Evaluating genetic ancestry and self-reported ethnicity in the context of carrier screening.

BACKGROUND: Current professional society guidelines recommend genetic carrier screening be offered on the basis of ethnicity, or when using expanded carrier screening panels, they recommend to compute residual risk based on ethnicity. We investigated the reliability of self-reported ethnicity in 9138 subjects referred to carrier screening. Self-reported ethnicity gathered from test requisition forms and during post-test genetic counseling, and genetic ancestry predicted by a statistical model, were compared for concordance. RESULTS: We identified several discrepancies between the two sources of self-reported ethnicity and genetic ancestry. Only 30.3% of individuals who indicated Mediterranean ancestry during consultation self-reported this on requisition forms. Additionally, the proportion of individuals who reported Southeast Asian but were estimated to have a different genetic ancestry was found to depend on the source of self-report. Finally, individuals who reported Latin American demonstrated a high degree of ancestral admixture. As a result, carrier rates and residual risks provided for patient decision-making are impacted if using self-reported ethnicity. CONCLUSION: Our analysis highlights the unreliability of ethnicity classification based on patient self-reports. We recommend the routine use of pan-ethnic carrier screening panels in reproductive medicine. Furthermore, the use of an ancestry model would allow better estimation of carrier rates and residual risks.

Association of Olfactory Performance With Motor Decline and Age at Onset in People With Parkinson Disease and the LRRK2 G2019S Variant.

BACKGROUND AND OBJECTIVES: There is clinical and phenotypic heterogeneity in LRRK2 G2019S Parkinson disease (PD), including loss of smell. Olfactory scores have defined subgroups of LRRK2 PD at baseline. We now extend this work longitudinally to better determine features associated with olfactory classes and to gain further insight into this heterogeneity. METHODS: Evaluation of 162 patients with LRRK2 PD and 198 patients with idiopathic PD (IPD) from the LRRK2 Ashkenazi Jewish Consortium was performed, with follow-up available for 92 patients with LRRK2 PD and 74 patients with IPD. Olfaction (University of Pennsylvania Smell Identification Test [UPSIT]), motor function (Unified Parkinson Disease Rating Scale), and cognition (Montreal Cognitive Assessment), as well as sleep, nonmotor, and mood, were measured. Gaussian mixture models were applied on the UPSIT percentile score to determine subgroups based on olfactory performance. Linear mixed effects models, using PD duration as the time scale, assessed the relationship between UPSIT subgroup membership and motor/cognitive change. RESULTS: Baseline olfaction was better in LRRK2 PD compared with IPD (mean UPSIT ± SD: 24.2 ± 8.8 vs 18.9 ± 7.6), with higher mean percentile scores (difference: 15.3 ± 11.6) (p < 0.001) and less frequent hyposmia (55.6% vs 85.4%; p < 0.001). Analysis suggested 3 classes among LRRK2 PD. Age at onset in LRRK2 PD was earlier in the worst olfaction group (group 1), compared with groups 2 and 3 (54.5 ± 11.1 vs 61.7 ± 9.3) (p = 0.012), and separately in the hyposmic group overall (55.0 ± 11.3 vs 61.7 ± 9.1) (p < 0.001). Longitudinal motor deterioration in LRRK2 PD was also significantly faster in the worst UPSIT group than the best UPSIT group (group 3 vs group 1: B = 0.31, SE = 0.35 vs B = 0.96, SE = 0.28) (rate difference = -0.65, SE = 0.29) (p = 0.03). However, olfactory group membership was not significantly associated with cognitive decline. DISCUSSION: In this large LRRK2 cohort with longitudinal analysis, we extend prior work demonstrating subgroups defined by olfaction in LRRK2 G2019S PD and show that the worst olfaction group has earlier age at PD onset and more rapid motor decline. This supports a subgroup of LRRK2 PD that might show more rapid change in a clinical trial of LRRK2-related agents and highlights the need to integrate careful phenotyping into allocation schema in clinical trials of LRRK2-related agents. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that worse olfactory scores were associated with an earlier age at symptomatic onset and a faster rate of motor deterioration in patients with LRRK2 PD.

Clinical profiles and outcomes of deep brain stimulation in G2019S LRRK2 Parkinson disease.

OBJECTIVE: The objective of this study was to evaluate clinical features and response to deep brain stimulation (DBS) in G2019S LRRK2-Parkinson disease (LRRK2-PD) and idiopathic PD (IPD). METHODS: The authors conducted a clinic-based cohort study of PD patients recruited from the Mount Sinai Beth Israel Genetics database of PD studies. The cohort included 87 participants with LRRK2-PD (13 who underwent DBS) and 14 DBS participants with IPD enrolled between 2009 and 2017. The baseline clinical features, including motor ratings and levodopa-equivalent daily dose (LEDD), were compared among LRRK2-PD patients with and without DBS, between LRRK2-PD with DBS and IPD with DBS, and between LRRK2-PD with subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) DBS. Longitudinal motor scores (Unified Parkinson's Disease Rating Scale-part III) and medication usage were also assessed pre- and postoperatively. RESULTS: Compared to LRRK2-PD without DBS (n = 74), the LRRK2-PD with DBS cohort (n = 13) had a significantly younger age of onset, longer disease duration, were more likely to have dyskinesia, and were less likely to experience hand tremor at disease onset. LRRK2-PD participants were also more likely to be referred for surgery because of severe dyskinesia (11/13 [85%] vs 6/14 [43%], p = 0.04) and were less likely to be referred for medically refractory tremor (0/13 [0%] vs 6/14 [43%], p = 0.02) than were IPD patients. Among LRRK2-PD patients, both STN-DBS and GPi-DBS targets were effective, although the sample size was small for both groups. There were no revisions or adverse effects reported in the GPi-DBS group, while 2 of the LRRK2-PD participants who underwent STN-DBS required revisions and a third reported depression as a stimulation-related side effect. Medication reduction favored the STN group. CONCLUSIONS: The LRRK2-PD cohort referred for DBS had a slightly different profile, including earlier age of onset and dyskinesia. Both the STN and GPi DBS targets were effective in symptom suppression. Patients with G2019S LRRK2 PD were well-suited for DBS therapy and had favorable motor outcomes regardless of the DBS target. LRRK2-DBS patients had longer disease durations and tended to have more dyskinesia. Dyskinesia commonly served as the trigger for DBS surgical candidacy. Medication-refractory tremor was not a common indication for surgery in the LRRK2 cohort.

Cognitive Functioning of Glucocerebrosidase (GBA) Non-manifesting Carriers.

Mutations and variants in the glucocerebrosidase (GBA) gene are among the most common genetic risk factors for the development of Parkinson's disease (PD). Yet, penetrance is markedly reduced, and less is known about the burden of carrying a single mutation among those without diagnosed PD. Motor, cognitive, psychiatric, and olfactory functioning were assessed in 30 heterozygous GBA mutation carriers without PD (the majority of whom had mild GBA mutations) and 49 non-carriers without PD. Study focus was on domains affected in GBA mutation carriers with PD, as well as those previously shown to be abnormal in GBA mutation carriers without PD. GBA mutation carriers showed poorer performance on the Stroop interference measure of executive functioning when controlling for age. There were no group differences in verbal memory, Montreal Cognitive Assessment (MoCA), overall motor score, or presence of REM sleep behavior disorder or depression. Although total olfaction scores did not differ, GBA mutation carriers with hyposmia had lower global cognition scores than those without hyposmia. As anticipated by the low penetrance of GBA mutations, these findings suggest that pre-manifest non-motor or motor features of PD may not present in most GBA mutation carriers. However, there is support that there may be a subtle difference in executive functioning among some non-manifesting heterozygous GBA mutation carriers, and, combined with olfaction, this may warrant additional scrutiny as a potential biomarker for pre-manifest and pre-clinical GBA related PD.

Dysregulation of mitochondrial and proteolysosomal genes in Parkinson's disease myeloid cells.

An increasing number of identified Parkinson's disease (PD) risk loci contain genes highly expressed in innate immune cells, yet their role in pathology is not understood. We hypothesize that PD susceptibility genes modulate disease risk by influencing gene expression within immune cells. To address this, we have generated transcriptomic profiles of monocytes from 230 individuals with sporadic PD and healthy subjects. We observed a dysregulation of mitochondrial and proteasomal pathways. We also generated transcriptomic profiles of primary microglia from brains of 55 subjects and observed discordant transcriptomic signatures of mitochondrial genes in PD monocytes and microglia. We further identified 17 PD susceptibility genes whose expression, relative to each risk allele, is altered in monocytes. These findings reveal widespread transcriptomic alterations in PD monocytes, with some being distinct from microglia, and facilitate efforts to understand the roles of myeloid cells in PD as well as the development of biomarkers.