Autoimmunity risk alleles in costimulation pathways

Summary:  The basis for susceptibility to common autoimmune diseases is a complex interplay between multiple genetic and environmental risk factors. We have now entered a new generation of genetic study designs which has not only furthered our understanding of the individual mechanisms involved in the common human autoimmune diseases but also has pointed towards common pathways. In this review we focus on costimulatory mechanisms with the most convincing association results in large collections of patients and control subjects. These include the genes encoding cytotoxic T-lymphocyte antigen-4, CD58, CD40, inducible T-cell costimulator ligand, CD244, CD226, tumor necrosis factor (TNF) (ligand) superfamily member 4, TNF superfamily member 15, and programmed cell death 1. The unbiased genome-wide association scans suggest that indeed immune related genes underlie the pathogenesis of human autoimmune disease with common involvement of costimulatory pathways. The identification of allelic variants associated with disease risk followed by understanding their functional outcomes and affected pathways provides a rationale approach for drug design.     

Maternal carrier screening with single-gene NIPS provides accurate fetal risk assessments for recessive conditions

PurposeThe purpose of this study was to evaluate the clinical performance of carrier screening for cystic fibrosis, hemoglobinopathies, and spinal muscular atrophy with reflex single-gene noninvasive prenatal screening (sgNIPS), which does not require paternal carrier screening.MethodsAn unselected sample of 9151 pregnant individuals from the general US pregnant population was screened for carrier status, of which 1669 (18.2%) were identified as heterozygous for one or more pathogenic variants and reflexed to sgNIPS. sgNIPS results were compared with newborn outcomes obtained from parent survey responses or provider reports for a cohort of 201 pregnancies.ResultsOverall, 98.7% of pregnant individuals received an informative result (no-call rate = 1.3%), either a negative carrier report or, if identified as heterozygous for a pathogenic variant, a reflex sgNIPS report. In the outcomes cohort, the negative predictive value of sgNIPS was 99.4% (95% CI = 96.0%-99.9%) and average positive predictive value (PPV) of sgNIPS was 48.3% (95% CI = 36.1%-60.1%). Importantly, personalized PPVs accurately reflected the percentage of affected pregnancies in each PPV range, and all pregnancies with a sgNIPS fetal risk of >9 in 10 (90% PPV) were affected.ConclusionAlthough traditional carrier screening is most effective when used to assess reproductive risk before pregnancy, more than 95% of the time it is pursued during a pregnancy and is complicated by incomplete uptake of paternal carrier screening (<50%) and misattributed paternity (～10%). Even in an idealized setting, when both partners have carrier screening, the maximum risk for having an affected pregnancy is 1 in 4 (equivalent of a 25% PPV). Carrier screening with sgNIPS during pregnancy is an alternative that does not require a paternal sample and provides accurate fetal risk in a timely manner that can be used for prenatal counseling and pregnancy management.     

Information preferences of high literacy pregnant women regarding informed consent models for genetic carrier screening

Objective

With the increasing carrier screening options being offered to pregnant women, it is critical to consider what information women want in an informed consent process, and how they make decisions regarding screening.

Methods

We surveyed 201 pregnant women.

Results

Subjects prefer “to have as much information as possible” (84%), and valued their physician's recommendations (82%) regarding screening. After reviewing two hypothetical scenarios, 71% of participants preferred more information about genetic carrier screening; however, some participants expressed concern that too much information can also lead to anxiety. When specifically asked about components of a potential informed consent process, the highest preferences were to include: the chance of having a child with the disorder (97%), the options for carriers (93%), the value and purpose of testing (91%), and the prognosis if a child has the disease (94%); preference for “symptoms” information differed based on scenario preference (p < 0.001).

Conclusion

This study is the first to document variation in patients’ views regarding the information desired as part of the informed consent process.

Practice implications

Providers should consider ways to ascertain their patients’ preferred informational style, and how to provide information in the amount and style that patients find useful in making decisions.     

Using a roster and haplotyping is useful in risk assessment for persons with intermediate and reduced penetrance alleles in Huntington disease

The risk of a person having a child with an inherited disorder, caused by an unstable triplet repeat, such as Huntington disease (HD), depends on the expansion of the mutation in that person, which is connected both to the biological nature of the mutation and to the person's relation to the carrier of the full mutation. Once the mutation causing HD was identified, we were able to diagnose sporadic patients. A sporadic patient can sometimes be connected to a known HD pedigree by using a roster. By haplotyping and calculating the posterior identity‐by‐descent probability, we could establish whether a connection was coincidental or not. Furthermore, we describe the frequency of intermediate and reduced penetrance alleles detected. Using the family history and the roster to search for a connection, we examined whether these alleles were on the HD haplotype of a family. It is important to know the origin of an intermediate or reduced penetrance allele because if it comes from an HD branch of the family or from the non‐HD affected side of the pedigree, different risks for relatives and penetrance ensue. In our study, most intermediate alleles came from the non–HD‐affected side of the pedigree and had a repeat size in the lower range with a negligible risk for expansion. Intermediate alleles on the HD haplotypes were larger and found in predictive test applicants from known families or relatives from new mutations with a higher risk for expansion. Reduced penetrance alleles in the higher range were mainly found in symptomatic and predictive test applicants from known families, with a considerable risk for penetrance, although at older age. We conclude that a roster, a thorough family history, and haplotyping in persons with intermediate and reduced penetrance alleles are essential in considering the risk of a person having (a child with) HD. © 2001 Wiley‐Liss, Inc.     

Experiences and attitudes of hereditary cancer screening patients in a consumer directed testing model

BackgroundSince 2015, the Information is Power initiative has offered free and reduced cost hereditary cancer screening to the North Alabama population with a consumer-initiated model. Patients received pre-test and post-test education through a genetic counseling video. Positive results also received a call from a genetic counselor.ObjectiveWe surveyed past Information is Power patients to assess if video education and electronic result delivery addressed the needs of a hereditary cancer screening population.MethodsAn electronic survey was sent out to Information is Power patients who opted into research contact. The survey assessed participant knowledge, satisfaction with result delivery, and perceived uncertainty after receiving test results.Results213 participants completed the survey. Eighteen percent of participants would have preferred individual communication with a genetics specialist about their results. Over 99 % of survey participants correctly interpreted a positive result, while 73 % correctly interpreted a negative result. Overall, participants were certain about the impact of their genetic test results.Practice ImplicationsThese findings support a model of population genetic testing and genetic counseling that is sustainable while meeting the educational needs of most participants. Observed misconceptions surrounding a negative result should be highlighted in future population screening patient resources to meet patient needs.     

FMR1 alleles in Tasmania: a screening study of the special educational needs population

The distribution of fragile X mental retardation-1 (FMR1) allele categories, classified by the number of CGG repeats, in the population of Tasmania was investigated in 1253 males with special educational needs (SEN). The frequencies of these FMR1 categories were compared with those seen in controls as represented by 578 consecutive male births. The initial screening was based on polymerase chain reaction analysis of dried blood spots. Inconclusive results were verified by Southern analysis of a venous blood sample. The frequencies of common FMR1 alleles in both samples, and of grey zone alleles in the controls, were similar to those in other Caucasian populations. Consistent with earlier reports, we found some (although insignificant) increase of grey zone alleles in SEN subjects compared with controls. The frequencies of predisposing flanking haplotypes among grey zone males FMR1 alleles were similar to those seen in other Caucasian SEN samples. Contrary to expectation, given the normal frequency of grey zone alleles, no premutation (PM) or full mutation (FM) allele was detected in either sample, with only 15 fragile X families diagnosed through routine clinical admissions registered in Tasmania up to 2002. An explanation of this discrepancy could be that the C19th founders of Tasmania carried few PM or FM alleles. The eight to ten generations since white settlement of Tasmania has been insufficient time for susceptible grey zone alleles to evolve into the larger expansions.     

Validation of lung cancer polygenic risk scores in a high-risk case-control cohort

PurposeScreening with low-dose computed tomography reduces lung cancer (LC) mortality. Risk prediction models used for screening selection do not include genetic variables. Here, we investigated the performance of previously published polygenic risk scores (PRSs) for LC, considering their potential to improve screening selection.MethodsWe validated 9 PRSs in a high-risk case-control cohort, comprising genotype data from 652 surgical patients with LC and 550 cancer-free, high-risk (PLCO_M2012 score ≥ 1.51%) participants of the Manchester Lung Health Check, a community-based LC screening program (n = 550). Discrimination (area under the curve [AUC]) between cases and controls was assessed for each PRS independently and alongside clinical risk factors.ResultsMedian age was 67 years, 53% were female, 46% were current smokers, and 76% were National Lung Screening Trial eligible. Median PLCO_M2012 score among controls was 3.4%, 80% of cases were early stage. All PRSs significantly improved discrimination, AUC increased between +0.002 (P = .02) and +0.015 (P < .0001), compared with clinical risk factors alone. The best-performing PRS had an independent AUC of 0.59. Two novel loci, in the DAPK1 and MAGI2 genes, were significantly associated with LC risk.ConclusionPRSs may improve LC risk prediction and screening selection. Further research, particularly examining clinical utility and cost-effectiveness, is required.     

新生儿G6PD缺乏症筛查及遗传咨询措施的研究

目的新生儿G6PD缺乏症筛查,计算发病率、基因频率,患儿治疗及遗传咨询。方法筛查用荧光分辨法,确诊用G6PD/6PGD比值测定法。结果2007年10月至2008年10月对我院新出生的9842例新生儿进行了G6PD缺乏症筛查,男性5286例,女性4556例,共检出确诊病例18例。发病率为1.83‰(18/9842),其中男性发病16例,为1.63‰(16/9842),女性2例,为0.2‰(2/9842)。男女比例8∶1。G6PD缺乏症基因频率为0.00303(16/5286)。18例病儿中,祖籍为上海浦东人,发病3例,占16.67%(3/18),祖籍为外地人口发生15例,占83.33%(15/18)。     

Communicating polygenic risk scores in the familial breast cancer clinic

ObjectiveTo describe the communication of polygenic risk scores (PRS) in the familial breast cancer setting.MethodsConsultations between genetic healthcare providers (GHP) and female patients who received their PRS for breast cancer risk were recorded (n = 65). GHPs included genetic counselors (n = 8) and medical practitioners (n = 5) (i.e. clinical geneticists and oncologists). A content analysis was conducted and logistic regression was used to assess differences in communication behaviors between genetic counselors (n = 8) and medical practitioners (n = 5).ResultsOf the 65 patients, 31 (47.7 %) had a personal history of breast cancer, 18 of whom received an increased PRS (relative risk >1.2). 25/34 unaffected patients received an increased PRS. Consultations were primarily clinician-driven and focused on biomedical information. There was little difference between the biomedical information provided by genetic counselors and medical practitioners. However, genetic counselors were significantly more likely to utilize strategies to build patient rapport and counseling techniques.ConclusionsOur findings provide one of the earliest reports on how breast cancer PRSs are communicated to women.Practice implicationsKey messages for communicating PRSs were identified, namely: discussing differences between polygenic and monogenic testing, the multifactorial nature of breast cancer risk, polygenic inheritance and current limitation of PRSs.     

Clinical implication of FMR1 intermediate alleles in a Spanish population

FMR1 premutation carriers (55‐200 CGGs) are at risk of developing Fragile X‐associated primary ovarian insufficiency as well as Fragile X‐associated tremor/ataxia syndrome. FMR1 premutation alleles are also associated with a variety of disorders, including psychiatric, developmental, and neurological problems. However, there is a major concern regarding clinical implications of smaller CGG expansions known as intermediate alleles (IA) or gray zone alleles (45‐54 CGG). Although several studies have hypothesized that IA may be involved in the etiology of FMR1 premutation associated phenotypes, this association still remains unclear. The aim of this study was to provide new data on the clinical implications of IA. We reviewed a total of 17 011 individuals: 1142 with primary ovarian insufficiency, 478 with movement disorders, 14 006 with neurodevelopmental disorders and 1385 controls. Similar IA frequencies were detected in all the cases and controls (cases 1.20% vs controls 1.39%, P = .427). When comparing the allelic frequencies of IA ≥ 50CGGs, a greater, albeit not statistically significant, number of alleles were detected in all the cohorts of patients. Therefore, IA below 50 CGGs should not be considered as risk factors for FMR1 premutation‐associated phenotypes, at least in our population. However, the clinical implication of IA ≥ 50CGGs remains to be further elucidated.     

HLA-A, -B, -C, -DRB1 and -DQB1 alleles and haplotypes in 951 Southeast Asia Malays from Peninsular Malaysia

A total of 951 Southeast Asia Malays from Peninsular Malaysia were genotyped for HLA-A, -B, -C -DRB1, and -DQB1 loci using polymerase chain reaction sequence-specific oligonucleotide probe hybridization methods. In this report, there were significant deviation from Hardy-Weinberg proportions for the HLA-A (p < 0.0001), -B (p < 0.0001), -DRB1 (p < 0.0001) and -DQB1 (p < 0.01) loci. Minor deviations from HWEP were detected for HLA-C (p = 0.01). This genotype data was available in Allele Frequencies Network Database (AFND) Gonzalez-Galarza et al. (2015).     

Prevalence and type distribution of high‐risk human papillomavirus infection in women undergoing voluntary cervical cancer screening in Italy

The aim of this survey was to assess the prevalence and distribution of oncogenic human papillomavirus (HPV) genotypes in women who underwent screening for cervical cancer in Italy. The correlation of genotypes with the cytological results was also evaluated. Cervical samples were collected from 9,947 self‐referring women for cervical cancer screening. Participants were screened by liquid‐based cytology and high‐risk HPV testing using the Hybrid Capture 2 test. Positive samples were genotyped by PCR. Samples (1,474; 14.8%) were positive for high‐risk HPV. The prevalence was 29.4% in the 15–19 years‐group, decreasing progressively to 6.1% at 50–54 years of age and increasing to 12.2% in those aged over 65 years. HPV 16 was the genotype detected most frequently followed by HPV 31, HPV 18, HPV 56, and HPV 51. HPV 16 or 18 were present in 4% of women with normal cytology and both were detected contemporarily in only 14 women. Twenty‐two percent of atypical squamous cells, 26% of low‐grade and 56% of high‐grade squamous intraepithelial lesions at cytology were positive for HPV 16 and/or 18. The prevalence of HPV infection in Italy is in agreement with that reported worldwide. HPV 16 was the prevalent genotype. The concomitant infection with HPV 16 and HPV 18 (vaccine targets) was found rarely. Apart from HPV 16 and 18, there was a substantial presence of HPV genotypes against which the vaccines available currently have shown cross‐protection efficacy. The findings of this study may contribute to reliable predictions on the potential efficacy of an HPV vaccine in clinical practice. J. Med. Virol. 81:529–535, 2009. © 2009 Wiley‐Liss, Inc.     

Accuracy in risk understanding among BRCA1/2-mutation carriers

ObjectiveBRCA1/2-mutation carriers are at high risk of developing cancer. Since they must weigh clinical recommendations and decide on risk-reducing measures, the correct understanding of their 10-year cancer risks is essential. This study focused on the accuracy of women’s subjective estimates of developing breast and ovarian cancer within ten years as prerequisite to reduce unnecessary prevention.Methods59 and 52 BRCA1/2-mutation carriers provided their individual risks of developing breast or ovarian cancer in the next 10 years, along with self-reported sociodemographic and psychosocial variables. Women’s risk estimates were compared with their objective cancer risks that had been communicated before.Results22.6% of counselees under- and 53.2% of the counselees overestimated their 10-year risk of developing breast cancer. As for ovarian cancer, 5.6% under- whereas 51.9% overestimated their risk. Neither demographic factors such as education, parenthood and age, nor a prior diagnosis of breast cancer or prophylactic surgery accounted for these variations in risk accuracy.ConclusionCurrently, risk communication during genetic counseling does not guarantee accurate risk estimation in BRCA-mutation carriers.Practice ImplicationsCounselors must be prepared to prevent overestimation. Counselees’ risk estimates need to be assessed and corrected to enable informed decision-making and reduce risks of unnecessary preventive efforts.     

应用单核苷酸多态性芯片研究单亲二体型来源及致病机制

 目的：探讨人类全基因组单核苷酸多态性芯片(single nucleotide polymorphism array, SNP array)在单亲二体型来源及致病机制研究和遗传咨询中的应用价值。方法：对具有唐氏综合征高风险、需行羊水胎儿细胞G 显带染色体核型分析的124例孕妇,应用SNP array对羊水中的胎儿细胞及父母双方的外周血细胞进行遗传学分析。结果：对羊水胎儿细胞进行SNP array分析发现,2例部分型16单亲二体型,1例位点为16p12.2～13.3和16q24.1～24.3,另1例位点为16q21～24.3。对胎儿双亲外周血细胞进行遗传学连锁分析发现,2例单亲二体型均为母源性。结论：16号染色体长、短臂末端可能分别存在导致胎儿生长受限的基因。 SNP array可探索单亲二体型的来源及致病机制,为产前遗传咨询提供帮助。     

Experience with carrier screening and prenatal diagnosis for 16 Ashkenazi Jewish genetic diseases

The success of prenatal carrier screening as a disease prevention strategy in the Ashkenazi Jewish (AJ) population has driven the expansion of screening panels as disease‐causing founder mutations have been identified. However, the carrier frequencies of many of these mutations have not been reported in large AJ cohorts. We determined the carrier frequencies of over 100 mutations for 16 recessive disorders in the New York metropolitan area AJ population. Among the 100% AJ‐descended individuals, screening for 16 disorders resulted in ～1 in 3.3 being a carrier for one disease and ～1 in 24 for two diseases. The carrier frequencies ranged from 0.066 (1 in 15.2; Gaucher disease) to 0.006 (1 in 168; nemaline myopathy), which averaged ～15% higher than those for all screenees. Importantly, over 95% of screenees chose to be screened for all possible AJ diseases, including disorders with lower carrier frequencies and/or detectability. Carrier screening also identified rare individuals homozygous for disease‐causing mutations who had previously unrecognized clinical manifestations. Additionally, prenatal testing results and experience for all 16 disorders (n = 574) are reported. Together, these data indicate the general acceptance, carrier frequencies, and prenatal testing results for an expanded panel of 16 diseases in the AJ population. Hum Mutat 31:1–11, 2010. © 2010 Wiley‐Liss, Inc.     

The HLA‐DRB1 risk alleles for multiple sclerosis are differentially expressed in blood cells of patients from Southern Italy

HLA gene expression has an important role in the autoimmune disease predisposition. We investigated the mRNA expression profile of the risk alleles HLA‐DRB1*15 and HLA‐DRB1*13 in a cohort of subjects both multiple sclerosis (MS) patients and healthy controls. Moreover, we explored the expression of the allele HLA‐DRB1*11 that is very frequent in our cohort from southern Italy. We found that the expression of MS‐associated alleles in heterozygous MS patients was always higher than the nonassociated alleles. The differential risk allele expression occurred also in nonaffected subjects, though with a lower increment compared to MS patients.