Interpretation of genome sequencing results in children with complex neuromotor phenotypes.

BACKGROUND

Although genetic diseases cause at least 30% of neuromotor disorders, genome sequencing is not routinely used for diagnosis in such patients. We assessed the diagnostic value in children with complex neuromotor phenotypes.

METHODS

We performed trio genome sequencing in 108 children with complex neuromotor phenotypes in 100 families. Genetic disease was diagnosed by a multidisciplinary clinical research team on the basis of each child's complete medical history, clinical course, family history, physical examination, imaging studies, and all other laboratory test results, as well as the findings on genome sequencing. Genetic variants that were suspected of being disease causing were subjected to orthogonal confirmation in a clinically accredited laboratory, which classified the variants it reported according to the ACMG/AMP guidelines.

FINDINGS: We diagnosed genetic diseases that explained the neuromotor phenotype in 53 of the 100 families studied. Almost all of these children had intellectual disability, a seizure disorder, and/or autism spectrum disorder in addition to neuromotor impairment. An important factor contributing to this high diagnostic rate was the use of each patient's complete clinical phenotype, instead of a "molecular diagnosis" based only on the ACMG/AMP variant classification.

CONCLUSIONS

Our findings demonstrate that complex neuromotor phenotypes in children are usually manifestations of a more generalized neurodevelopmental disorder and that the ACMG/AMP classification alone is insufficient to establish or exclude a causal relationship between a genomic variant and a suspected genetic disease.

FUNDING: Canadian Institutes of Health Research, British Columbia Children's Hospital Foundation, and Michael Smith Health Research BC.