Oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling and therapeutic implications

Alfredo Iacoangeli; Allison A Dilliott; Ahmad Al Khleifat; Peter M Andersen; Nazlı A Başak; Johnathan Cooper-Knock; Philippe Corcia; Philippe Couratier; Mamede deCarvalho; Vivian E Drory; Jonathan D Glass; Marc Gotkine; Yosef M Lerner; Orla Hardiman; John E Landers; Russell L McLaughlin; Jesus S Mora Pardina; Karen Morrison; Susana Pinto; Monica Povedano; Christopher E Shaw; Pamela J Shaw; Vincenzo Silani; Nicola Ticozzi; Philip van Damme; Leonard H van den Berg; Patrick Vourc'h; Markus Weber; Jan Herman Veldink; Richard Dobson; Guy A Rouleau; Ammar Al-Chalabi; Sali M K Farhan

doi:10.1136/jnnp-2024-335364

Oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling and therapeutic implications

Alfredo Iacoangeli, Allison A Dilliott, Ahmad Al Khleifat, Peter M Andersen, Nazlı A Başak, Johnathan Cooper-Knock, Philippe Corcia, Philippe Couratier, Mamede deCarvalho, Vivian E Drory, Jonathan D Glass, Marc Gotkine, Yosef M Lerner, Orla Hardiman, John E Landers, Russell L McLaughlin, Jesus S Mora Pardina, Karen Morrison, Susana Pinto, Monica PovedanoChristopher E Shaw, Pamela J Shaw, Vincenzo Silani, Nicola Ticozzi, Philip van Damme, Leonard H van den Berg, Patrick Vourc'h, Markus Weber, Jan Herman Veldink, Richard Dobson, Guy A Rouleau, Ammar Al-Chalabi, Sali M K Farhan

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

Abstract

BACKGROUND: Despite several studies suggesting a potential oligogenic risk model in amyotrophic lateral sclerosis (ALS), case-control statistical evidence implicating oligogenicity with disease risk or clinical outcomes is limited. Considering its direct clinical and therapeutic implications, we aim to perform a large-scale robust investigation of oligogenicity in ALS risk and in the disease clinical course.

METHODS: We leveraged Project MinE genome sequencing datasets (6711 cases and 2391 controls) to identify associations between oligogenicity in known ALS genes and disease risk, as well as clinical outcomes.

RESULTS: In both the discovery and replication cohorts, we observed that the risk imparted from carrying multiple ALS rare variants was significantly greater than the risk associated with carrying only a single rare variant, both in the presence and absence of variants in the most well-established ALS genes. However, in contrast to risk, the relationships between oligogenicity and ALS clinical outcomes, such as age of onset and survival, did not follow the same pattern.

CONCLUSIONS: Our findings represent the first large-scale, case-control assessment of oligogenicity in ALS and show that oligogenic events involving known ALS risk genes are relevant for disease risk in ~6% of ALS but not necessarily for disease onset and survival. This must be considered in genetic counselling and testing by ensuring to use comprehensive gene panels even when a pathogenic variant has already been identified. Moreover, in the age of stratified medication and gene therapy, it supports the need for a complete genetic profile for the correct choice of therapy in all ALS patients.

Original language	English
Article number	jnnp-2024-335364
Journal	Journal of neurology, neurosurgery, and psychiatry
DOIs	https://doi.org/10.1136/jnnp-2024-335364
Publication status	E-pub ahead of print - 13 Feb 2025

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10.1136/jnnp-2024-335364

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Iacoangeli, A., Dilliott, A. A., Al Khleifat, A., Andersen, P. M., Başak, N. A., Cooper-Knock, J., Corcia, P., Couratier, P., deCarvalho, M., Drory, V. E., Glass, J. D., Gotkine, M., Lerner, Y. M., Hardiman, O., Landers, J. E., McLaughlin, R. L., Pardina, J. S. M., Morrison, K., Pinto, S., ... Farhan, S. M. K. (2025). Oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling and therapeutic implications. Journal of neurology, neurosurgery, and psychiatry, Article jnnp-2024-335364. Advance online publication. https://doi.org/10.1136/jnnp-2024-335364

@article{dc4f1d8b14154319a016dffb6b273cee,

title = "Oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling and therapeutic implications",

abstract = "BACKGROUND: Despite several studies suggesting a potential oligogenic risk model in amyotrophic lateral sclerosis (ALS), case-control statistical evidence implicating oligogenicity with disease risk or clinical outcomes is limited. Considering its direct clinical and therapeutic implications, we aim to perform a large-scale robust investigation of oligogenicity in ALS risk and in the disease clinical course.METHODS: We leveraged Project MinE genome sequencing datasets (6711 cases and 2391 controls) to identify associations between oligogenicity in known ALS genes and disease risk, as well as clinical outcomes.RESULTS: In both the discovery and replication cohorts, we observed that the risk imparted from carrying multiple ALS rare variants was significantly greater than the risk associated with carrying only a single rare variant, both in the presence and absence of variants in the most well-established ALS genes. However, in contrast to risk, the relationships between oligogenicity and ALS clinical outcomes, such as age of onset and survival, did not follow the same pattern.CONCLUSIONS: Our findings represent the first large-scale, case-control assessment of oligogenicity in ALS and show that oligogenic events involving known ALS risk genes are relevant for disease risk in ~6% of ALS but not necessarily for disease onset and survival. This must be considered in genetic counselling and testing by ensuring to use comprehensive gene panels even when a pathogenic variant has already been identified. Moreover, in the age of stratified medication and gene therapy, it supports the need for a complete genetic profile for the correct choice of therapy in all ALS patients.",

author = "Alfredo Iacoangeli and Dilliott, {Allison A} and {Al Khleifat}, Ahmad and Andersen, {Peter M} and Ba{\c s}ak, {Nazlı A} and Johnathan Cooper-Knock and Philippe Corcia and Philippe Couratier and Mamede deCarvalho and Drory, {Vivian E} and Glass, {Jonathan D} and Marc Gotkine and Lerner, {Yosef M} and Orla Hardiman and Landers, {John E} and McLaughlin, {Russell L} and Pardina, {Jesus S Mora} and Karen Morrison and Susana Pinto and Monica Povedano and Shaw, {Christopher E} and Shaw, {Pamela J} and Vincenzo Silani and Nicola Ticozzi and {van Damme}, Philip and {van den Berg}, {Leonard H} and Patrick Vourc'h and Markus Weber and Veldink, {Jan Herman} and Richard Dobson and Rouleau, {Guy A} and Ammar Al-Chalabi and Farhan, {Sali M K}",

note = "{\textcopyright} Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY. Published by BMJ Group.",

year = "2025",

month = feb,

day = "13",

doi = "10.1136/jnnp-2024-335364",

language = "English",

journal = "Journal of neurology, neurosurgery, and psychiatry",

issn = "0022-3050",

publisher = "BMJ Publishing Group Ltd",

}

Iacoangeli, A, Dilliott, AA, Al Khleifat, A, Andersen, PM, Başak, NA, Cooper-Knock, J, Corcia, P, Couratier, P, deCarvalho, M, Drory, VE, Glass, JD, Gotkine, M, Lerner, YM, Hardiman, O, Landers, JE, McLaughlin, RL, Pardina, JSM, Morrison, K, Pinto, S, Povedano, M, Shaw, CE, Shaw, PJ, Silani, V, Ticozzi, N, van Damme, P, van den Berg, LH, Vourc'h, P, Weber, M, Veldink, JH, Dobson, R, Rouleau, GA, Al-Chalabi, A & Farhan, SMK 2025, 'Oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling and therapeutic implications', Journal of neurology, neurosurgery, and psychiatry. https://doi.org/10.1136/jnnp-2024-335364

TY - JOUR

T1 - Oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling and therapeutic implications

AU - Iacoangeli, Alfredo

AU - Dilliott, Allison A

AU - Al Khleifat, Ahmad

AU - Andersen, Peter M

AU - Başak, Nazlı A

AU - Cooper-Knock, Johnathan

AU - Corcia, Philippe

AU - Couratier, Philippe

AU - deCarvalho, Mamede

AU - Drory, Vivian E

AU - Glass, Jonathan D

AU - Gotkine, Marc

AU - Lerner, Yosef M

AU - Hardiman, Orla

AU - Landers, John E

AU - McLaughlin, Russell L

AU - Pardina, Jesus S Mora

AU - Morrison, Karen

AU - Pinto, Susana

AU - Povedano, Monica

AU - Shaw, Christopher E

AU - Shaw, Pamela J

AU - Silani, Vincenzo

AU - Ticozzi, Nicola

AU - van Damme, Philip

AU - van den Berg, Leonard H

AU - Vourc'h, Patrick

AU - Weber, Markus

AU - Veldink, Jan Herman

AU - Dobson, Richard

AU - Rouleau, Guy A

AU - Al-Chalabi, Ammar

AU - Farhan, Sali M K

PY - 2025/2/13

Y1 - 2025/2/13

N2 - BACKGROUND: Despite several studies suggesting a potential oligogenic risk model in amyotrophic lateral sclerosis (ALS), case-control statistical evidence implicating oligogenicity with disease risk or clinical outcomes is limited. Considering its direct clinical and therapeutic implications, we aim to perform a large-scale robust investigation of oligogenicity in ALS risk and in the disease clinical course.METHODS: We leveraged Project MinE genome sequencing datasets (6711 cases and 2391 controls) to identify associations between oligogenicity in known ALS genes and disease risk, as well as clinical outcomes.RESULTS: In both the discovery and replication cohorts, we observed that the risk imparted from carrying multiple ALS rare variants was significantly greater than the risk associated with carrying only a single rare variant, both in the presence and absence of variants in the most well-established ALS genes. However, in contrast to risk, the relationships between oligogenicity and ALS clinical outcomes, such as age of onset and survival, did not follow the same pattern.CONCLUSIONS: Our findings represent the first large-scale, case-control assessment of oligogenicity in ALS and show that oligogenic events involving known ALS risk genes are relevant for disease risk in ~6% of ALS but not necessarily for disease onset and survival. This must be considered in genetic counselling and testing by ensuring to use comprehensive gene panels even when a pathogenic variant has already been identified. Moreover, in the age of stratified medication and gene therapy, it supports the need for a complete genetic profile for the correct choice of therapy in all ALS patients.

AB - BACKGROUND: Despite several studies suggesting a potential oligogenic risk model in amyotrophic lateral sclerosis (ALS), case-control statistical evidence implicating oligogenicity with disease risk or clinical outcomes is limited. Considering its direct clinical and therapeutic implications, we aim to perform a large-scale robust investigation of oligogenicity in ALS risk and in the disease clinical course.METHODS: We leveraged Project MinE genome sequencing datasets (6711 cases and 2391 controls) to identify associations between oligogenicity in known ALS genes and disease risk, as well as clinical outcomes.RESULTS: In both the discovery and replication cohorts, we observed that the risk imparted from carrying multiple ALS rare variants was significantly greater than the risk associated with carrying only a single rare variant, both in the presence and absence of variants in the most well-established ALS genes. However, in contrast to risk, the relationships between oligogenicity and ALS clinical outcomes, such as age of onset and survival, did not follow the same pattern.CONCLUSIONS: Our findings represent the first large-scale, case-control assessment of oligogenicity in ALS and show that oligogenic events involving known ALS risk genes are relevant for disease risk in ~6% of ALS but not necessarily for disease onset and survival. This must be considered in genetic counselling and testing by ensuring to use comprehensive gene panels even when a pathogenic variant has already been identified. Moreover, in the age of stratified medication and gene therapy, it supports the need for a complete genetic profile for the correct choice of therapy in all ALS patients.

UR - http://www.scopus.com/inward/record.url?scp=85217920833&partnerID=8YFLogxK

U2 - 10.1136/jnnp-2024-335364

DO - 10.1136/jnnp-2024-335364

M3 - Article

C2 - 39947885

SN - 0022-3050

JO - Journal of neurology, neurosurgery, and psychiatry

JF - Journal of neurology, neurosurgery, and psychiatry

M1 - jnnp-2024-335364

ER -

Oligogenic structure of amyotrophic lateral sclerosis has genetic testing, counselling and therapeutic implications

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