Femke de Vries

Benefits and burdens of using a SNP array in pregnancies at increased risk for the common aneuploidies.

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.

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

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.

False Negative NIPT Results: Risk Figures for Chromosomes 13, 18 and 21 Based on Chorionic Villi Results in 5967 Cases and Literature Review

Non-invasive prenatal testing (NIPT) demonstrated a small chance for a false negative result. Since the “fetal” DNA in maternal blood originates from the cytotrophoblast of chorionic villi (CV), some false negative results will have a biological origin. Based on our experience with cytogenetic studies of CV, we tried to estimate this risk. 5967 CV samples of pregnancies at high risk for common aneuplodies were cytogenetically investigated in our centre between January 2000 and December 2011. All cases of fetal trisomy 13, 18 and 21 were retrospectively studied for the presence of a normal karyotype or mosaicism < 30% in short-term cultured (STC-) villi. 404 cases of trisomies 13, 18 and 21 were found amongst 5967 samples (6,8%). Of these 404 cases, 14 (3,7%) had a normal or low mosaic karyotype in STC-villi and therefore would potentially be missed with NIPT. It involved 2% (5/242) of all trisomy 21 cases and 7.3% (9/123) of all trisomy 18 cases. In 1:426 (14/5967) NIPT samples of patients at high risk for common aneuploidies, a trisomy 18 or 21 will potentially be missed due to the biological phenomenon of absence of the chromosome aberration in the cytotrophoblast.

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

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

Prenatal diagnosis of susceptibility loci for neurodevelopmental disorders - genetic counseling and pregnancy outcome in 57 cases

Whole genome array testing not only provides an increased diagnostic yield of pathogenic causative findings, but it may also reveal so called susceptibility loci (SL) for neurodevelopmental disorders. The goal of this study was to evaluate the pregnancy outcomes in SL cases and to establish a protocol for pregnancy management, follow‐up and additional investigations.

The influence of SNP-based chromosomal microarray and NIPT on the diagnostic yield in 10,000 fetuses with and without fetal ultrasound anomalies

Prenatal diagnostics has been impacted by technological changes in the past decade, which have affected the diagnostic yield. The aim of this study was to evaluate the impact of SNP array and noninvasive prenatal testing (NIPT) on the diagnostic yield and the number of invasive tests in our center. The frequency of pathogenic fetal unbalanced chromosome aberrations was studied in 10,005 cases referred for prenatal testing in 2009–2015. Chromosomal SNP microarray analysis replaced karyotyping in all invasively tested pregnancies and since 2014 a choice between NIPT and diagnostic testing with microarray was offered to women with an increased risk for common aneuploidy. The introduction of microarray led to an additional yield of submicroscopic pathogenic chromosome aberrations: 3.6% in fetuses with ultrasound anomalies and 1.9% in fetuses without ultrasound anomalies. The introduction of NIPT led to a decrease of invasive tests and of diagnostic yield. Moreover, a diagnostic delay in about 1:350 cases was observed. Since 20%–33% of pathogenic fetal chromosome aberrations are different from the common aneuploidies and triploidy, whole‐genome analysis should be offered after invasive sampling. Because NIPT (as a second screening) has led to a decreased diagnostic yield, it should be accompanied by an appropriate pretest counseling.

Is prenatal cytogenetic diagnosis with genomic array indicated in pregnancies at risk for a molecular or metabolic disorder

Is prenatal cytogenetic diagnosis with genomic array indicated in pregnancies at risk for a molecular or metabolic disorder?

Clinical experience of unexpected findings in prenatal array testing.

AIM The aim of this study was to evaluate whether unexpected diagnoses (UD) made by prenatal array testing contribute to pregnancy management. PATIENTS & METHODS In 2010-2015 in 19/4043 (0.5%) pregnancies an UD was made. The clinical usefulness of UDs was assessed based on the couples responses during post-test counseling and their decisions. RESULTS In 16/19 cases, the UD was helpful either for the couples in making a decision about the course of their pregnancy, for perinatal management or family genetic counseling. CONCLUSION The majority of the pregnant couples found the UDs relevant for pregnancy management and genetic counseling. This adds another motive for offering whole genome array during pregnancy in patients who wish broad testing of their fetus.

CSTB null mutation associated with microcephaly, early developmental delay, and severe dyskinesia

The CSTB gene encodes for cystatin B, an inhibitor of lysosomal cysteine protease (cathepsins B, H, L, and S).1 CSTB mutations have been associated with type 1 progressive myoclonic epilepsy, also known as Unverricht-Lundborg (ULD) disease, or Baltic myoclonus.2,3 A total of 90% of all disease alleles consists of an expansion of at least 30 times of an unstable 12-nucleotide stretch (dodecamer 5′-CCCCGCCCCGCG-3′) in the CSTB promoter region. Homozygosity for this expansion is considered the founder mutation in the Finnish population. Few other mutations have been described, among these the p.Arg68*, but until now only as compound heterozygous with the dodecamer expansion.4–6 Expression of the p.Arg68* mutation in vitro indicates that the truncated protein is rapidly degraded, confirming that it is a null mutation.7 Between the ages of 6 and 16 years, ULD begins with stimulus-sensitive myoclonus and generalized tonic-clonic seizures, which can be worsened by phenytoin, followed by ataxia and slow neurodegeneration. Here we report on the first 2 patients with a homozygous p.Arg68* null mutation.

Unexpected finding of uniparental disomy mosaicism in term placentas: Is it a common feature in trisomic placentas?

Non‐invasive prenatal testing (NIPT) detects placental chromosome aberrations. When amniocentesis reveals a normal karyotype, confined placental mosaicism (CPM) may be assumed. In order to confirm this, placental cytogenetic studies were performed.