PLXNA2 as a candidate gene in patients with intellectual disability

Abstract

Intellectual disability (ID) is one of the most common disabilities in humans. In an effort to contribute to the expanding genetic landscape of ID, we describe a novel autosomal recessive ID candidate gene. Combined autozygome/exome analysis was performed in two unrelated consanguineous families with ID. Each of the two families had a novel homozygous likely deleterious variant in PLXNA2 and displayed the core phenotype of ID. PLXNA2 belongs to a family of transmembrane proteins that function as semaphorin receptors. Sema5A-PlexinA2 is known to regulate brain development in mouse, and Plxna2À/À mice display defective associative learning, sociability, and sensorimotor gating. We note the existence of variability in the phenotype among the three patients, including the existence of variable degree of ID, ranging from borderline intellectual functioning to moderate-severe ID, and the presence of cardiac anomalies in only one of the patients. We propose incomplete penetrance as a possible explanation of the observed difference in phenotypes. Future cases will be needed to support the proposed link between PLXNA2 and ID in humans.

A Novel Loss-of-Function SEMA3E Mutation in a Patient with Severe Intellectual Disability and Cognitive Regression

“…In general, mutations in SEMA3E and in other members of the family, including neuropilin and plexin receptors, have so far mainly been linked to GD [ 8 ]. However, recent evidence, including this work, strongly supports that this class of molecules might also be implicated in broader NDDs [ 6 , 15 , 16 , 17 , 18 ].…”

“…Further, emerging evidence strongly supports that this class of molecules might also be implicated in the pathogenesis of broader neurodevelopmental disorders (NDDs). This has been highlighted by association of chromosome microdeletions, including SEMA5A and SEMA7A genes with autism spectrum disorder (ASD) and co-diagnosed ID [ 15 , 16 ], as well as by recent studies unveiling links between PLXNA3 , PLXNA2 , and PLXNA1 receptor variants with NDD syndromes [ 6 , 17 , 18 ].…”

RhoG-Binding Domain of Elmo1 Ameliorates Excessive Process Elongation Induced by Autism Spectrum Disorder-Associated Sema5A

“…On the other hand, cells expressing R676C or S951C protein achieved approximately 50% or 70% differentiation phenotypes, respectively (Figure 4A,B). Since the effect was, at least in part, inhibited by the pretreatment with the respective antibodies against Plexin-B3, Plexin-A2, and Plexin-A3 (Figure S1), this implies that all Sema5A receptor candidates reported previously [35][36][37][38] likely contribute to responses to Sema5A. In addition, in cells expressing the wild type, R676C, or S951C proteins, neuronal differentiation markers' growth-associated protein 43 (GAP43) and Tau were increased, following the induction of differentiation (Figure 5A,B).…”

Integrative systems biology characterizes immune-mediated neurodevelopmental changes in murine Zika virus microcephaly

“… 36 Plxna2 PLXNA2 Intellectual disability Loss of function (−) Altuame et al. 37 Tcf4 TCF4 Intellectual disability, hypotonia, stereotypic movements Loss of function (++) Amiel et al. Zweier et al.…”