Testing for Multiple Congenital Anomalies: Microarray or Exome First?

When an infant presents with multiple congenital anomalies (MCA)—two or more structural defects in different organ systems—the diagnostic question is rarely whether to test genetically, but which test to run first. The practical choice usually comes down to chromosomal microarray (CMA) versus exome sequencing (ES).

The short answer: these assays detect different classes of variation and often work best in sequence. CMA resolves copy-number imbalances; ES resolves sequence-level variants. Choosing between them—or ordering both—depends on the phenotype, the acuity of the clinical situation, and the yield you expect to gain.

Frequently asked questions

Should microarray or exome come first for congenital anomalies?

It depends on the phenotype. Chromosomal microarray is a strong first-tier choice for nonspecific multiple anomalies, while exome sequencing may lead when a monogenic syndrome is strongly suspected or when a rapid answer is needed in a critically ill neonate.

What does microarray detect that exome does not?

Microarray detects copy-number variants—large deletions, duplications, and, on SNP arrays, regions of homozygosity and some triploidy. Standard exome analysis is optimized for single-nucleotide and small insertion/deletion variants, though many pipelines now call copy-number changes too.

What is the diagnostic yield of each test?

Chromosomal microarray yields a diagnosis in roughly 15–20% of children with anomalies and developmental disability. Exome sequencing adds approximately 25–40% additional yield in cohorts already negative on microarray or karyotype.

Can both tests be ordered together?

Yes. Because they capture different variant types, concurrent or reflex testing is increasingly common, especially for acutely ill infants where turnaround time is limited and the differential is broad.

Is karyotype still useful?

Karyotype remains useful when a balanced rearrangement, marker chromosome, or aneuploidy such as trisomy 21 is suspected clinically. Microarray misses balanced translocations because gene dosage is unchanged.

Why multiple congenital anomalies demand a genomic approach

MCA patterns—whether a recognizable syndrome or an undefined constellation—reflect disrupted developmental programs. The underlying cause may be a chromosomal dosage change, a single-gene disorder, an imprinting defect, or a non-genetic exposure. Because the genetic causes span several scales of variation, no single legacy test captures them all.

Historically, karyotype and targeted FISH led the workup. Today, the ACMG consensus statement by Miller and colleagues established CMA as a first-tier test for individuals with developmental delay, intellectual disability, and multiple anomalies, given its higher resolution than karyotype.

What chromosomal microarray does well

CMA scans the genome for gains and losses of genetic material. Array-CGH platforms compare patient DNA to a reference; SNP arrays add genotype information that reveals regions of homozygosity and can flag uniparental disomy or consanguinity.

Strengths

• Detects pathogenic copy-number variants such as 22q11.2 deletion or 1p36 deletion syndromes.
• Uncovers dosage imbalances too small for karyotype resolution.
• SNP content flags regions of homozygosity relevant to recessive disease and imprinting disorders.

Limits

CMA cannot detect balanced rearrangements, single-nucleotide variants, or most small insertions and deletions. A structurally abnormal infant with a normal microarray may still harbor a monogenic disorder that only sequencing will reveal.

What exome sequencing adds

ES reads the protein-coding regions—about 1–2% of the genome that carries the majority of known disease-causing variants. For MCA driven by a single-gene disorder, exome is often the only assay that reaches a molecular diagnosis.

Evidence for exome as a front-line tool has matured. The ACMG evidence-based clinical guideline on exome and genome sequencing supports ES/GS as a first- or second-tier test for pediatric patients with congenital anomalies or intellectual disability, citing superior or comparable yield versus a stepwise approach.

In critically ill neonates, rapid trio exome or genome sequencing can return actionable results within days, shortening diagnostic odysseys and informing management. Multiple cohort studies report diagnostic yields in the 25–40% range once chromosomal causes are excluded.

A practical framework for choosing

The decision is rarely binary. Consider these factors:

• Phenotype specificity. A recognizable single-gene syndrome (for example, a suspected RASopathy or a well-defined skeletal dysplasia) favors ES or a targeted panel first. A nonspecific multi-system pattern favors CMA first.
• Acuity. An unstable neonate with a broad differential may warrant rapid trio ES/GS up front, sometimes alongside CMA.
• Prior results. A normal karyotype does not exclude a microdeletion; a normal CMA does not exclude a monogenic cause—reflex to the complementary test.
• Copy-number coverage in the pipeline. Some exome pipelines now call CNVs, narrowing the gap, but validation and resolution vary by laboratory.

When to run both

Concurrent CMA and ES is reasonable when the phenotype is severe or undefined, time matters, and the family can be counseled about the possibility of variants of uncertain significance and incidental findings. Ordering both avoids sequential delays but requires clear consent and interpretation support.

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