G ; Stuve, O ; Zhou, Y ; Taylor, B ; Kilpatrick, T ; Martinelli-Boneschi, F ; Cree, BAC ; Oksenberg, JR ; Hauser, SL ; Baranzini, SE. / Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis. In: Annals of Neurology. 2018 ; Vol. 84, No. 1. pp. 51-63.
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abstract = "Objective: Primary progressive multiple sclerosis (PPMS) causes accumulation of neurological disability from disease onset without clinical attacks typical of relapsing multiple sclerosis (RMS). However, whether genetic variation influences the disease course remains unclear. We aimed to determine whether mutations causative of neurological disorders that share features with multiple sclerosis (MS) contribute to risk for developing PPMS. Methods: We examined whole-genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects of European ancestry. We selected pathogenic variants exclusively found in PPMS patients that cause monogenic neurological disorders and performed two rounds of replication genotyping in 746 PPMS, 3,049 RMS, and 1,000 healthy subjects. To refine our findings, we examined the burden of rare, potentially pathogenic mutations in 41 genes that cause hereditary spastic paraplegias (HSPs) in PPMS (n = 314), secondary progressive multiple sclerosis (SPMS; n = 587), RMS (n = 2,248), and healthy subjects (n = 987) genotyped using the MS replication chip. Results: WGS and replication studies identified three pathogenic variants in PPMS patients that cause neurological disorders sharing features with MS: KIF5A p.Ala361Val in spastic paraplegia 10; MLC1 p.Pro92Ser in megalencephalic leukodystrophy with subcortical cysts, and REEP1 c.606 + 43G>T in Spastic Paraplegia 31. Moreover, we detected a significant enrichment of HSP-related mutations in PPMS patients compared to controls (risk ratio [RR] = 1.95; 95{\%} confidence interval [CI], 1.27–2.98; p = 0.002), as well as in SPMS patients compared to controls (RR = 1.57; 95{\%} CI, 1.18–2.10; p = 0.002). Importantly, this enrichment was not detected in RMS. Interpretation: This study provides evidence to support the hypothesis that rare Mendelian genetic variants contribute to the risk for developing progressive forms of MS. Ann Neurol 2018;83:51–63. {\circledC} 2018 American Neurological Association",
author = "X Jia and L Madireddy and S Caillier and A Santaniello and F Esposito and G Comi and O Stuve and Y Zhou and B Taylor and T Kilpatrick and F Martinelli-Boneschi and BAC Cree and JR Oksenberg and SL Hauser and SE Baranzini",
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T1 - Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis

AU - Jia, X

AU - Madireddy, L

AU - Caillier, S

AU - Santaniello, A

AU - Esposito, F

AU - Comi, G

AU - Stuve, O

AU - Zhou, Y

AU - Taylor, B

AU - Kilpatrick, T

AU - Martinelli-Boneschi, F

AU - Cree, BAC

AU - Oksenberg, JR

AU - Hauser, SL

AU - Baranzini, SE

PY - 2018

Y1 - 2018

N2 - Objective: Primary progressive multiple sclerosis (PPMS) causes accumulation of neurological disability from disease onset without clinical attacks typical of relapsing multiple sclerosis (RMS). However, whether genetic variation influences the disease course remains unclear. We aimed to determine whether mutations causative of neurological disorders that share features with multiple sclerosis (MS) contribute to risk for developing PPMS. Methods: We examined whole-genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects of European ancestry. We selected pathogenic variants exclusively found in PPMS patients that cause monogenic neurological disorders and performed two rounds of replication genotyping in 746 PPMS, 3,049 RMS, and 1,000 healthy subjects. To refine our findings, we examined the burden of rare, potentially pathogenic mutations in 41 genes that cause hereditary spastic paraplegias (HSPs) in PPMS (n = 314), secondary progressive multiple sclerosis (SPMS; n = 587), RMS (n = 2,248), and healthy subjects (n = 987) genotyped using the MS replication chip. Results: WGS and replication studies identified three pathogenic variants in PPMS patients that cause neurological disorders sharing features with MS: KIF5A p.Ala361Val in spastic paraplegia 10; MLC1 p.Pro92Ser in megalencephalic leukodystrophy with subcortical cysts, and REEP1 c.606 + 43G>T in Spastic Paraplegia 31. Moreover, we detected a significant enrichment of HSP-related mutations in PPMS patients compared to controls (risk ratio [RR] = 1.95; 95% confidence interval [CI], 1.27–2.98; p = 0.002), as well as in SPMS patients compared to controls (RR = 1.57; 95% CI, 1.18–2.10; p = 0.002). Importantly, this enrichment was not detected in RMS. Interpretation: This study provides evidence to support the hypothesis that rare Mendelian genetic variants contribute to the risk for developing progressive forms of MS. Ann Neurol 2018;83:51–63. © 2018 American Neurological Association

AB - Objective: Primary progressive multiple sclerosis (PPMS) causes accumulation of neurological disability from disease onset without clinical attacks typical of relapsing multiple sclerosis (RMS). However, whether genetic variation influences the disease course remains unclear. We aimed to determine whether mutations causative of neurological disorders that share features with multiple sclerosis (MS) contribute to risk for developing PPMS. Methods: We examined whole-genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects of European ancestry. We selected pathogenic variants exclusively found in PPMS patients that cause monogenic neurological disorders and performed two rounds of replication genotyping in 746 PPMS, 3,049 RMS, and 1,000 healthy subjects. To refine our findings, we examined the burden of rare, potentially pathogenic mutations in 41 genes that cause hereditary spastic paraplegias (HSPs) in PPMS (n = 314), secondary progressive multiple sclerosis (SPMS; n = 587), RMS (n = 2,248), and healthy subjects (n = 987) genotyped using the MS replication chip. Results: WGS and replication studies identified three pathogenic variants in PPMS patients that cause neurological disorders sharing features with MS: KIF5A p.Ala361Val in spastic paraplegia 10; MLC1 p.Pro92Ser in megalencephalic leukodystrophy with subcortical cysts, and REEP1 c.606 + 43G>T in Spastic Paraplegia 31. Moreover, we detected a significant enrichment of HSP-related mutations in PPMS patients compared to controls (risk ratio [RR] = 1.95; 95% confidence interval [CI], 1.27–2.98; p = 0.002), as well as in SPMS patients compared to controls (RR = 1.57; 95% CI, 1.18–2.10; p = 0.002). Importantly, this enrichment was not detected in RMS. Interpretation: This study provides evidence to support the hypothesis that rare Mendelian genetic variants contribute to the risk for developing progressive forms of MS. Ann Neurol 2018;83:51–63. © 2018 American Neurological Association

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DO - 10.1002/ana.25263

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VL - 84

SP - 51

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JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

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ER -