Short tandem repeat expansions in LRP12 are absent in cohorts of familial and sporadic amyotrophic lateral sclerosis patients of European ancestry

Lyndal Henden; Liam G Fearnley; Dean Southwood; Andrew Smith; Dominic B Rowe; Matthew C Kiernan; Roger Pamphlett; Melanie Bahlo; Ian P Blair; Kelly L Williams

doi:10.1080/21678421.2024.2348636

Short tandem repeat expansions in LRP12 are absent in cohorts of familial and sporadic amyotrophic lateral sclerosis patients of European ancestry

Amyotroph Lateral Scler Frontotemporal Degener. 2024 May 10:1-4. doi: 10.1080/21678421.2024.2348636. Online ahead of print.

Authors

Lyndal Henden¹, Liam G Fearnley^{2

3}, Dean Southwood¹, Andrew Smith¹, Dominic B Rowe¹, Matthew C Kiernan^{4

5}, Roger Pamphlett^{4

6

7}, Melanie Bahlo^{2

3}, Ian P Blair¹, Kelly L Williams¹

Affiliations

¹ Macquarie University Motor Neuron Disease Research Centre, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, 2109, Australia.
² Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
³ Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
⁴ Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia.
⁵ Department of Neurology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
⁶ Discipline of Pathology, The University of Sydney, Sydney, NSW, Australia, and.
⁷ Department of Neuropathology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

PMID: 38726482
DOI: 10.1080/21678421.2024.2348636

Abstract

In patients of Asian ancestry, a heterozygous CGG repeat expansion of >100 units in LRP12 is the cause of oculopharyngodistal myopathy type 1 (OPDM1). Repeat lengths of between 61 and 100 units have been associated with rare amyotrophic lateral sclerosis (ALS) cases of Asian ancestry, although with unusually long disease duration and without significant upper motor neuron involvement. This study sought to determine whether LRP12 CGG repeat expansions were also present in ALS patients of European ancestry. Whole-genome sequencing data from 608 sporadic ALS patients, 35 familial ALS probands, and 4703 neurologically normal controls were screened for LRP12 CGG expansions using ExpansionHunter v4. All individuals had LRP12 CGG repeat lengths within the normal range of 3-25 units. To date, LRP12 CGG repeat expansions have not been reported in ALS patients of European ancestry and may be limited to rare ALS patients of Asian ancestry and atypical clinical presentations.

Keywords: Amyotrophic lateral sclerosis; LRP12; short tandem repeat expansions.