New Imaging and Clinical Manifestations of NDMSBA Disorder Caused by a Novel Homozygous Missense Variant of PLAA

Background: Phospholipase A-2-activating protein (PLAP) has essential roles in biological pathways. Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (NDMSBA) is a complex neurodevelopmental disease caused by defects in the PLAA gene (MIM: 603873). Herein, we aimed to detect the potential genetic factors contributing to the NDMSBA phenotype in a 2.5-year-old affected male in an Iranian consanguineous family.Methods: After meticulously performing neuroimaging and clinical examinations, due to heterogeneity of neurodevelopmental diseases, the proband was subjected to paired-end whole-exome sequencing (WES). The candidate variant was confirmed by Sanger sequencing and different in silico predictions were used to show the pathogenicity of the variant. Results: The brain magnetic resonance imaging revealed lissencephaly, polymicrogyria, severe subcortical, deep and deep white matter signal abnormalities, thinning of the corpus callosum, and severe vermis atrophy. Interestingly, we detected a novel homozygous missense variant, NM_001031689.3:c.2264A>G;p.(Asp755Gly) in the PLAA gene. To the best of our knowledge, this variant is the second one identified within the PUL domain (PLAP, Ufd3p, and Lub1p) of PLAP and also the sixth reported variant throughout the PLAA gene. In silico analyses underscored the pathogenicity of the variant. Conclusions: The present study demonstrated severe cerebral and cerebellar white matter signal abnormalities, hypertelorism, strabismus, and drooling in the proband as the novel manifestation of NDMSBA that in turn caused by a novel likely pathogenic missense variant. Further studies are required to confirm how this variant contributes to NDMSBA.