Clinicopathological characteristics of Belgian SORL1 mutation carriers

To determine the clinicopathological phenotype of Belgian Alzheimer’s disease (AD) patients carrying rare premature terminating codon (PTC) and predicted damaging missense variants in the sortilin-related receptor ( SORL1 ) gene. We performed a detailed clinicopathological analysis of SORL1 PTC mutation and rare predicted-damaging missense carriers identified in a memory-clinic based AD research cohort and a cohort of patients referred for genetic testing. Carriers were identified through whole-exome sequencing or targeted resequencing of SORL1 . We identified 7 PTC and 31 missense variant carriers, of which 17 were novel. All SORL1 PTC carriers received a probable ( n = 6) or definite ( n = 1) AD diagnosis. Median onset age was 64.0 years (interquartile range (IQR), 59.0–64.0 years). All PTC carriers presented with amnestic features. A positive familial history was reported in five PTC carriers and unknown for the remaining 2 carriers. Segregation analysis in an EOAD family showed an unclear segregation pattern with SORL1 p.Ile1748fs present in two affected and one unaffected family members, and absent in one affected relative. Most missense carriers (74%) were diagnosed with AD. Other diagnoses included PPA-FTD, CAA and Parkinson’s disease. Median onset age was 64.0 years (IQR, 58.0-67.5). A positive familial history was reported in 11 (57.9%, 11/19) missense carriers. Segregation analysis of SORL1 missense mutations in two AD families showed no clear co-segregation. Most SORL1 carriers presented with amnestic dementia, with exception of some missense variant carriers. Onset age of both PTC and missense carriers was earlier than in the full cohort, with an early-onset in 60.5% (23/38). Familial load was increased in PTC carriers, suggesting SORL1 contributes to familial clustering in AD. Segregation analysis suggests incomplete penetrance or existence of additional yet unknown modifiers for at least some of the mutations. The presence of SORL1 variants in Parkinson’s disease patients and development of parkinsonism in others could indicate contribution of SORL1 in non-AD neurodegenerative diseases, though this finding requires confirmation. Further characterization of SORL1 mutation carriers and pedigrees is needed to implement SORL1 genotyping in the clinical diagnostic setting and genetic counseling.