Molecular karyotyping in the diagnosis of developmental neurocognitive disorders

Establishing an etiological diagnosis in patients with developmental neurocognitive disorders involving intellectual disability represents a common challenge in clinical genetics. Although more than 400 monogenic diseases with intellectual disability as a trait have been delineated, chromosomal disorders represent the majority of known causes to date. Excluding Down syndrome, high-resolution molecular karyotyping is able to reveal a causative chromosomal imbalance in 18% of unselected patients, while microscopic karyotyping would detect a causal aberration in only 4% of cases. Increasing resolution, however, also increases the number of benign copy number variants detected, which may hamper the interpretation of results. Indicators of disease associated copy number changes include aberration size, gene content and segregation of the aberration with the phenotype within a family. Ultimately, causality can only be proven when multiple cases with a similar genotype and phenotype have been observed.