A Novel ACTB Truncating Variant in a Neonate with ACTB-Related Neurodevelopmental Disorder with Features Overlapping...

ACTB loss-of-function (LoF) variants cause a pleiotropic neurodevelopmental disorder with overlapping but distinct features compared to classic Baraitser-Winter cerebrofrontofacial syndrome (BW-CFFS), which is typically driven by gain-of-function missense variants. We report a neonate with an ACTB-related neurodevelopmental disorder harboring a novel truncating ACTB variant diagnosed via whole genome sequencing (WGS). The male infant, born at 38 weeks (2,160 g), exhibited a broad nasal bridge, epicanthic folds, and infraorbital creases, resembling his mother. Echocardiography revealed a ventricular septal defect and patent ductus arteriosus, while abdominal CT showed a horseshoe kidney. Despite normal karyotype and microarray results, WGS identified a heterozygous ACTB frameshift variant, c.952del (p.Thr318LeufsTer8), confirmed in the infant and mother by Sanger sequencing. The variant was absent in the maternal grandparents, indicating a de novo origin in the mother, and was transmitted to the proband with markedly variable expressivity. This case highlights WGS's utility in early diagnosis of multiple congenital anomalies caused by ACTB LoF variants, facilitating prompt intervention and accurate genetic counseling.