Genetic causes of the lissencephaly spectrum: insights from chromosomal microarray and clinical/whole-exome sequencing.

AIM: To determine the diagnostic yield of comprehensive genetic testing in patients with neuroimaging findings suggestive of lissencephaly spectrum disorders and to characterize novel pathogenic variants contributing to the genetic architecture of the spectrum.

METHODS

We reviewed clinical and genetic findings of 23 patients with neuroimaging features suspected of the lissencephaly spectrum who underwent genetic testing at the Children's Hospital Zagreb between 2016 and 2025. Clinical data were obtained from medical records and outpatient assessments by clinical geneticists. Genetic testing included chromosomal microarray, clinical exome sequencing, and whole-exome sequencing.

RESULTS

A molecular diagnosis was established in 15 of 23 patients (65.2%). The pathogenic variants involved genes related to microtubule function (DCX, TUBA1A, TUBB2B, DYNC1H1) and variants in transcriptional and regulatory genes (FOXG1, WDR62). Four novel (likely) pathogenic variants were detected in well-established lissencephaly genes (DCX, TUBA1A, FOXG1, and WDR62). Although most cases involved single-gene variants, three patients had pathogenic copy number variants (1q43q44, 22q11.21, and Xq22.3q23 deletions).

CONCLUSION

Exome sequencing when used as a first-line test, complemented by chromosomal microarray, provides a high diagnostic yield in patients with lissencephaly spectrum disorders. This integrated approach facilitates precise diagnosis, informs prognosis, enables targeted follow-up, and supports comprehensive genetic counselling.