Ashkenazi Jewish Patients Research Articles

Parkinson’s disease in patients and obligate carriers of Gaucher disease

BackgroundGaucher disease is an autosomal recessive disorder caused by glucocerebrosidase gene mutations. Accumulating evidence from several Parkinson’s disease cohorts of varying ethnicities suggests that glucocerebrosidase mutations even in the heterozygous state (carriers) may be a susceptibility factor for Parkinson’s. Very few studies have analyzed the frequency of Parkinson’s in carriers and individuals with Gaucher disease. ObjectiveTo determine frequency of Parkinson’s in patients with Gaucher disease and obligate carriers of glucocerebrosidase mutations and compare it with a control group. MethodsA questionnaire was completed by 100 Ashkenazi Jewish Gaucher patients followed at our center and 109 ethnicity-matched controls with no personal or family history of Gaucher disease. ResultsFrequency of Parkinson’s was higher in Gaucher patients (8/100) than in controls (0/109; P = 0.0024). Frequency of Parkinson’s in obligate carriers (11/200) was higher than controls (6/218), but the difference was not statistically significant (P = 0.215). Average age of onset of Parkinson’s was earlier in Gaucher patients (57.2) than the general population and in obligate carriers (60) when compared with controls (76.8; P = 0.01). The L444P genotype was more frequent in Gaucher patients who reported a parent with Parkinson’s (36.40%) than those who did not (4.50%). ConclusionOur study suggests that the risk for developing Parkinson’s may be higher in affected versus carriers of glucocerebrosidase mutations and suggests that L444P may pose a higher risk of developing Parkinson’s than other mutations. It also confirms previous findings that the age of onset of Parkinson’s associated with glucocerebrosidase mutations is earlier than in the general population.

BRCA mutations and outcome in epithelial ovarian cancer (EOC): Experience in ethnically diverse groups.

5078 Background: EOC patients with BRCA mutations have been reported to have better prognosis than non-hereditary (NH) matched cases, an advantage shown especially in the Ashkenazi-Jewish (AJ) population. We have analyzed our experience in our ethnically diverse patient cohort from NYC, Israel and Italy. Methods: A retrospective chart review of patients diagnosed with Stage IC-IV EOC between 1995-2008 at the NYU Cancer Institute, Tel Aviv Sourasky MC and Padova Clinical Cancer Centers. Out of >700 patients, 183 were tested for BRCA mutations and evaluated. Results: Median age was 55.5 (range 31–83 years). Out of 183, 86 are carriers of BRCA1/2 mutations and 97 tested negative, 67 and 19 are carriers of BRCA1 and BRCA2 mutation respectively. Carrier frequency in EOC population is 46% (45/97) in AJ's and 48% (41/86) in non-AJ's. AJ patients had the following BRCA1 mutations: 185delAG (29), 5382insC (5), unknown (UK) (2) and BRCA2 mutations: 6174delT (8), UK (1). Non-AJ's were divided by ethnicities into non-AJ, Caucasian, African-American, Hispanic, Middle Eastern or unknown. Non-AJ Jewish patients had BRCA1 mutations in 185delAG (7) and BRCA2 in 6174delT (1), UK (1). Non-Jewish Caucasians exhibited the widest variation of mutation types, with the following BRCA1 sites: 185delAG, K1702X (5223A>T), E1373X, 3829delT, 185delAT, IVS11+1G>A, 5385insC, 5083del19>stop1670, 1720delAF>stop536, 1806C/T>Igu536Ter, del ex1a-2, cod1486ex14:4575delAstop1504, 5563G7A;Trp1815stop, 5181delGTT(Val1688del) and UK and the following BRCA2 sites: 6174delT (2), 5301insA (1), 802delAT (1), cod2960ex22:9106C/t (1), cod68ex3:432delAstop79 (1), 7408A/T;Arg2394stop (1). One African-American patient with BRCA1 at 1294del40, 1 Hispanic BRCA1 at 185delAG. OS was significantly prolonged for BRCA carriers at 93.6 months versus 63.2 months [95% CI: 44.5-91.7] (p=0.0016) for NH. Conclusions: Our data reports a wide variety of BRCA mutations in an ethnically diverse EOC population and confirms that BRCA mutations carriers have a better prognosis with a longer median survival compared to NH population. A larger cohort might manifest prognostic differences between the different types of mutations.

The LRRK2 G2019S mutation is associated with Parkinson disease and concomitant non-skin cancers

In view of the fact that cancer patterns in patients with Parkinson disease (PD) differ from the general population, we aimed to verify whether patients with PD with LRRK2 mutations have an increased risk for particular cancer types. In this cross-sectional study, eligible consenting Jewish patients with PD were genotyped for the predominant LRRK2 G2019S mutation. Oncologic data were obtained by personal interview and reviewing patients' files. Stepwise logistic regression was applied to model the probability of cancer occurrence in carriers vs noncarriers. Overall, 79/490 (16.1%) genotyped patients carried the G2019S mutation. Seventy-seven (16%) were diagnosed with cancer; of those, 67 (14%) with a non-skin cancer. Eighteen (23%) carriers vs 49 (12%) noncarriers had a non-skin cancer (p = 0.01, odds ratio [OR] = 2.18, 95% confidence interval [CI] 1.19-3.99). A significant ethnicity effect was noted (p = 0.045, OR = 1.84, 95% CI 1.02-3.34). Among Ashkenazi patients, age and LRRK2 emerged as significant using stepwise logistic regression including age, gender, and LRRK2 status as explanatory variables. The OR for LRRK2 mutation carriers adjusted for age was 3.38 (95% CI 1.64-6.97, p = 0.0009). Ashkenazi Jewish patients with PD who harbor the G2019S LRRK2 mutation are more likely to have a concomitant non-skin cancer than noncarriers.

Genome‐wide association study of N370S homozygous Gaucher disease reveals the candidacy of CLN8 gene as a genetic modifier contributing to extreme phenotypic variation

Mutations in GBA1 gene result in defective acid β-glucosidase and the complex phenotype of Gaucher disease (GD) related to the accumulation of glucosylceramide-laden macrophages. The phenotype is highly variable even among patients harboring identical GBA1 mutations. We hypothesize that modifier gene(s) underlie phenotypic diversity in GD and performed a GWAS study in Ashkenazi Jewish patients with type 1 GD (GD1), homozygous for N370S mutation. Patients were assigned to mild, moderate, or severe disease categories using composite disease severity scoring systems. Whole-genome genotyping for >500,000 SNPs was performed to search for association signals using OQLS algorithm in 139 eligible patients. Several SNPs in linkage disequilibrium within the CLN8 gene locus were associated with the GD1 severity: SNP rs11986414 was associated with GD1 severity at P value 1.26 × 10(-6) . Compared to mild disease, risk allele A at rs11986414 conferred an odds ratio of 3.72 for moderate/severe disease. Loss of function mutations in CLN8 causes neuronal ceroid-lipofuscinosis, but our results indicate that its increased expression may protect against severe GD1. In cultured skin fibroblasts, the relative expression of CLN8 was higher in mild GD compared to severely affected patients, in whom CLN8 risk alleles were overrepresented. In an in vitro cell model of GD, CLN8 expression was increased, which was further enhanced in the presence of bioactive substrate, glucosylsphingosine. Taken together, CLN8 is a candidate modifier gene for GD1 that may function as a protective sphingolipid sensor and/or in glycosphingolipid trafficking. Future studies should explore the role of CLN8 in pathophysiology of GD.

Case report: BRCA in the Ashkenazi population: are current testing guidelines too exclusive?

The BRCA1/2 genes account for a significant portion of hereditary breast and ovarian cancers and they are especially prevalent in the Ashkenazi Jewish population. Women who have a mutation can prevent breast and ovarian cancer with surgical intervention. We describe an Ashkenazi Jewish patient who illustrates that current testing criteria are too restrictive, particularly for this population of patients. The patient's sister was diagnosed with breast cancer at age 33; however, she was not a mutation carrier. Based on practice guidelines, the patient was not recommended genetic testing. She subsequently underwent direct-to-consumer (DTC) testing and discovered that she was a mutation carrier. This case demonstrates the need for clinicians to be aware of the higher prevalence of BRCA mutations in the Ashkenazi population. It also exemplifies the need to involve medical professionals, including genetic counselors, in the dissemination of DNA test results.

Combined OXPHOS complex I and IV defect, due to mutated complex I assembly factor C20ORF7

Defects of the mitochondrial oxidative phosphorylation (OXPHOS) system are frequent causes of neurological disorders in children. Linkage analysis and DNA sequencing identified a new founder p.G250V substitution in the C20ORF7 complex I chaperone in five Ashkenazi Jewish patients from two families with a combined OXPHOS complex I and IV defect presenting with Leigh's syndrome in infancy. Complementation with the wild type gene restored complex I, but only partially complex IV activity. Although the pathogenic mechanism remains elusive, a C20ORF7 defect should be considered not only in isolated complex I deficiency, but also in combination with decreased complex IV. Given the significant 1:290 carrier rate for the p.G250V mutation among Ashkenazi Jews, this mutation should be screened in all Ashkenazi patients with Leigh's syndrome prior to muscle biopsy.

Mood and cognition in leucine‐rich repeat kinase 2 G2019S Parkinson's disease

The behavioral and cognitive features of the leucine-rich repeat kinase G2019S mutation in Parkinson's disease in the Ashkenazi Jewish population are not well described; therefore, we sought to more systematically characterize these features using a semistructured psychiatric interview and neuropsychological testing. Twenty-one Ashkenazi Jewish patients having the leucine-rich repeat kinase G2019S mutation were compared with age- and sex-matched Ashkenazi Jewish patients with Parkinson's disease without mutations. Although overall rates of affective disorders were not greater in mutation carriers, the carriers exhibited a 6-fold increased risk of premorbid affective disorders (odds ratio, 6.0; P = .10), as determined by the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders-IV. Of interest, we identified 2 leucine-rich repeat kinase carriers with bipolar disorder; no mutation-negative subjects had this diagnosis. Performance on the Hopkins Verbal Learning Test-Revised, Judgment of Line Orientation, and Frontal Assessment Battery was consistent with previous reports and did not differ between groups. Study findings suggest a possible association between premorbid mood disorders and leucine-rich repeat kinase Parkinson's disease, warranting further evaluation.

Recruitment in the Internet era: An efficient strategy for a study of breast cancer risk.

1531 Background: The NYU Jewish Women’s Breast and Ovarian Cancer Genetics Study (JWBOCGS) employed 3 recruitment strategies to develop a large cohort of Ashkenazi Jewish (AJ) women for a breast cancer genome-wide association study. Two successful studies of cancer risk in the AJ population serve as historical comparisons ( Struewing JP et al. 1997.NEJM 336:1401-1408; King MC et al. 2003. Science 302:643-646). Methods: The recruitment modalities include clinic-based enrollment, community outreach events, and Internet-based self-identification through the Avon/Love Army of Women (AOW). Enrollment involves completing a questionnaire and providing a saliva sample. AOW recruitment was launched nationally by e-blast on November 10, 2010. The recruitment strategies were compared by subjects enrolled, number of recruitment sites, and time. Results: The table summarizes the recruitment yields. As of February 1, 2011, 3145 AJ women responded to the AOW e-blast, 2,768 (88.0%) completed the online eligibility survey, 1,396 (50.4%) are eligible, and 271 completed enrollment within the first 11 weeks. Conclusions: Internet-based recruitment through AOW is an efficient strategy regarding time and number of recruitment sites. This effort has also been less cumbersome than traditional methods employed in this and other studies. Utilization of AOW expanded the reach of this study to a national level. Recruitment summary. Study Eligibility Strategy No. of sites/events No. of subjects Time JWBOCGS AJ women: High risk family or low risk > 60 y.o. Clinic 4 sites 506 8/08-12/10 (28 mo.) Outreach 19 educational events 3 conference exhibits 223 1/09-5/10 (17 mo.) AOW 1 site 271 11/10-2/11 (11 wks.) Struewing et al. AJ men and women > 20 y.o. Posters, media announcements 15 sites 5,318 Prior to 5/97 (9 wks.) King et al. AJ patients with breast cancer Clinic 12 sites 1,008 9/96-12/00 (51 mo.)

Predicting Diabetic Nephropathy Using a Multifactorial Genetic Model

AimsThe tendency to develop diabetic nephropathy is, in part, genetically determined, however this genetic risk is largely undefined. In this proof-of-concept study, we tested the hypothesis that combined analysis of multiple genetic variants can improve prediction.MethodsBased on previous reports, we selected 27 SNPs in 15 genes from metabolic pathways involved in the pathogenesis of diabetic nephropathy and genotyped them in 1274 Ashkenazi or Sephardic Jewish patients with Type 1 or Type 2 diabetes of >10 years duration. A logistic regression model was built using a backward selection algorithm and SNPs nominally associated with nephropathy in our population. The model was validated by using random “training” (75%) and “test” (25%) subgroups of the original population and by applying the model to an independent dataset of 848 Ashkenazi patients.ResultsThe logistic model based on 5 SNPs in 5 genes (HSPG2, NOS3, ADIPOR2, AGER, and CCL5) and 5 conventional variables (age, sex, ethnicity, diabetes type and duration), and allowing for all possible two-way interactions, predicted nephropathy in our initial population (C-statistic = 0.672) better than a model based on conventional variables only (C = 0.569). In the independent replication dataset, although the C-statistic of the genetic model decreased (0.576), it remained highly associated with diabetic nephropathy (χ2 = 17.79, p<0.0001). In the replication dataset, the model based on conventional variables only was not associated with nephropathy (χ2 = 3.2673, p = 0.07).ConclusionIn this proof-of-concept study, we developed and validated a genetic model in the Ashkenazi/Sephardic population predicting nephropathy more effectively than a similarly constructed non-genetic model. Further testing is required to determine if this modeling approach, using an optimally selected panel of genetic markers, can provide clinically useful prediction and if generic models can be developed for use across multiple ethnic groups or if population-specific models are required.

A Missense Mutation in DHDDS, Encoding Dehydrodolichyl Diphosphate Synthase, Is Associated with Autosomal-Recessive Retinitis Pigmentosa in Ashkenazi Jews

Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal degenerations caused by mutations in at least 50 genes. Using homozygosity mapping in Ashkenazi Jewish (AJ) patients with autosomal-recessive RP (arRP), we identified a shared 1.7 Mb homozygous region on chromosome 1p36.11. Sequence analysis revealed a founder homozygous missense mutation, c.124A>G (p.Lys42Glu), in the dehydrodolichyl diphosphate synthase gene (DHDDS) in 20 AJ patients with RP of 15 unrelated families. The mutation was not identified in an additional set of 109 AJ patients with RP, in 20 AJ patients with other inherited retinal diseases, or in 70 patients with retinal degeneration of other ethnic origins. The mutation was found heterozygously in 1 out of 322 ethnically matched normal control individuals. RT-PCR analysis in 21 human tissues revealed ubiquitous expression of DHDDS. Immunohistochemical analysis of the human retina with anti-DHDDS antibodies revealed intense labeling of the cone and rod photoreceptor inner segments. Clinical manifestations of patients who are homozygous for the c.124A>G mutation were within the spectrum associated with arRP. Most patients had symptoms of night and peripheral vision loss, nondetectable electroretinographic responses, constriction of visual fields, and funduscopic hallmarks of retinal degeneration. DHDDS is a key enzyme in the pathway of dolichol, which plays an important role in N-glycosylation of many glycoproteins, including rhodopsin. Our results support a pivotal role of DHDDS in retinal function and may allow for new therapeutic interventions for RP.

Glucocerebrosidase gene has an alternative upstream promoter, which has features and expression characteristic of housekeeping genes

Database searches have shown that a part of glucocerebrosidase (GBA) transcripts may originate at an alternative upstream promoter (P2) located 2.6kb upstream of the known (P1) GBA promoter. The putative alternative transcripts contained one or two extra exons (exon −2 or exons −2, −1, respectively), but the first ATG codon and predicted amino-acid sequence are the same as in the transcript from P1. Luciferase assays confirmed promoter activity of both sites in HepG2 cells: the P1 construct exhibited the highest activity of luciferase (17.82±1.10 relative luciferase units), while the P2 construct reached 3.01±0.43 relative luciferase units. Serial 5′ deletions of P2 led to changes in reporter activity, the most prominent decreases were observed in deletion constructs carrying bases −353 to −658, and −353 to −920 (numbered as in NM_001005750.1), respectively. This suggests that the P2 core promoter is contained within the region of −920bp to −1311bp.Three P2 transcription initiation sites were found by 5′ RACE at positions 347, 380, and 413bp upstream of the +1 ATG. The expression stability of transcripts from P2, P1 was studied in 20 human tissues and was higher than that of GAPDH and ACTB, which are commonly used as reference housekeeping genes. The P2 contains an unmethylated CpG island, multiple Sp-1 consensus binding sites and, unlike P1, does not contain a TATA box, features all common to the majority of housekeeping gene promoters.We have examined DNA samples from a phenotypically diverse group of twenty Ashkenazi Jewish Gaucher patients homozygous for the common mild mutation N370S. Both P1 and P2, as well as exons −2 and −1, did not contain any sequence variations, with the exception of the known polymorphism rs10908459 found on one allele. The phenotypical differences in the patients were thus not explained by nucleotide variations in both promoters.

Mutations in the glucocerebrosidase gene confer a risk for Parkinson disease in North Africa

Heterozygous mutations in the glucocerebrosidase gene ( GBA ) encoding the enzyme deficient in Gaucher disease (GD), an autosomal recessive lysosomal storage disease, are the most common risk factors for parkinsonism in several populations. A large meta-analysis, pooling genotyping data for the most common mutations from 16 different centers in the United States, Europe, Israel, and Asia, yielded a combined odds ratio (OR) for GBA mutations in subjects with Parkinson disease (PD) of >51 but did not include North Africans. Ashkenazi Jewish patients with PD had the highest mutation frequency (∼20%) (controls, 3%). The common LRRK2 G2019S mutation was also very frequent in Ashkenazi Jews (familial, 28%; isolated, 10%).2 This mutation, on the same haplotype,3 was also frequent in North African patients with PD (familial, 36%; isolated, 39%), who might, therefore, also have a high frequency of GBA mutations,2 although GBA mutations were not a risk factor for PD in Tunisian Berber Arabs.4 ### Methods. We studied 194 unrelated patients with PD as reported previously5 and 177 ethnically matched control subjects, all of North African ancestry. Most patients were from Algeria (n = 147), Morocco (n = 23), Tunisia (n = 14), and Libya (n = 1), and 9 were of unknown origin. Mean ± SD age at onset was 50.9 ± 12.9 years (range 12–78 years), mean age at examination was 58.8 ± 13.3 years (range 14–83 years), mean disease duration was 7.5 ± 5.9 years (range 0–35 years), 52% …

BRCA germline mutations in women with uterine serous carcinoma--still a debate.

To determine the incidence of BRCA1 and BRCA2 mutations in an enlarged series of uterine serous carcinoma (USC) patients and to determine whether patients with USC are associated with a personal or familial history of breast or ovarian carcinoma. A cohort of all consecutive patients with diagnosed USC was identified for 9 years. Family pedigrees were drawn as far back and laterally as possible. In all patients, genomic DNA was extracted from peripheral blood samples and analyzed for the 3 mutations common in Ashkenazi Jewish patients. All patients went through total abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Tubal, ovarian, and peritoneal carcinoma were ruled out clinically and pathologically in all patients. Of 51 consecutive patients with USC in Ashkenazi Jews studied, we identified 13 patients (25.5%) who were previously found to have breast carcinoma, 17 patients (33.3%) who had a first-degree relative with breast or ovarian carcinoma, and 8 patients (15.7%) who were found to be carriers of 1 of the 3 BRCA germline mutations. This series of USC patients, the largest consecutive series to date, suggests a higher incidence of BRCA carriers among Ashkenazi Jews as compared with the general population. This high rate of BRCA germline mutations in USC patients coupled with a high rate of personal and familial cancer histories may suggest that USC is associated with the hereditary breast-ovarian syndrome. This potential association of USC to the BRCA-associated cancer spectrum may have implications for the clinical management and intervention of unaffected BRCA1-2 germline mutation carriers. However, at the current time, there are insufficient data to provide evidence-based guidelines regarding the optimal timing or specific intervention to prevent cancers in these high-risk women.

Evidence for association of the GLI2 gene with tardive dyskinesia in patients with chronic schizophrenia

Tardive dyskinesia (TD) occurs in approximately 20% of patients exposed to long-term antipsychotic treatment and may be influenced by genetic predisposition, in addition to clinical risk factors. In this study, we implemented a two-step approach to identify susceptibility genes for TD. First, we performed a secondary analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) genome-wide association study (GWAS) dataset to identify candidate genes for TD severity. A total of 327 schizophrenia patients treated with antipsychotics who participated in the CATIE trial were included in a TD severity GWAS (approximately 495,000 SNPs). Cases were defined as demonstrating involuntary movements of a mild degree in two or more body regions or of a moderate to severe degree in at least one body region on at least two separate evaluations, whereas controls were completely free of abnormal involuntary movement on all evaluations. Using logistic regression and controlling for population stratification and relevant clinical risk factors, none of the associated SNPs reached GWAS significance; however, several promising SNPs were identified for follow-up investigation. In the second step, we performed an association study of the top 25 SNPs in an independent sample of 170 Jewish, Israeli, schizophrenia patients (retrospective, cross-sectional design). Association of the SNP rs3943552 T allele in the GLI2 gene with TD was observed in a subsample of Ashkenazi Jewish patients (N = 96, P = 0.018; P = 6.2 × 10⁻⁵ in the CATIE sample). The GLI2 gene encodes a transcription factor that participates in the development of the dopaminergic system during embryogenesis. Taken together, our findings support a possible contribution of GLI2 to TD susceptibility.

Abstract 3265: Immortalization and comprehensive characterization of a human ovarian adenocarcinoma cell line derived from an Ashkenazi Jewish patient

Abstract We have established and characterized a new ovarian cancer cell line derived from stage IV serous ovarian adenocarcinoma metastatic tissue from a 47 year old Ashkenazi Jewish patient. The patient developed ovarian cancer at age 44 and died of the disease at age 48. The tissue was obtained after an extensive secondary cytoreductive intraperitoneal surgery. Prior to the surgery the patient underwent primary cytoreduction followed by several systemic therapies with recurrences. A culture of the metastatic tissue was transfected with Simian Virus 40 Large T-Antigen and telomerase. The cell line has been in culture on and off during 3 years. The identity of the cell line was confirmed by Short Tandem Repeat genotyping on genomic DNA extracted from early and late passages as well as from frozen metastatic tissue. The cell line was further characterized by array-Comparative Genomic Hybridization and gene expression microarray; and by Spectral Karyotyping and Fluorescent In Situ Hybridization. The results of these analyses were compared, when appropriate, with those of frozen metastatic tissue. A low level of genetic instability was detected in the cell line, but the karyotypes seem to be near diploid and relatively stable, after several years of cultivation. We believe that this novel ovarian cancer cell line could contribute to the understanding of the molecular genetic basis of the disease in this advanced stage, and be representative of the tumors of a great number of patients that become resistant to the majority if not all known cancer therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3265.

Familial Mediterranean Fever in Ashkenazi Jews: The Mild End of the Clinical Spectrum

To characterize familial Mediterranean fever (FMF) in Ashkenazi patients, a Jewish subgroup in which FMF has rarely been described before. A retrospective analysis, comparing demographic, clinical, and genetic measures of the cohort of Ashkenazi Jewish patients with FMF (n = 57), followed at the National Center for FMF in Israel, to age and sex matched patients of Iraqi Jewish (n = 62) and North African Jewish (NAJ; n = 61) origin. Age at disease onset and diagnosis was earlier in NAJ than among Ashkenazi and Iraqi patients. Family history of FMF was described by only 30% of Ashkenazi patients as opposed to the majority of Iraqi and NAJ patients (p = 0.001). The frequency of abdominal and febrile attacks was similar among the 3 groups, while chest and joint attacks were far less common in Ashkenazi and Iraqi compared to NAJ patients. A good response to colchicine was noted in a similar proportion of Ashkenazi and Iraqi patients (82-84%) as opposed to only 56% of NAJ patients (p = 0.0001). Proteinuria, renal failure, and amyloidosis were most frequent among the NAJ patients (18, 6.6, and 9.8% compared to 5.3, 0, and 3.5% and 1.6, 0, and 0% in Ashkenazi and Iraqi patients, respectively). Ashkenazi patients with FMF stand at the mildest end of the clinical spectrum of FMF. This is notwithstanding the tendency for amyloidosis, the frequency of which is not trivial and which deserves particular awareness.

Exploring perceptions of genetic testing: An examination of perceived accuracy over time

Objective Despite the potential impact of perceptions of genetic testing, little research has examined these perceptions. The current study examined factors associated with perceived accuracy of genetic testing to detect BRCA1/2 mutations and change in perceived accuracy. Methods Participants were recruited through advertisements, community groups, and local oncologists and gynecologists. Ashkenazi Jewish patients ( N = 120) at increased risk for BRCA1/2 genetic mutations were surveyed in a repeated-measures design with assessments at three time points: pre-counseling, post-counseling, and post-testing. Results Better knowledge of cancer genetics related to higher perceived accuracy before counseling. Lower perceived risk of developing ovarian cancer was associated with increased perceived accuracy, while greater distress regarding gene status was associated with decreased perceived accuracy. Genetic test results were unrelated to change in perceived accuracy. Conclusion The results offer an initial look at how patients form perceptions of genetic testing. Both cognitive factors and affective factors relate to how patients perceived the accuracy of testing and how their perception changes over time. Practice implications Understanding cognitive and affective factors which may impact patients’ perceptions of genetic testing is important. Specifically, attention should be paid to educating patients regarding cancer genetics and encouraging adaptive coping strategies to deal with distress.

The Expanding Role of Genetics in the Lewy Body Diseases

The Expanding Role of Genetics in the Lewy Body Diseases

Polymorphisms in the IBD5 Locus Are Associated With Crohn Disease in Pediatric Ashkenazi Jewish Patients

To analyze the IBD5 locus in a homogenous cohort of Ashkenazi Jewish (AJ) children with Crohn disease (CD). A total of 83 AJ children with CD and 73 AJ healthy controls were studied. Genotyping for single nucleotide polymorphisms (SNPs) including OCTN1 (SLC22A4; 1672C-->T), OCTN2 (SLC22A5; 207G-->C), IGR2096, IGR2198, and IGR2230 genes was performed using the TaqMan system. NOD2/CARD15 variants also were typed using established methods. All IBD5 SNPs tested were in linkage disequilibrium (D'>0.8), and showed significant association with CD in our cohort of AJ children. The IGR2096 SNP, which is not located within the same linkage disequilibrium block as the OCTN1 and 2 SNPs, showed an even stronger association with CD (P = 0.017; odds ratio = 1.7). Patients with CD who had the OCTN1 susceptibility allele were more likely to carry 1 of the 3 NOD2/CARD15 SNPs tested (P = 0.01; odds ratio = 4.8). We have demonstrated a significant association between the IBD5 locus and CD in a homogenous cohort of pediatric AJ patients. Due to the tight linkage disequilibrium in the region, it is not possible to identify the causative IBD5 variant. Future functional studies will ultimately reveal the causative gene variant at this locus.

NDUFS4 mutations cause Leigh syndrome with predominant brainstem involvement

Complex I deficiency is a frequent cause of Leigh syndrome. We describe a non-consanguineous Ashkenazi–Sephardic Jewish patient with Leigh syndrome due to complex I deficiency. The clinical and neuroradiological presentation showed predominant brainstem involvement. Blue native polyacrylamide gel electrophoresis analysis revealed an impaired assembly of complex I. The patient was found to be compound heterozygous of two mutations in the NDUFS4 gene: p.Asp119His (a novel mutation) and p.Lys154 fs (recently described in an Ashkenazi Jewish family). These findings support the suggestion that the p.Lys154 fs mutation in NDUFS4 should be evaluated in Ashkenazi Jewish patients presenting with early onset Leigh syndrome even before enzymatic studies. Our results further demonstrated that NDUFS4 presents a hotspot of mutations in the genetic apparatus of oxidative phosphorylation and the correct assembly of the subunit it encodes is essential for completion of the assembly of complex I.