Exome Sequencing Resolving a Complex Pediatric Neurodevelopmental Disorder After Inconclusive Prenatal Testing: A Case Report.

BACKGROUND

Prenatal detection of fetal structural anomalies often prompts chromosomal analysis; however, chromosomal microarray analysis (CMA) has limited diagnostic yield for monogenic disorders. Whole-exome sequencing (WES) has emerged as a powerful tool for identifying single-gene etiologies, particularly in cases with complex neurodevelopmental phenotypes.

CASE PRESENTATION: We report a female infant presenting with prenatally detected ventriculomegaly and inconclusive chromosomal testing. Prenatal investigations, including karyotyping and genome-wide chromosomal sequencing, identified several copy number variants classified as variants of uncertain significance but failed to establish a definitive diagnosis. Postnatally, the patient developed progressive neurological abnormalities, including microcephaly, facial dysmorphism, dystonic movements, and severe global developmental delay. Trio-based whole-exome sequencing identified a heterozygous de novo pathogenic missense variant in the DDX3X gene (c.976C>T; p.Arg326Cys), establishing the diagnosis of DDX3X-related neurodevelopmental disorder.

CONCLUSIONS

This case highlights the diagnostic limitations of standard prenatal chromosomal testing in detecting monogenic neurodevelopmental disorders and underscores the critical role of timely genetic counseling and exome sequencing. Earlier selective implementation of WES during pregnancy could have enabled an earlier diagnosis, improved prognostic counseling, and optimized clinical decision-making.