Genome-wide association studies (GWAS) involve testing genetic variants across the genomes of many individuals to identify genotype–phenotype associations. GWAS have revolutionized the field of complex disease genetics over the past decade, providing numerous compelling associations for human complex traits and diseases. Despite clear successes in identifying novel disease susceptibility genes and biological pathways and in translating these findings into clinical care, GWAS have not been without controversy. Prominent criticisms include concerns that GWAS will eventually implicate the entire genome in disease predisposition and that most association signals reflect variants and genes with no direct biological relevance to disease. In this Review, we comprehensively assess the benefits and limitations of GWAS in human populations and discuss the relevance of performing more GWAS. Despite the success of human genome-wide association studies (GWAS) in associating genetic variants and complex diseases or traits, criticisms of the usefulness of this study design remain. This Review assesses the pros and cons of GWAS, with a focus on the cardiometabolic field.

Benefits and limitations of genome-wide association studies.

Prenatal diagnosis by chromosomal microarray analysis.

The Use of Chromosomal Microarray Analysis in Prenatal Diagnosis

https://scholarlypublications.universiteitleiden.nl/access/item%3A3006453/view

Origin and clinical relevance of chromosomal aberrations other than the common trisomies detected by genome-wide NIPS: Results of the TRIDENT study

Objective
To establish the frequency of pathogenic submicroscopic chromosome aberrations in fetuses that are not at increased risk for unbalanced structural chromosome aberrations, a systematic literature search was performed The aim was to determine whether high resolution testing for submicroscopic aberrations is beneficial in a general pregnant population

Methods
On 3rd June 2016 Embase and PubMed databases were systematically searched for all relevant articles on prevalence of pathogenic submicroscopic CNVs in fetuses tested due to advanced maternal age or parental anxiety Relevant full text articles were analyzed and based on the extracted data the prevalence of submicroscopic CNVs was calculated

Results
Meta-analysis was conducted in a pooled cohort of 10,614 fetuses based on the 10 largest studies (N > 300) of a total of 19 relevant studies In 084%, 95%CI [055%, 130%] of fetuses a submicroscopic pathogenic aberration was detected prenatally The onset/penetrance of the submicroscopic findings was studied in 10,314 fetuses out of 8 papers that presented aberrant cases with all necessary details The pooled estimates resulting from meta-analysis of the data indicated that in 037%, 95% CI [027%, 052%] an early onset syndromic disorder was detected, in 030%, 95% CI [014%, 067%] a susceptibility CNV was found, and in 011%, 95% CI [005%, 021%] cases of late onset diseases were reported The prevalence of early onset syndromic disorders due to a submicroscopic aberration was calculated to be 1:270 When the risk for submicroscopic aberrations would be added to the individual risk for microscopic chromosome aberrations, all pregnant women have a risk higher than 1:180 for a relevant chromosome aberration, and pregnant women under 36 years old have a higher risk for submicroscopic pathogenic aberrations than for Down syndrome

Conclusion
This systematic review shows that a significant proportion of fetuses in a general pregnant population carry a submicroscopic pathogenic CNV Based on these figures all women should be informed on their individual risk for all pathogenic chromosome aberrations and not only for common trisomies

https://obgyn.onlinelibrary.wiley.com/doi/epdf/10.1002/uog.17533

Frequency of submicroscopic chromosomal aberrations in pregnancies without increased risk for structural chromosomal aberrations: systematic review and meta-analysis

To evaluate the diagnostic value of single-nucleotide polymorphism (SNP) array testing in 1033 fetuses with ultrasound anomalies we investigated the prevalence and genetic nature of pathogenic findings. We reclassified all pathogenic findings into three categories: causative findings; unexpected diagnoses (UD); and susceptibility loci (SL) for neurodevelopmental disorders. After exclusion of trisomy 13, 18, 21, sex-chromosomal aneuploidy and triploidies, in 76/1033 (7.4%) fetuses a pathogenic chromosome abnormality was detected by genomic SNP array: in 19/1033 cases (1.8%) a microscopically detectable abnormality was found and in 57/1033 (5.5%) fetuses a pathogenic submicroscopic chromosome abnormality was detected. 58% (n=44) of all these pathogenic chromosome abnormalities involved a causative finding, 35% (n=27) a SL for neurodevelopmental disorder, and 6% (n=5) a UD of an early-onset untreatable disease. In 0.3% of parental samples an incidental pathogenic finding was encountered. Our results confirm that a genomic array should be the preferred first-tier technique in fetuses with ultrasound anomalies. All UDs involved early-onset diseases, which is beneficial for the patients to know. It also seems that UDs occur at a comparable frequency among microscopic and submicroscopic pathogenic findings. SL were more often detected than in pregnancies without ultrasound anomalies.

/pdf/prenatal-snp-array-testing-in-1000-fetuses-with-ultrasound-bfb83s5yur.pdf

Prenatal SNP array testing in 1000 fetuses with ultrasound anomalies: causative, unexpected and susceptibility CNVs.

Another Rare Prenatal Case of Post-Zygotic Mosaic Trisomy 17 Femke A.T. de Vries, Lutgarde C.P. Govaerts, Jeroen Knijnenburg, Maarten F.C.M. Knapen, Gr etel G. Oudesluijs, Debora Lont, Petra Noomen, Katja de Graaff, Malgorzata I. Srebniak, and Diane Van Opstal* Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands Department of Obstetrics and Gynaecology, Erasmus MC, Rotterdam, The Netherlands Department of Obstetrics and Gynaecology, Reinier de Graaf Gasthuis, Voorburg, The Netherlands

Another rare prenatal case of post-zygotic mosaic trisomy 17.

We present the nature of pathogenic SNP array findings in pregnancies without ultrasound (US) abnormalities and show the additional diagnostic value of SNP array as compared with rapid aneuploidy detection and karyotyping. 1,330 prenatal samples were investigated with a 0.5-Mb SNP array after the exclusion of the most common aneuploidies. In 2.7% (36/1,330) of the cases, pathogenic chromosome aberrations were found; a microscopically detectable abnormality in 0.7% and a submicroscopic aberration in 2%. Our results show that in addition to the age- or screening-related aneuploidy risk, in pregnancies without US abnormalities, there is a risk of 1:148 (9/1,330) for a (sub)microscopic abnormality associated with an early-onset often severe disease, 1:222 (6/1,330) for a submicroscopic aberration causing an early-onset disease, 1:74 (18/1,330) for carrying a susceptibility locus for a neurodevelopmental disorder, and 1:443 (3/1,330) for a late-onset disorder (hereditary neuropathy with liability to pressure palsies in all three cases). These risk figures are important for adequate pretest counseling so that prospective parents can make informed individualized choices between targeted prenatal testing and broad testing with SNP array. Based on our results, we believe if invasive testing is performed, SNP array should be the preferred cytogenetic technique irrespective of the indication.

Benefits and Burdens of Using a SNP Array in Pregnancies at Increased Risk for the Common Aneuploidies

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Prenatal SNP array testing in 1000 fetuses with ultrasound anomalies: causative, unexpected and susceptibility CNVs.

Another rare prenatal case of post-zygotic mosaic trisomy 17.

Benefits and Burdens of Using a SNP Array in Pregnancies at Increased Risk for the Common Aneuploidies