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. 2021 Dec 7;8(1):e647.
doi: 10.1212/NXG.0000000000000647. eCollection 2022 Feb.

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

Sarah J Eger  1 , Yann Le Guen  1 , Raiyan R Khan  1 , Jacob N Hall  1 , Gabriel Kennedy  1 , Greg Zaharchuk  1 , Julien Couthouis  1 , William S Brooks  1 , Dennis Velakoulis  1 , Valerio Napolioni  1 , Michaël E Belloy  1 , Clifton L Dalgard  1 , Elizabeth C Mormino  1 , Aaron D Gitler  1 , Michael D Greicius  1
Affiliations

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

Sarah J Eger et al. Neurol Genet. .

Abstract

Objectives: The 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).

Methods: Eight individuals in a South Asian family provided DNA for genetic testing and underwent a neurologic examination.

Results: The 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.

Discussion: The 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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Figures

Figure 1
Figure 1. Family Pedigree Demonstrating F386L Segregates With Early-Onset AD
III-24 (arrow) is the proband. III-39 (gray symbol) is cognitively normal but amyloid PET positive. A solid black symbol indicates that the individual was either clinically diagnosed with AD by the authors or the family provided sufficient medical record detail of the diagnosis. A half-black symbol indicates that the individual was suspected by the family to have been affected but was not formally diagnosed. Additional clinical and anecdotal information is included in eAppendix 2, links.lww.com/NXG/A504. Plus (+) and minus (−) signs indicate F386L carrier or noncarrier status (genetic testing described in eAppendix 3, links.lww.com/NXG/A504). Females are depicted as circles and males as squares. Ages represent age at death (for those marked as deceased with a diagonal line through the symbol) or current age.
Figure 2
Figure 2. Simultaneous MRI and Amyloid PET in (A) the Proband at Age 45 Years and (B) the Male Cousin at Age 36 Years
(A) The proband's FLAIR images (first row) demonstrate only trace periventricular white matter changes. The florbetaben PET images (second row) are positive for cortical amyloid and show prominent amyloid deposition in the striatum. The brainstem was used as the reference region for the standardized uptake value ratios (SUVRs). (B) The unaffected male cousin's FLAIR images (third row) are normal. His florbetaben PET images (fourth row) are positive and display similar striatal deposition to (A) that is not seen in older unrelated noncarriers (see eAppendix 4, links.lww.com/NXG/A504).
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