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

TL;DR

Whole-exome sequencing diagnosed a rare neurodevelopmental disorder in a child after prenatal tests failed to identify the cause.

Contribution

Demonstrates the diagnostic value of trio-based exome sequencing in resolving complex pediatric neurodevelopmental disorders after inconclusive prenatal testing.

Findings

Standard prenatal chromosomal testing failed to detect a monogenic cause of fetal CNS anomalies.

Trio-based whole-exome sequencing identified a de novo pathogenic missense variant in the DDX3X gene.

Earlier use of exome sequencing in complex CNS anomalies could improve diagnostic yield and counseling.

Abstract

What are the main findings?
Prenatal chromosomal testing (karyotype, MLPA, and chromosome sequencing) may fail to detect monogenic causes of fetal central nervous system anomalies, even in the presence of ventriculomegaly.Trio-based whole-exome sequencing enabled the definitive postnatal diagnosis of a DDX3X-related neurodevelopmental disorder caused by a de novo pathogenic missense variant.

Prenatal chromosomal testing (karyotype, MLPA, and chromosome sequencing) may fail to detect monogenic causes of fetal central nervous system anomalies, even in the presence of ventriculomegaly.

Trio-based whole-exome sequencing enabled the definitive postnatal diagnosis of a DDX3X-related neurodevelopmental disorder caused by a de novo pathogenic missense variant.

What are the implications of the main findings?
Earlier selective implementation of prenatal exome sequencing in fetuses with complex or non-isolated CNS anomalies could significantly improve diagnostic yield and prognostic counseling.Integration of clinical genetics into multidisciplinary prenatal care pathways is essential to optimize decision-making, perinatal planning, and family counseling.

Earlier selective implementation of prenatal exome sequencing in fetuses with complex or non-isolated CNS anomalies could significantly improve diagnostic yield and prognostic counseling.

Integration of clinical genetics into multidisciplinary prenatal care pathways is essential to optimize decision-making, perinatal planning, and family counseling.

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.

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