Diagnostic Services Pediatrics Test Summary Chromosomal Microarray, Postnatal, ClariSure® Oligo-SNP The American College of Medical Genetics (ACMG) Test Code: 16478(X) recommends CMA testing as a first-line genetic test for developmental delay, intellectual disability, ASDs, and Specimen Requirements: 10 mL room-temperature whole multiple congenital anomalies.2,4 This recommendation blood (sodium-heparin, green-top tube); 5 mL minimum is based, in part, on a literature review that included over 21,000 patients with developmental delay/intellectual CPT Code*: 81229 disability, ASDs, or multiple congenital anomalies. The diagnostic yield was 15% to 20% for CMA testing versus ~3% for G-banded karyotyping and ~6% for subtelomeric Clinical Use fluorescence in situ hybridization (FISH) in combination • Determine the genetic etiology of developmental with G-banded karyotyping.5 In individuals with complex delay, intellectual disability, autism spectrum disorders ASDs, CMA testing can result in a diagnostic yield of over (ASDs; pervasive developmental disorders), and 25%.2 ACMG still considers karyotyping a first-line test multiple congenital anomalies when patients are suspected of having a recognizable • Confirm or exclude the diagnosis of known chromosomal syndrome such as trisomy 21 or 18, Turner chromosomal syndromes syndrome, or Klinefelter syndrome.2,4 • Further define ambiguities arising from cytogenetic The oligonucleotide-single nucleotide polymorphism or FISH studies (oligo-SNP) array contains over 2.6 million probes and • Assist in clinical management and genetic counseling covers regions of known and likely CNVs. It can confirm the diagnosis of suspected disorders associated with known Clinical Background chromosomal syndromes and is especially well suited Global developmental delay, intellectual disability (mental for determining the genetic cause of less well-described retardation), ASDs, and multiple congenital anomalies may disorders. The oligo-SNP format provides extensive be caused by environmental factors, genetic factors, or a information across the genome allowing precise definition combination of both. Determining the cause is important of breakpoints and detection of uniparental disomy, copy for long-term patient management and genetic counseling. number neutral regions of homozygosity (ROH), and, in Chromosomal abnormalities such as copy number variants some cases, consanguinity. (CNVs) are known to cause developmental delay and intellectual disability.1 CNVs are also estimated to occur Refer to the Table for a list of selected genes and in 8% to 21% of patients with ASDs.2 Chromosomal associated disorders. microarray (CMA) testing is a powerful method of identifying CNVs, many of which are associated with Individuals Suitable for Testing clinically actionable conditions.3 • Individuals with unexplained developmental delay, intellectual disability, ASDs, or multiple congenital anomalies Chromosomal Microarray, Postnatal, ClariSure® Oligo-SNP ClariSure® Postnatal, Microarray, Chromosomal Summary Test Diagnostic Services Pediatrics Method Interpretive Information • DNA preparation The presence of specific chromosomal alterations – DNA extraction and digestion by previously associated with developmental delay, restriction enzymes intellectual disability, ASDs, or multiple congenital anomalies suggests that these findings are most likely – Selective polymerase chain reaction (PCR) the cause of the respective disorder. Findings with amplification of digested DNA uncertain clinical significance (equivocal findings) may – Purification and fragmentation of amplified DNA be followed up with parental testing to help distinguish • Hybridization to the oligo-SNP microarray pathogenic from benign results. A CNV is more likely to be pathogenic if the same CNV is detected in an affected – ~750,000 SNP probes for genotyping (copy number parent; conversely, a CNV is more likely to be benign if it is neutral event detection, eg, ROH) and CNV detection detected in an unaffected parent.5 Other clinical situations – 1.9 million copy number probes evenly spaced across may also require follow-up with parental testing. the genome for CNV detection Although the array provides extensive information across • Microarray analysis the genome, normal results do not rule out the possibility – Software comparison of fluorescence scans of of chromosomal abnormalities. This assay may not detect patient DNA with reference DNA data rearrangements that do not result in a gain or loss of genetic material (eg, balanced reciprocal translocations or – Determination of copy number gains/losses and inversions) or mosaic abnormalities or aberrations smaller copy number neutral ROH than the resolution of the array. The array effectively – FISH probes may be used for confirmation genotypes SNPs across the genome, but it will not detect of deletions point mutations or other alterations at the single gene • Resolution set at >50 kb for copy number loss and level for the purposes of carrier or mutational analysis for >200 kb for copy number gain any particular disease. • Results reported by a board-certified geneticist; include Additional assistance in interpretation of results is 6 an ISCN description of any genomic abnormality available from Quest Diagnostics Genetic Counselors by detected and a clinical interpretation. CNVs known to calling 866-GENE-INFO (866-436-3463). have no phenotypic consequences are not reported. Table. Selected Genes and Associated Disorders in the Chromosomal Microarray, Postnatal, ClariSure® Oligo-SNP Test This table contains some of the more common disorders associated with CNVs that are detectable by this method; however, it is not comprehensive. OMIM # Disorder Gene Target Gene Map Locus 607872 1p36 deletion syndrome Multiple 1p36 612474 1q21.1 deletion syndrome Multiple 1q21.1 274000 1q21.1 deletion syndrome (thrombocytopenia- Multiple 1q21.1 absent radius [TAR] syndrome) 612475 1q21.1 duplication syndrome Multiple 1q21.1 612513 2p16.1-p15 deletion syndrome Multiple 2p16.1-p15 612313 2q32-q33 deletion syndrome Multiple 2q32-q33 609425 3q29 microdeletion syndrome Multiple in 3q29, 3q29 including PAK2 and DLG1 OMIM # Disorder Gene Target Gene Map Locus 612001 15q13.3 microdeletion syndrome Multiple 15q13.3 610443 17q21.31 microdeletion syndrome MAPT, CRHR1 17q21.31 608363 22q11.2 microduplication syndrome Duplication of 3-Mb 22q11.2 region in 22q11 611867 22q11.2 deletion syndrome, distal Multiple 22q11.2 606232 22q13.3 deletion syndrome SHANK3 22q13.3 610253 9q34.3 deletion syndrome EHMT1 9q34.3 300200 Adrenal hypoplasia, congenital NROB1 Xp21.3-p21.2 118450 Alagille syndrome JAG1 20p12 Albinism, oculocutaneous, type II OCA2 15q11.2-q12 203200 All unique subtelomeric regions Multiple 41 subtelomeres All unique pericentromeric regions Multiple 43 pericentromeric regions 141750 Alpha-thalassemia/mental retardation syndrome, HBA1, HBA2, SOX8 16pter-p13.3 deletion type Alzheimer disease-1, APP-related APP 21q21 104760 Aneuploidy Multiple All chromosomes 105830 Angelman syndrome UBE3A 15q11.2-q13 106210 Aniridia, type II PAX6 11p13 607941 Atrial septal defect 2 GATA4 8p23.1-p22 608636 Autism susceptibility Duplication of 15q11-q13 15q11 611913 Autism susceptibility Multiple 16p11.2 300495 Autism, X-linked, susceptibility NLGN4X Xp22.33 400003 400026 Azoospermia factors (a, b, and c) DAZ 1-4 Yq11 400027 209900 Bardet-Biedl syndrome 14 CEP290 12q21.3 602522 Bartter syndrome, infantile, BSND 1p31 with sensorineural deafness 109400 Basal cell nevus syndrome (Gorlin syndrome) PTCH1 9q22.3 CDKN1C 11p15.5 130650 Beckwith-Wiedemann syndrome H19 11p15.5 KCNQ1OT1 11p15.5 110100 Blepharophimosis, ptosis, and epicanthus FOXL2 3q23 inversus 600430 Brachydactyly-mental retardation syndrome Deletion 2q37 2q37 113650 Branchiootorenal syndrome 1 EYA1 8q13.3 300300 Bruton agammaglobulinemia tyrosine kinase BTK Xq21.3-q22 Diagnostic Services Pediatrics OMIM # Disorder Gene Target Gene Map Locus 166700 Buschke-Ollendorff syndrome LEMD3 12q14 114290 Campomelic dysplasia SOX9 17q24.3-q25.1 115470 Cat eye syndrome 22q11 118220 Charcot-Marie-Tooth disease, PMP22 17p11.2 demyelinating, type 1A 214800 CHARGE syndrome CHD7 8q12.1 119600 Cleidocranial dysplasia RUNX2 6p21 122470 Cornelia de Lange syndrome NIPBL 5p13.1 123450 Cri-du-chat syndrome Multiple 5p15.2 176450 Currarino syndrome HLXB9 7q36 220200 Dandy-Walker syndrome ZIC4, ZIC1 3q24 142340 Diaphragmatic hernia, congenital CHD2, NR2F2 15q26.1 188400 DiGeorge/Velocardiofacial syndrome 1 HIRA, TBX1 22q11.2 192430 601362 DiGeorge/Velocardiofacial syndrome 2 Unknown 10p14-p13 300018 Dosage-sensitive sex reversal NROB1 Xp21.3-p21.2 190685 Down syndrome critical region Multiple 21q22.3 300672 Epileptic encephalopathy, early infantile, 2 CDKL5 Xp22 175100 Familial adenomatous polyposis (FAP)/Gardner APC 5q21-q22 syndrome 164280 Feingold syndrome MYCN 2p24.1 175700 Greig cephalopolysyndactyly syndrome GLI3 7p13 162500 Hereditary neuropathy with pressure palsies PMP22 17p11.2 (HNPP) 306955 Heterotaxy, visceral, X-linked ZIC3 Xq26.2 236100 Holoprosencephaly 1 TMEM1 21q22.3 157170 Holoprosencephaly 2 SIX3 2p21 142945 Holoprosencephaly 3 SHH 7q36 142946 Holoprosencephaly 4 TGIF 18p11.3 609637 Holoprosencephaly 5 ZIC2 13q32 610828 Holoprosencephaly 7 PTCH1 9q22.3 142900 Holt-Oram syndrome TBX5 12q24.1 307030 Hyperglycerolemia (glycerol kinase deficiency) GK Xp21.3-p21.2 300474 146255 Hypoparathyroidism, sensorineural deafness, GATA3 10p15 renal disease (HDR) OMIM # Disorder Gene Target Gene Map Locus 147791