MAP1B related syndrome: Case presentation and review of literature

Abstract

The microtubule-associated protein 1B (MAP1B) gene serves an important role in axonal growth and brain development. Its expression is known to be elevated in regions that retain high brain plasticity and is regulated by the fragile X mental retardation protein. MAP1B mutations have recently been associated with a phenotype including periventricular nodular heterotopia (PVNH), intellectual disability (ID), seizures, and dysmorphic features. We describe a child presenting with global developmental delays, ID, microcephaly, short stature, seizures, dysmorphic features, and prenatal alcohol exposure with a de novo nonsense MAP1B mutation (c.2035G>T, p.Glu679X) detected on whole exome sequencing (WES). His brain MRI showed PVNH and dysgenesis of the corpus callosum. While significant prenatal alcohol exposure could have modified his phenotype, we believe that this patient presents with features that cannot be explained by fetal alcohol exposure alone. This is the first case report that describes dysmorphic features associated with MAP1B mutations in detail along with supporting pictures and review of previous reported phenotypes. This case not only highlights the value of WES as a screening tool for unrecognized syndromes, but also supports the need for a better description of the phenotype associated with newly detected genetic syndromes by molecular screening. K E Y W O R D S dysmorphic, intellectual disability, MAP1B, PVNH, WES

Epilepsy phenotypes associated with MAP1B‐related brain malformations

“…Our finding of corpus callosum thinning in two patients and hypomyelination in one patient is consistent with a MAP1B null mouse model (MAP1Bdelta93), in which heterozygotes had agenesis of the corpus callosum with dysmyelinated axonal bundles of cortical neurons [11]. Recently, another child with PVH, dysgenesis of the corpus callosum, and a de novo MAP1B nonsense variant has also been reported [8].…”

“…We [8]. In contrast, we provide a detailed description of phenotypes in four members of a family with febrile and afebrile seizures, photosensitivity, and behavioral comorbidities.…”

“…Recently, exome sequencing of 202 individuals with sporadic PVH revealed loss-of-function variants in MAP1B to be associated with frontally predominant PVH and peri-sylvian polymicrogyria [6]. Other MAP1B loss-of-function variants have been reported in patients with developmental delay, intellectual disability, or autism spectrum [7][8][9]. However, there is a lack of data about neurologic manifestations of MAP1B-associated PVH.…”

Diagnostic performance of automated, streamlined, daily updated exome analysis in patients with neurodevelopmental delay

“…A female patient (ID: 399) presented with GDD, heterotopia, failure to thrive, seizures, and facial dysmorphism. She had the LP variant in MAP1B (NM_005909.4: c.6715del), but the initial report was inconclusive in Feb 2020 since this gene-phenotype association had been reported but not yet registered in OMIM (Julca et al 2019 ). On June 22, 2020, periventricular nodular heterotopia 9 (OMIM 618918) caused by the MAP1B variant was registered as a new entry.…”

FOS Rescues Neuronal Differentiation of Sox2-Deleted Neural Stem Cells by Genome-Wide Regulation of Common SOX2 and AP1(FOS-JUN) Target Genes

“…We compared this list of SOX2 targets with our list of SOX2 and AP1 co-bound genes, to determine if they were regulated by SOX2/AP1 interplay, and we found that a consistent number of them displayed concomitant binding events of SOX2 and AP1 in their genomic loci. Among these, notable examples are Btg2 [ 24 , 25 , 26 ], Lrp4 [ 27 ], Map1b [ 28 , 29 , 30 ], Tmem 108 [ 31 , 32 ], Nkx2-2 [ 33 , 34 , 35 ], Wnt3 [ 36 ], Gli2 [ 37 ], Egr2/Egr [ 38 ], Plxnb3 [ 39 ], Gbx2 [ 40 ], Gsx1 [ 41 , 42 ], Jun [ 43 ], Tenm4 [ 44 ] (some of them are shown as example in Figure 5 B). Strikingly, when these 340 downregulated genes were analyzed using the STRING database, which matches functional interactions across protein networks by unbiased literature mining [ 45 ], we uncovered a SOX2/AP1-centered regulatory network composed of neuronal players ( Figure 6 B,C and Figure S4; Table S6 ).…”