PLXNA1 developmental encephalopathy with syndromic features: A case report and review of the literature

Abstract

Developmental encephalopathies constitute a broad and genetically heterogeneous spectrum of disorders associated with global developmental delay, intellectual disability, frequent epilepsy, and other neurofunctional abnormalities. Here, we report a male presenting with infantile onset epilepsy and syndromic features resembling Dubowitz syndrome identified to have a de novo PLXNA1 variant by whole exome sequencing. This constitutes the second report of PLXNA1 sequence variation associated with early onset epilepsy, and the first to expand on the clinical features of this emerging disorder. This reports suggests that nonsynonymous de novo sequence variations in PLXNA1 are associated with a novel human phenotype characterized by intractable early onset epilepsy, intellectual disability, and syndromic features.

Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies

“…However, this concept does not implicate the action of the Plexin-A1 co-receptor NRP1 and other protein-protein-interactions of the receptor. Furthermore, two of the previously published monoallelic de novo missense variants reside in extracellular domains of Plexin-A1 16 , 17 analogous to the here reported de novo missense variant in patient F:II-1. Finally, we report one de novo LoF variant in a neonate with severe neonatal hypotonia (L:II-3), which resides also in the extracellular domains of Plexin-A1.…”

“…Additionally, the patient reported by Park et al showed prominence of ventricles. 16 plxna1a SB MO morphants showed hypoplasia of forebrain, midbrain, and hindbrain obtained in the transgenic reporter fish Tg ( -3.1ngn1:GFP ) ( Figure 4J ). Accordingly, six of our 10 patients presented with structural cerebral anomalies (C:II-2, D:II-1, D:II-2, E:II-1, G:II-1, H:II-1) ( Table 1 , Figure 4G,H ).…”

“…Previously, three studies reported monoallelic de novo variants in PLXNA1 to be associated with infantile-onset epilepsy, intellectual disability with autism spectrum disorder (ASD), epileptic encephalopathy, or schizophrenia in the respective patients. 16 - 19 …”

Neuropathological Findings in a Case of Parkinsonism and Developmental Delay Associated with a Monoallelic Variant in PLXNA1

“…During embryogenesis, Plexin‐A joins with neuropilin to form a receptor for a group of chemorepellants called semaphorins that are important in axon guidance 1 . Due to its important role in axonal guidance and cell migration in the developing nervous system, pathogenic variants in PLXNA1 have been reported in individuals with developmental encephalopathy, seizures, dysmorphic features, and midline anomalies 2‐5 …”

Rare variant screening and burden analysis of PLXNA1 in Parkinson's disease

“…PLXNA1 is a transmembrane receptor for semaphorins, a large family of proteins that act as axonal guidance cues during nervous system development. Pathogenic variants in PLXNA1 were originally reported in individuals with neurological disorders such as epileptic encephalopathies, epilepsy, and neurodevelopmental syndrome, mainly comprising developmental delay and eye anomalies [12, 13]. Recently, a heterozygous nonsense PLXNA1 variant p.Glu1121Ter was identified as the candidate disease cause for a 38‐year‐old patient with developmental delay and parkinsonism [5], suggesting a potential role of PLXNA1 in parkinsonism.…”