Clinical Deep Phenotyping of Mutation Carriers.

Background And Objectives: Putative loss-of-function (pLOF) variants that increase Alzheimer disease (AD) risk were identified; however, deep phenotypic characterization of these variants in mutation carriers is limited. We aimed to obtain deep clinical phenotypes of pLOF mutation carriers from a large retrospectively reviewed series.

Methods: Genotypes were determined for 5,353 individuals evaluated at Mayo Clinic for 6 reported pLOF variants (p.E709fs, p.Trp1214X, p.L1403fs, c.4416+2T>G, p.E1679X, and c.5570+5G>C). Medical records of 100 mutation carriers were reviewed for demographics, clinical phenotypes, and diagnoses. Eleven mutation carriers had autopsy-based neuropathologic diagnoses.

Results: We confirmed that pLOF mutations confer AD risk in our series of 2,495 participants with AD and 2,858 cognitively unaffected participants. Clinical review of 100 mutation carriers demonstrated phenotypic variability of clinical presentations with both memory and nonmemory cognitive impairment and a subset presenting with motor symptoms. There was a wide range of age at onset of cognitive symptoms (ages 56-92 years, mean = 75.6). Ten of the 11 autopsied mutation carriers had AD neuropathology. pLOF mutation carriers had higher rates of depression (41.6%) and first-degree relatives with cognitive impairment (38.1%) compared with the general population.

Discussion: Our study provides a deep clinical review of phenotypic characteristics of mutation carriers for 6 pLOF mutations. Although memory impairment was the most common initial symptom, nonmemory cognitive and/or motor symptoms were present in a substantial number of mutation carriers, highlighting the heterogeneity of clinical features associated with these mutations. Likewise, although AD neuropathology is the most common, it is not the only autopsy-based diagnosis. Presence of earlier ages at onset, higher rates of depression, and first-degree relatives with cognitive impairment among mutation carriers suggest that these genetic variants may have more aggressive clinical features than AD in the general population. This deep phenotyping study of pLOF mutation carriers provides essential genotype-phenotype correlations for future precision medicine approaches in the clinical setting.