Chromosomal microarray analysis as a first‐tier clinical diagnostic test: Estonian experience

Abstract

Chromosomal microarray analysis (CMA) is now established as the first-tier cytogenetic diagnostic test for fast and accurate detection of chromosomal abnormalities in patients with developmental delay/intellectual disability (DD/ID), multiple congenital anomalies (MCA), and autism spectrum disorders (ASD). We present our experience with using CMA for postnatal and prenatal diagnosis in Estonian patients during 2009–2012. Since 2011, CMA is on the official service list of the Estonian Health Insurance Fund and is performed as the first-tier cytogenetic test for patients with DD/ID, MCA or ASD. A total of 1191 patients were analyzed, including postnatal (1072 [90%] patients and 59 [5%] family members) and prenatal referrals (60 [5%] fetuses). Abnormal results were reported in 298 (25%) patients, with a total of 351 findings (1–3 per individual): 147 (42%) deletions, 106 (30%) duplications, 89 (25%) long contiguous stretches of homozygosity (LCSH) events (>5 Mb), and nine (3%) aneuploidies. Of all findings, 143 (41%) were defined as pathogenic or likely pathogenic; for another 143 findings (41%), most of which were LCSH, the clinical significance remained unknown, while 61 (18%) reported findings can now be reclassified as benign or likely benign. Clinically relevant findings were detected in 126 (11%) patients. However, the proportion of variants of unknown clinical significance was quite high (41% of all findings). It seems that our ability to detect chromosomal abnormalities has far outpaced our ability to understand their role in disease. Thus, the interpretation of CMA findings remains a rather difficult task requiring a close collaboration between clinicians and cytogeneticists.

Frequency of fetal karyotype abnormalities in women undergoing invasive testing in the absence of ultrasound and other high-risk indications

“…As providers move to molecular genetics approaches, the residual risk will be significantly increased. One of the largest prenatal CMA studies found that the frequency of pathogenic or likely pathogenic Copy Number Variants (CNVs) detectable by CMA in women with normal karyotypes and anatomically normal fetuses is 1.65% (1/61) and other smaller studies of fetuses with normal ultrasound results report supporting values . Based on the available data, some professional bodies, such as ACOG, recommend that ‘chromosomal microarray analysis be made available to any patient choosing to undergo invasive diagnostic testing’ .…”

The Diagnostic Utility of Single Long Contiguous Stretches of Homozygosity in Patients without Parental Consanguinity

“…Multiple LCSHs on different chromosomes that indicate close parental consanguinity, as well as LCSHs that cover the majority of single chromosomes and are caused by UPD, have been studied during the last few years, and their clinical implications are, therefore, better understood [Papenhausen et al, 2011;Wang et al, 2015]. Single LCSHs in patients without parental consanguinity are not infrequently found during routine diagnostics in centers where SNP array technology is in use, but their clinical significance remains unclear in most of the cases [Zilina et al, 2014]. Reporting a variant of uncertain significance (VUCS) can cause anxiety in patients and frustration in referring doctors who are not specialists in the field of medical genetics [Coughlin et al, 2012;Zilina et al, 2014].…”

“…Single LCSHs in patients without parental consanguinity are not infrequently found during routine diagnostics in centers where SNP array technology is in use, but their clinical significance remains unclear in most of the cases [Zilina et al, 2014]. Reporting a variant of uncertain significance (VUCS) can cause anxiety in patients and frustration in referring doctors who are not specialists in the field of medical genetics [Coughlin et al, 2012;Zilina et al, 2014]. Therefore, it is of great importance to work toward minimizing the number of reported VUCSs.…”

“…All the diagnostic CMA analyses in Estonia are performed in 1 diagnostic laboratory (Department of Genetics, United Laboratories, Tartu University Hospital) using single nucleotide polymorphism (SNP) genotyping technology. An overview of the Estonian experience during the first years employing CMAs in clinical diagnostics was recently published by Zilina et al [2014]. In contrast to array comparative genomic hybridization, SNP arrays also enable the detection of copy number neutral loss of heterozygosity regions, also known as regions of homozygosity or long contiguous stretches of homozygosity (LCSHs).…”

Autistic spectrum disorders: A review of clinical features, theories and diagnosis

“…In another study, it was observed that many of the ASD‐associated genes detected using WES were linked with the fragile X protein and involved in synaptic plasticity (Iossifov et al, 2012). On the other hand, chromosomal microarray analysis is a cytogenetic assay used for the detection of chromosomal abnormalities in patients diagnosed with ASD (Zilina et al, 2014). Among these abnormalities, it was found that GABA receptor subunit genes GABRB3, GABRA5 and GABRG3 were closely associated with the pathophysiology of ASD (Kim et al, 2006; Klauck, 2006; Vorstman et al, 2006).…”