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.

BACKGROUND-Duplications and deletions in the human genome can cause disease or predispose persons to disease. Advances in technologies to detect these changes allow for the routine identification of submicroscopic imbalances in large numbers of patients.

Purpose Copy number variants (CNVs) have emerged as a major cause of human disease such as autism and intellectual disabilities. Because CNVs are common in normal individuals, determining the functional and clinical significance of rare CNVs in patients remains challenging. The adoption of whole-genome chromosomal microarray analysis (CMA) as a first-tier diagnostic test for individuals with unexplained developmental disabilities provides a unique opportunity to obtain large CNV datasets generated through routine patient care. Methods A consortium of diagnostic laboratories was established [the International Standards for Cytogenomic Arrays (ISCA) consortium] to share CNV and phenotypic data in a central, public database. We present the largest CNV case-control study to date comprising 15,749 ISCA cases and 10,118 published controls, focusing our initial analysis on recurrent deletions and duplications involving 14 CNV regions. Results Compared to controls, fourteen deletions, and seven duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. Conclusion Given the rapid expansion of clinical CMA testing, very large datasets will be available to determine the functional significance of increasingly rare CNVs. This data will provide an evidenced-based guide to clinicians across many disciplines involved in the diagnosis, management, and care of these patients and their families.