PT  - JOURNAL ARTICLE
AU  - Campbell, Alana S.
AU  - Ho, Charlotte C.G.
AU  - Atık, Merve
AU  - Allen, Mariet
AU  - Lincoln, Sarah
AU  - Malphrus, Kimberly
AU  - Nguyen, Thuy
AU  - Oatman, Stephanie R.
AU  - Corda, Morgane
AU  - Conway, Olivia
AU  - Strickland, Samantha
AU  - Petersen, Ronald C.
AU  - Dickson, Dennis W.
AU  - Graff-Radford, Neill R.
AU  - Ertekin-Taner, Nilüfer
TI  - Clinical Deep Phenotyping of <em>ABCA7</em> Mutation Carriers
AID  - 10.1212/NXG.0000000000000655
DP  - 2022 Apr 01
TA  - Neurology Genetics
PG  - e655
VI  - 8
IP  - 2
4099  - http://ng.neurology.org/content/8/2/e655.short
4100  - http://ng.neurology.org/content/8/2/e655.full
SO  - Neurol Genet2022 Apr 01; 8
AB  - Background and Objectives Putative loss-of-function (pLOF) ABCA7 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 ABCA7 pLOF mutation carriers from a large retrospectively reviewed series.Methods Genotypes were determined for 5,353 individuals evaluated at Mayo Clinic for 6 reported ABCA7 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 ABCA7 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. ABCA7 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 ABCA7 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 ABCA7 pLOF mutation carriers provides essential genotype-phenotype correlations for future precision medicine approaches in the clinical setting.ABCA7=ATP-binding cassette, subfamily A, member 7; AD=Alzheimer disease; AGD=argyrophilic grain disease; APP=amyloid precursor protein; AUT=autopsy-confirmed participants; CBS=corticobasal syndrome; DLBD=diffuse Lewy body disease; FTD=frontotemporal dementia; JS=clinical participants from Mayo Clinic, Jacksonville, FL; MCI=mild cognitive impairment; mRNA=messenger RNA; OR=odds ratio; PA=pathologic aging; PD=Parkinson disease; pLOF=putative loss of function; PPA=primary progressive aphasia; PSP=progressive supranuclear palsy; QC=quality control; RS=clinical participants from Mayo Clinic, Rochester, MN.