Confirming Pathogenicity of the F386L PSEN1 Variant in a South Asian Family with Early-Onset Alzheimer Disease

Sarah J. Eger; Yann Le Guen; Raiyan R. Khan; Jacob N. Hall; Gabriel Kennedy; Greg Zaharchuk; Julien Couthouis; William S. Brooks; Dennis Velakoulis; Valerio Napolioni; Michaël E. Belloy; Clifton L. Dalgard; Elizabeth C. Mormino; Aaron D. Gitler; Michael D. Greicius

doi:10.1212/NXG.0000000000000647

Confirming Pathogenicity of the F386L PSEN1 Variant in a South Asian Family with Early-Onset Alzheimer Disease

Sarah J. Eger^*, Yann Le Guen, Raiyan R. Khan, Jacob N. Hall, Gabriel Kennedy, Greg Zaharchuk, Julien Couthouis, William S. Brooks, Dennis Velakoulis, Valerio Napolioni, Michaël E. Belloy, Clifton L. Dalgard, Elizabeth C. Mormino, Aaron D. Gitler, Michael D. Greicius

^*Corresponding author for this work

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

Abstract

ObjectivesThe F386L PSEN1 variant has been reported in 1 Japanese family with limited clinical information. We aimed to prove that F386L is pathogenic by demonstrating that it segregates with early-onset Alzheimer disease (AD).MethodsEight individuals in a South Asian family provided DNA for genetic testing and underwent a neurologic examination.ResultsThe female proband was diagnosed with AD at age 45 years and died at age 49 years. She had a CSF biomarker profile consistent with AD, and her florbetaben PET scan was amyloid positive with high uptake in the striatum. Her MRI showed no prominent white matter disease. Her affected relatives had an age at onset range of 38-57 years and had imaging and biomarker profiles similar to hers.DiscussionThe results presented here, in conjunction with the prior report, confirm the pathogenicity of F386L. Furthermore, our study highlights the importance of studying families from underrepresented populations to identify or confirm the pathogenicity of rare variants that may be specific to certain genetic ancestries.

Original language	English
Article number	e647
Journal	Neurology: Genetics
Volume	8
Issue number	1
DOIs	https://doi.org/10.1212/NXG.0000000000000647
State	Published - 7 Feb 2022
Externally published	Yes

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Eger, S. J., Le Guen, Y., Khan, R. R., Hall, J. N., Kennedy, G., Zaharchuk, G., Couthouis, J., Brooks, W. S., Velakoulis, D., Napolioni, V., Belloy, M. E., Dalgard, C. L., Mormino, E. C., Gitler, A. D., & Greicius, M. D. (2022). Confirming Pathogenicity of the F386L PSEN1 Variant in a South Asian Family with Early-Onset Alzheimer Disease. Neurology: Genetics, 8(1), Article e647. https://doi.org/10.1212/NXG.0000000000000647

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title = "Confirming Pathogenicity of the F386L PSEN1 Variant in a South Asian Family with Early-Onset Alzheimer Disease",

abstract = "ObjectivesThe F386L PSEN1 variant has been reported in 1 Japanese family with limited clinical information. We aimed to prove that F386L is pathogenic by demonstrating that it segregates with early-onset Alzheimer disease (AD).MethodsEight individuals in a South Asian family provided DNA for genetic testing and underwent a neurologic examination.ResultsThe female proband was diagnosed with AD at age 45 years and died at age 49 years. She had a CSF biomarker profile consistent with AD, and her florbetaben PET scan was amyloid positive with high uptake in the striatum. Her MRI showed no prominent white matter disease. Her affected relatives had an age at onset range of 38-57 years and had imaging and biomarker profiles similar to hers.DiscussionThe results presented here, in conjunction with the prior report, confirm the pathogenicity of F386L. Furthermore, our study highlights the importance of studying families from underrepresented populations to identify or confirm the pathogenicity of rare variants that may be specific to certain genetic ancestries.",

author = "Eger, {Sarah J.} and {Le Guen}, Yann and Khan, {Raiyan R.} and Hall, {Jacob N.} and Gabriel Kennedy and Greg Zaharchuk and Julien Couthouis and Brooks, {William S.} and Dennis Velakoulis and Valerio Napolioni and Belloy, {Micha{\"e}l E.} and Dalgard, {Clifton L.} and Mormino, {Elizabeth C.} and Gitler, {Aaron D.} and Greicius, {Michael D.}",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.",

year = "2022",

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Eger, SJ, Le Guen, Y, Khan, RR, Hall, JN, Kennedy, G, Zaharchuk, G, Couthouis, J, Brooks, WS, Velakoulis, D, Napolioni, V, Belloy, ME, Dalgard, CL, Mormino, EC, Gitler, AD & Greicius, MD 2022, 'Confirming Pathogenicity of the F386L PSEN1 Variant in a South Asian Family with Early-Onset Alzheimer Disease', Neurology: Genetics, vol. 8, no. 1, e647. https://doi.org/10.1212/NXG.0000000000000647

TY - JOUR

T1 - Confirming Pathogenicity of the F386L PSEN1 Variant in a South Asian Family with Early-Onset Alzheimer Disease

AU - Eger, Sarah J.

AU - Le Guen, Yann

AU - Khan, Raiyan R.

AU - Hall, Jacob N.

AU - Kennedy, Gabriel

AU - Zaharchuk, Greg

AU - Couthouis, Julien

AU - Brooks, William S.

AU - Velakoulis, Dennis

AU - Napolioni, Valerio

AU - Belloy, Michaël E.

AU - Dalgard, Clifton L.

AU - Mormino, Elizabeth C.

AU - Gitler, Aaron D.

AU - Greicius, Michael D.

PY - 2022/2/7

Y1 - 2022/2/7

N2 - ObjectivesThe F386L PSEN1 variant has been reported in 1 Japanese family with limited clinical information. We aimed to prove that F386L is pathogenic by demonstrating that it segregates with early-onset Alzheimer disease (AD).MethodsEight individuals in a South Asian family provided DNA for genetic testing and underwent a neurologic examination.ResultsThe female proband was diagnosed with AD at age 45 years and died at age 49 years. She had a CSF biomarker profile consistent with AD, and her florbetaben PET scan was amyloid positive with high uptake in the striatum. Her MRI showed no prominent white matter disease. Her affected relatives had an age at onset range of 38-57 years and had imaging and biomarker profiles similar to hers.DiscussionThe results presented here, in conjunction with the prior report, confirm the pathogenicity of F386L. Furthermore, our study highlights the importance of studying families from underrepresented populations to identify or confirm the pathogenicity of rare variants that may be specific to certain genetic ancestries.

AB - ObjectivesThe F386L PSEN1 variant has been reported in 1 Japanese family with limited clinical information. We aimed to prove that F386L is pathogenic by demonstrating that it segregates with early-onset Alzheimer disease (AD).MethodsEight individuals in a South Asian family provided DNA for genetic testing and underwent a neurologic examination.ResultsThe female proband was diagnosed with AD at age 45 years and died at age 49 years. She had a CSF biomarker profile consistent with AD, and her florbetaben PET scan was amyloid positive with high uptake in the striatum. Her MRI showed no prominent white matter disease. Her affected relatives had an age at onset range of 38-57 years and had imaging and biomarker profiles similar to hers.DiscussionThe results presented here, in conjunction with the prior report, confirm the pathogenicity of F386L. Furthermore, our study highlights the importance of studying families from underrepresented populations to identify or confirm the pathogenicity of rare variants that may be specific to certain genetic ancestries.

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Confirming Pathogenicity of the F386L PSEN1 Variant in a South Asian Family with Early-Onset Alzheimer Disease

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