# Three Unrelated Children With Childhood Apraxia of Speech: Exome Sequencing and Functional Gene Analysis Imply a Role of Laminin‐511 in Early Neurodevelopment

## TL;DR

This study explores the genetic basis of childhood apraxia of speech and finds that multiple genetic variants converge on a network involving laminin-511, which is important for early brain development.

## Contribution

The study identifies a functional gene network involving laminin-511 linked to childhood apraxia of speech and related neurodevelopmental disorders.

## Key findings

- High gene expression of LAMA5 and LAMB1, encoding laminin-511 subunits, was observed in the developing cerebellum.
- A dense gene network with 32 nodes and 73 edges was identified, showing significant network enrichment.
- Genetic heterogeneity in CAS cases converges on a functional network involving laminin-511 and cerebellar development.

## Abstract

Childhood apraxia of speech (CAS) is characterized by motor discoordination in the speech domain and also in fine and gross motor systems, implicating the early developing cerebellum. Comorbidity with autism spectrum disorder (ASD) and other neurodevelopmental conditions has been observed. The genetic etiology is highly heterogeneous. Here, we present three unrelated individuals with CAS and concomitant fine and gross motor involvement but different genetic variants of interest. The DNA of the cases and their parents underwent exome sequencing and variant filtering. Using publicly available data, the genes of interest derived from the variants were investigated for expression rates in the early developing brain. Known and putative protein–protein interactions among the genes of highest confidence were identified. Of 28 variants in 28 different genes, variants with highest confidence were situated in FOXN4, LAMA5, LAMB1, LRRK2, and USP17L2. High gene expression rates in the developing cerebellum were observed for LAMA5 and LAMB1. These genes encode the α5 and β1 subunits, respectively, of the heterotrimeric extracellular laminin‐511 complex, a major component of the basal membrane in many tissues. Network analysis of the five high‐confidence genes required expansion with only one additional gene, CDK6, to arrive at a fully connected network. The addition of four genes and inclusion of transcriptional regulation as an additional edge type allowed connecting all 28 genes of interest to arrive at a dense connectome with 32 nodes and 73 edges, representing a network enrichment with p value of < 0.001, suggesting that our network has significantly more interactions than expected under random conditions. We conclude that high levels of genetic heterogeneity converge on a functional gene network governed by stimulation of cells through laminin‐511 with shared direct or regulatory expression in the developing cerebellum and phenotypic overlaps of CAS, ASD, and other neurodevelopmental disorders.