Loss-of-function variant in the LRR domain of SLITRK2 implicated in a neurodevelopmental disorder

Abstract

Background: Neurodevelopmental disorders are characterized by different combinations of intellectual disability (ID), communication and social skills deficits, and delays in achieving motor or language milestones. SLITRK2 is a postsynaptic cell-adhesion molecule that promotes neurite outgrowth and excitatory synapse development. Methods and Results: In the present study, we investigated a single patient segregating Neurodevelopmental disorder. SLITRK2 associated significant neuropsychological issues inherited in a rare X-linked fashion have recently been reported. Whole-exome sequencing and data analysis revealed a novel nonsense variant [c.789T>A; p.(Cys263*); NM_032539.5; NP_115928.1] in exon 5 of the SLITRK2 gene (MIM# 300561). Three-dimensional protein modeling revealed substantial changes in the mutated SLITRK2 protein, which might lead to nonsense-medicated decay. Conclusion: This study confirms the role of SLITRK2 in neuronal development and highlights the importance of including the SLITRK2 gene in the screening of individuals presenting neurodevelopmental disorders.

Keywords: SLITRK2; developmental anomaly; neurodevelopmental disorders; nonsense mutation; novel mutation; whole-exome sequencing.

FIGURE 1

(A) Pedigree of the kindred segregating neurodevelopmental disorders. Circles represent females and squares represent male family members. The filled symbol designates the affected individual. Sanger sequencing results for each family member are also shown. (B) Structure of SLITRK2. The figure likely delineates different domains or regions within the SLITRK2 gene. The labeled variant [p.(Cys263*)] specifies an alteration at position 263 of the SLITRK2 protein. “p.Cys263”denotes the affected amino acid sequence, and the asterisk indicates a premature stop codon, suggesting an early termination of protein synthesis due to the variant.

FIGURE 2

(A–D) MRI of individual II-1 revealed delayed white matter myelination, suggesting that the process of myelin formation in the white matter of the brain has not progressed at the expected rate for an individual of that person’s age. Additionally, the MRI revealed an underdeveloped corpus callosum. The corpus callosum is a vital structure that connects the left and right hemispheres of the brain, allowing for the communication and transfer of information between the two sides. An underdeveloped corpus callosum can lead to impaired communication and integration of information between the brain’s hemispheres, potentially affecting various cognitive functions, motor coordination, and sensory processing.

FIGURE 3

Whole-exome sequencing filtration steps. The steps, including analyzing the variant calling files to screen out homozygous and heterozygous variants, are shown. The variants are then classified according to the American College of Medical Genetics (ACMG) classification guidelines and further filtered using the minor allele frequency (MAF). After that, using USCS (known associated genes) and different online prediction tools, the pathogenicity of the variants was determined. Once the variant is screened through all these steps, Sanger sequencing of the variant in all the family members is performed using standard methods.

FIGURE 4

(A) Schematic representation of the SLITRK2 domains, which include the N-terminal LRR domain and the C-terminal LRR domain. The arrow shows the position of the identified variant (Cys263Ter) in the present study. (B) Partial amino acid sequence of SLITRK2. The green-colored Cys263 shows its conservation and important role across different species.

FIGURE 5

Predicted structure of SLITRK2 showing wild type (Cys263) and mutated protein (Cys263*). The three-dimensional protein structure of mutated SLITRK2 (Cys263*), suggesting key changes in the secondary structure that might result in a shorter and non-functional protein, which might result in degradation.

FIGURE 6

qPCR of the affected family showing a substantial decrease in the expression of SLITRK2 in the index compared with the other family members, showing that the variant identified in the index causes disease.

FIGURE 7

Interaction of SLITRK2 with other important players that might be associated with NDDs in our patient (https://genemania.org/), supporting the important and yet unexplored role of this gene in causing NDDs in humans.