Question

A child presents with learning difficulties and is suspected to have an intellectual disability. What is the next best investigation to determine the underlying genetic cause?

• A. FISH
• B. Karyotyping
• C. Microarray
• D. PCR

Hint:

First-Tier Genetic Workup for Unexplained Intellectual Disability GDD Autism:
1. Chromosomal Microarray Analysis (CMA) $\rightarrow$ Highest diagnostic yield (15--20%) for submicroscopic CNVs.
2. Fragile X DNA testing ($FMR1$ repeat analysis) $\rightarrow$ Parallel first-tier test in males.
Conventional karyotyping is NO LONGER the primary initial investigation!

Answer 1

The Correct Option is C

Concept:
Intellectual disability (ID) and global developmental delay (GDD) have a diverse spectrum of underlying genetic etiologies, including chromosomal aneuploidies, submicroscopic copy number variations (CNVs), and single-gene mutations.
According to clinical genetics guidelines (including the American College of Medical Genetics and Genomics - ACMG), Chromosomal Microarray (CMA) is the universally recommended first-tier genetic test for evaluating unexplained intellectual disability, autism spectrum disorder, and multiple congenital anomalies.
Explanation:
• Chromosomal Microarray (CMA), including array Comparative Genomic Hybridization (aCGH) and Single Nucleotide Polymorphism (SNP) arrays, detects submicroscopic microdeletions and microduplications across the entire genome at a vastly higher resolution ($>$ 10--100 times greater) than conventional G-banded karyotyping.

• CMA provides a diagnostic yield of approximately 15% to 20% in individuals with unexplained developmental delay and intellectual disability, compared to only 3% to 5% for standard G-banded karyotyping.

• Conventional karyotyping is limited to identifying macroscopic chromosomal abnormalities larger than 5 to 10 megabases (Mb) and is now reserved as a first-line test only when a specific common aneuploidy (such as Trisomy 21) or structural chromosomal rearrangement (e.g., balanced translocation) is strongly suspected clinically.

• Fluorescence In Situ Hybridization (FISH) is a targeted technique useful only when a specific microdeletion syndrome (such as Williams syndrome or 22q11.2 deletion syndrome) is already clinically suspected, and it cannot screen the entire genome simultaneously.

• Polymerase Chain Reaction (PCR) is utilized for targeted single-gene or repeat-expansion testing (such as $FMR1$ trinucleotide repeat analysis for Fragile X syndrome), but it is not a broad genome-wide screening modality for unexplained ID.
Final Answer:
Chromosomal Microarray (CMA) is the first-tier diagnostic genetic investigation of choice for evaluating children with unexplained developmental delay and intellectual disability.