The use of artificial intelligence tools in the elucidation of cases of neurodevelopmental disorders

Introduction: Neurodevelopmental disorders (NDD) form a complex set of differential diagnoses in clinical practice. Research tools, neuroimaging, cytogenetics, and next-generation sequencing (NGS) aid in elucidation. Still, the complexity of phenotypes, the absence of local genetic data leading to many variants of uncertain significance (VUS) and barriers to accessing such tests are limiting factors.

Objective: Case presentation, showing how the use of artificial intelligence (AI) tools can help target the etiology of NDD.

Methods: Male, 13 years old, with developmental delay, moderate intellectual disability, and extensive diagnostic journey by more than 40 specialists, with conflicting diagnoses, including guilting the family for the lack of patient adequate stimulation. On examination was observed hypertelorism, downward palpebral fissure, long nasolabial philtrum, large ears, thick eyebrows, short nose with wide columella, thick and everted lips. Investigational testing with no changes except for brain MRIs from 2019 and 2022 with T2 and flair hypersignal in the periventricular and subcortical white matter in the frontal lobes. NGS panel of leukodystrophies with 835 genes was performed reporting VUSes in heterozygosity 13 of them (ACY1, CNTNAP2, CYP2U1, FGFRL1, NIPBL, RPS6KA3, NT5C2, SLC1A2, SLC46A1, WDR73, ZNF335, ACADS, GALC).

Results: The refinement started by discarding variants in genes with a recessive pattern or not consistent with the case phenotype. Afterwards, the Face2Fene® AI tool was used, which indicated a high gestalt for Coffin-Lowry Syndrome, a X-linked NDD syndrome caused by RPS6KA3 mutations. A segregation study was carried out in the mother, concluding that it was a de novo mutation. The updated information was shared with the laboratory, which reclassified the variant RPS6KA3 c.709C>T (p.Pro237Ser) from VUS to Pathogenic, confirming the diagnosis of Coffin-Lowry Syndrome.

Conclusions: The finding of VUS is common when requesting genetic panels and exome, especially in Hispanic population. The case presented showed how the association of the phenotype with analysis of family segregation and the use of AI tools are allies in shortening the journey of patients with NDD, enabling proper follow-up and treatment.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
18 September 2023