More and more rare genetic variants are being detected in the human genome, and it is believed that besides common variants, some rare variants also explain part of the phenotypic variance for human diseases. Due to the importance of rare variants, many statistical methods have been proposed to test for associations between rare variants and human traits. However, in existing studies, most methods only test for associations between multiple loci and one trait; therefore, the joint information of multiple traits has not been considered simultaneously and sufficiently. In this article, we present a study of testing for associations between rare variants and multiple traits, where trait value can be binary, ordinal, quantitative and/or any mixture of them. Based on the method of generalized Kendall's τ, a nonparametric method called NM-RV is proposed. A new kernel function for U-statistic, which could incorporate the information of each rare variant itself, is also presented and is expected to enhance the power of rare variant analysis. We further consider the asymptotic distribution of the proposed association test statistic. Our simulation work suggests that the proposed method is more powerful and robust than existing methods in testing for associations between rare variants and multiple traits, especially for multivariate ordinal traits.

The use of non-anonymized human genome data is becoming increasingly popular in research. Here we review the proceedings of a special meeting on this topic that took place at European Molecular Biology Organization (EMBO) in December 2014. The main points discussed centered on how to achieve ‘anonymity,’ ‘trust,’ and ‘protection of data’ in relation to new genomic technologies and research. Following our report of this meeting, we also raise three further issues for future consideration: the harmonization of international law in relation to genetic data protection; the complex issues around the ‘dividual’ nature of genetic data; and the growing commercial value of personal data. In conclusion, we stress the importance of scientists working in the area of genomic research engaging in interdisciplinary collaborations with humanities and social science scholars and addressing these complicated issues.

Precision medicine, incorporating personalized medicine, is an emerging medical model that holds great promise for improving the prevention, diagnosis and treatment of many diseases. The future success of precision medicine, however, depends on the establishment of large databases that collate diverse data, including family genealogies, disease histories, drug sensitivities and genomic data. Herein I raise some of the social and ethical challenges that such a system faces, specifically: the enrolment of volunteers into large genetic databases; the need for a change in mindset of clinicians, patients and the wider public; and the need for interdisciplinary ethics considering the emerging issues. Finally I argue that the future potential of ‘personalized’ medicine crucially depends on ‘collective’ participation of informed citizens.

Induced pluripotent stem (iPS) cells have great potential in regenerative medicine, including cell replacement therapies and disease modelling in vitro. However, with this potential comes several challenges, including clinical safety, reprogramming and differentiation efficiency, and compromised functionality of differentiated cell types after transplantation. Many of these issues arise from imprecise control of cell fate. With large-scale sequencing and genome-editing technologies we can now precisely manipulate the genome, which has expanded our knowledge of functional cell types and cell identity. These technologies may improve our efforts in generating iPS-derived therapeutic cells and in development of therapies for human diseases.

Hereditary mixed polyposis is a genetically heterogeneous, autosomal dominant condition with adenomatous, hyperplastic and juvenile polyps. We conducted a comprehensive clinical evaluation of a large Ashkenazi Jewish family with this phenotype and performed extensive genetic testing. As seen in one previous report, a 40 kb duplication upstream of GREM1 segregated with the polyposis/colon cancer phenotype in this kindred. Our study confirms the association of GREM1 with mixed polyposis and further defines the phenotype seen with this mutation. This gene should be included in the test panel for all Jewish patients with mixed polyposis and may be considered in any Ashkenazi patient with unexplained hereditary colon cancer when mutations in other hereditary colon cancer genes have been ruled out.

Although many genome-wide association studies have been performed, the identification of disease polymorphisms remains important. It is now suspected that many rare disease variants induce the association signal of common variants in linkage disequilibrium (LD). Based on recent development of genetic models, the current study provides explanations of the existence of rare variants with high impacts and common variants with low impacts. Disease variants are neither necessary nor sufficient due to gene–gene or gene–environment interactions. A new method was developed based on theoretical aspects to identify both rare and common disease variants by their genotypes. Common disease variants were identified with relatively small odds ratios and relatively small sample sizes, except for specific situations in which the disease variants were in strong LD with a variant with a higher frequency. Rare disease variants with small impacts were difficult to identify without increasing sample sizes; however, the method was reasonably accurate for rare disease variants with high impacts. For rare variants, dominant variants generally showed better Type II error rates than recessive variants; however, the trend was reversed for common variants. Type II error rates increased in gene regions containing more than two disease variants because the more common variant, rather than both disease variants, was usually identified. The proposed method would be useful for identifying common disease variants with small impacts and rare disease variants with large impacts when disease variants have the same effects on disease presentation.

The pathogenesis of the development and progression of thyroid cancer (TC) is far from being clear at present. Accumulated evidence suggests that it is a complex polygenic disorder for which genetic factors play an important role in disease aetiology. Here we review the literature to report the genetic variations and alterations that have been described in the aetiology of TC. The functional effects of some mutations and single nucleotide polymorphisms on TC are validated, establishing the role of sequence variations in this cancer. However, large prospective studies are still required to evaluate the diagnostic and prognostic value of these genetic determinants in clinical practice.

Whole-exome sequencing for clinical applications is now an integral part of medical genetics practice. Though most studies are performed in order to establish diagnoses in individuals with rare and clinically unrecognizable disorders, due to the constantly decreasing costs and commercial availability, whole-exome sequencing has gradually become the initial tool to study patients with clinically recognized disorders when more than one gene is responsible for the phenotype or in complex phenotypes, when variants in more than one gene can be the cause for the disease. Here we report a patient presenting with a complex phenotype consisting of severe, adult-onset, dilated cardiomyopathy, hearing loss and developmental delay, in which exome sequencing revealed two genetic variants that are inherited from a healthy mother: a novel missense variant in the CASK gene, mutations in which cause a spectrum of neurocognitive manifestations, and a second variant, in MYBPC3, that is associated with hereditary cardiomyopathy. We conclude that although the potential for co-occurrence of rare diseases is higher when analyzing undefined phenotypes in consanguineous families, it should also be given consideration in the genetic evaluation of complex phenotypes in non-consanguineous families.

The genomic control (GC) approach is extensively used to effectively control false positive signals due to population stratification in genome-wide association studies (GWAS). However, GC affects the statistical power of GWAS. The loss of power depends on the magnitude of the inflation factor (λ) that is used for GC. We simulated meta-analyses of different GWAS. Minor allele frequency (MAF) ranged from 0·001 to 0·5 and λ was sampled from two scenarios: (i) random scenario (empirically-derived distribution of real λ values) and (ii) selected scenario from simulation parameter modification. Adjustment for λ was considered under single correction (within study corrected standard errors) and double correction (additional λ corrected summary estimate). MAF was a pivotal determinant of observed power. In random λ scenario, double correction induced a symmetric power reduction in comparison to single correction. For MAF <5%, GC significantly reduced power for genetic risks ranging from 1·2 to 1·4 (n = 10–20). Rising MAF attenuated the correction effect of λ adjustment. Moderate λ approach yielded more conservative results for population stratification adjustment, especially for MAF <5%. Large λ approach yielded an approximate two fold decrease in power when compared to moderate λ approach and almost four fold when the original random λ scenario was considered. Meta-analysis power can be adequate to detect significant variants even for double GC correction when effect size exceeds >1·2 and MAF >5%. Our results provide a quick but detailed index for power considerations of future meta-analyses of GWAS that enables a more flexible design from early steps based on the number of studies accumulated in different groups and the λ values observed in the single studies.

Inherited optic neuropathies are a heterogeneous group of disorders characterized by mild to severe visual loss, colour vision deficit, central or paracentral visual field defects and optic disc pallor. Optic atrophies can be classified into isolated or non-syndromic and syndromic forms. While multiple modes of inheritance have been reported, autosomal dominant optic atrophy and mitochondrial inherited Leber's hereditary optic neuropathy are the most common forms. Optic atrophy type 1, caused by mutations in the OPA1 gene is believed to be the most common hereditary optic neuropathy, and most patients inherit a mutation from an affected parent. In this study we used whole-exome sequencing to investigate the genetic aetiology in a patient affected with isolated optic atrophy. Since the proband was the only affected individual in his extended family, and was a product of consanguineous marriage, homozygosity mapping followed by whole-exome sequencing were pursued. Exome results identified a novel de novo OPA1 mutation in the proband. We conclude, that though de novo OPA1 mutations are uncommon, testing of common optic atrophy-associated genes such as mitochondrial mutations and OPA1 gene sequencing should be performed first in single individuals presenting with optic neuropathy, even when dominant inheritance is not apparent.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID) and co-morbid autism. It is caused by an amplification of the CGG repeat (>200), which is known as the full mutation, within the 5′UTR of the FMR1 gene. Expansions between 55–200 CGG repeats are termed premutation and are associated with a greater risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated premature ovarian insufficiency. Intermediate alleles, also called the grey zone, include approximately 45–54 repeats and are considered borderline. Individuals with less than 45 repeats have a normal FMR1 gene. We report the occurrence of CGG expansions of the FMR1 gene in Chile among patients with ID and families with a known history of FXS. Here, we present a retrospective review conducted on 2321 cases (2202 probands and 119 relatives) referred for FXS diagnosis and cascade screening at the Institute of Nutrition and Food Technology (INTA), University of Chile. Samples were analysed using traditional cytogenetic methods and/or PCR. Southern blot was used to confirm the diagnosis. Overall frequency of FMR1 expansions observed among probands was 194 (8·8%), the average age of diagnosis was 8·8 ± 5·4 years. Of 119 family members studied, 72 (60%) were diagnosed with a CGG expansion. Our results indicated that the prevalence of CGG expansions of the FMR1 gene among probands is relatively higher than other populations. The average age of diagnosis is also higher than reference values. PCR and Southern blot represent a reliable molecular technique in the diagnosis of FXS.

Recent advances in biological and computational technologies are changing the way different social groups imagine race, gender, kinship, citizenship and disease risk. Existing taxonomies are being displaced or reconfigured, impacting the ways in which people are governed, how lives are lived, how groups are known and how power is exercised. Herein we report on a two-day international symposium that we co-organized, titled ‘The molecularization of identity: science and subjectivity in the 21st century,’ that was held on 29–30 April 2016 at the Program on Science, Technology and Society, at Harvard University. The symposium drew upon the tools and expertise from multiple disciplines and diverse geographical regions and consisted of 24 original research presentations and an interdisciplinary roundtable. Specific attention was paid to the bioethical, material and lived dimensions of recent developments in molecular technologies, and discussions interrogated the complex ways in which the ‘molecular realm’ is an emerging site for constituting human identities in the 21st century. Herein we summarize some of the key findings of the conference and raise three further issues for practitioners and researchers to consider in relation to the broader impact of genetics research. Namely: transnational governance of emerging biotechnologies; representation of different interest groups in policy decisions; and rights of access to emerging technologies.

Marfan syndrome is an autosomal dominant connective tissue disorder, predominantly affecting the ocular, skeletal and cardiovascular systems. Here, we present the results of the first genetic testing in 40 Ukrainian Marfan (-like) patients and 10 relatives. We applied a targeted next generation sequencing panel comprising FBN1 and 13 thoracic aortic aneurysm genes. We identified 27 causal mutations in FBN1, obtaining a mutation yield of 67·5%. A significant difference in age at aortic surgery between mutation positive and negative patients was observed. Thus, we conclude that genetic testing is important to identify patients at higher risk for developing life-threatening cardiovascular complications.

DNA methylation is an epigenetic marker that has been shown to vary significantly across different tissues. Taking advantage of the methylation differences between placenta-derived cell-free DNA and maternal blood, several groups employed different approaches for the discovery of fetal-specific biomarkers. The aim of this study was to analyse whole-genome fetal and maternal methylomes in order to identify and confirm the presence of differentially methylated regions (DMRs). We have initially utilized methylated DNA immunoprecipitation (MeDIP) and next-generation sequencing (NGS) to identify genome-wide DMRs between chorionic villus sampling (CVS) and female non-pregnant plasma (PL) and peripheral blood (WBF) samples. Next, using specific criteria, 331 fetal-specific DMRs were selected and confirmed in eight CVS, eight WBF and eight PL samples by combining MeDIP and in-solution targeted enrichment followed by NGS. Results showed higher enrichment in CVS samples as compared to both WBF and PL samples, confirming the distinct methylation levels between fetal and maternal DNA for the selected DMRs. We have successfully implemented a novel approach for the discovery and confirmation of a significant number of fetal-specific DMRs by combining for the first time MeDIP and in-solution targeted enrichment followed by NGS. The implementation of this double-enrichment approach is highly efficient and enables the detailed analysis of multiple DMRs by targeted NGS. Also, this is, to our knowledge, the first reported application of MeDIP on plasma samples, which leverages the implementation of our enrichment methodology in the detection of fetal abnormalities in maternal plasma.