Consensus Statement: Chromosomal Microarray Is a First-Tier Clinical Diagnostic Test for Individuals with Developmental Disabilities or Congenital Anomalies

Abstract

Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA). Performing CMA and G-banded karyotyping on every patient substantially increases the total cost of genetic testing. The International Standard Cytogenomic Array (ISCA) Consortium held two international workshops and conducted a literature review of 33 studies, including 21,698 patients tested by CMA. We provide an evidence-based summary of clinical cytogenetic testing comparing CMA to G-banded karyotyping with respect to technical advantages and limitations, diagnostic yield for various types of chromosomal aberrations, and issues that affect test interpretation. CMA offers a much higher diagnostic yield (15%-20%) for genetic testing of individuals with unexplained DD/ID, ASD, or MCA than a G-banded karyotype ( approximately 3%, excluding Down syndrome and other recognizable chromosomal syndromes), primarily because of its higher sensitivity for submicroscopic deletions and duplications. Truly balanced rearrangements and low-level mosaicism are generally not detectable by arrays, but these are relatively infrequent causes of abnormal phenotypes in this population (<1%). Available evidence strongly supports the use of CMA in place of G-banded karyotyping as the first-tier cytogenetic diagnostic test for patients with DD/ID, ASD, or MCA. G-banded karyotype analysis should be reserved for patients with obvious chromosomal syndromes (e.g., Down syndrome), a family history of chromosomal rearrangement, or a history of multiple miscarriages.

Copy number variations in 375 patients with oesophageal atresia and/or tracheoesophageal fistula

“…We assessed the CNVs according to the consensus statement for chromosomal microarray analysis described by Miller et al 17 Our study design was based on the assumptions that CNVs are most likely to contribute to the abnormal phenotype in congenital anomalies if (I) a CNV is absent in large cohorts of unaffected individuals, (II) is absent in the unaffected parents of the affected individual and/or (III) is absent or has a population frequency below or comparable to the disease frequency, and (IV) if it targets relevant genes or noncoding RNAs. Recurrence of loci affected by de novo CNVs in single cases could indicate loci harbouring genes mutated or otherwise affected in larger disease cohorts.…”

Phase determination using chromosomal microarray and fluorescence in situ hybridization in a patient with early onset Parkinson disease and two deletions in PRKN

“…CMA also allows clinicians to rule out common genetic etiologies for any additional features noted on patient examination. These features may include learning difficulties, such as those noted in our patient, speech or developmental delays, autism, and other indications that have been shown to be driven by CNV (Miller et al., 2010; Rehman, Dhamija, Williams, & Barrett, 2015). …”

Importance of genetic testing in global health during the evaluation of familial microcephaly

“…Chromosomal microarray is currently indicated as the most cost‐effective genetic test of choice in such instances, as it is superior to G‐banded karyotype with regard to diagnostic yield in individuals with multiple congenital anomalies, neurodevelopmental delays, intellectual disability, and autism, especially in more severely impacted individuals, and is useful in providing diagnostic information for individuals with epilepsy 5, 6, 7.…”