EP103: Speech development gene pathways: Would genome sequencing in nonverbal individuals provide a link?

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Speech and language delays or loss is one of the first symptoms reported in many neurodevelopmental disorders. We evaluated genome sequencing (GS) results in a subset of patients from the precision genomics clinic who had limited speech or were nonverbal, with or without autism spectrum disorder (ASD), intellectual delays, and seizures to identify common genetic variants/network. Clinical genome sequencing was obtained and relevant genetic variants were analyzed to identify recurring pathways or genes. Fifteen individuals in our cohort had this combination of phenotypic characteristics. Four had pathogenic or likely pathogenic variants in SLC16A2, PHF6, ERCC8 genes that were relevant to the phenotype, and one in MME, an incidental finding; 10 patients had one or more variants of uncertain significance (VUS) and 1 had a negative test result reported. SLC16A2 causes Allan-Herndon-Dudley syndrome, which causes an X-linked intellectual delay combined with abnormal thyroid hormone levels. The gene encodes for a Monocarboxylate transporter 8 protein. It also functions as a specific thyroid hormone transporter with abnormalities speculated to result from transport of triiodothyronine into neurons. Variants in PHF6 cause Borjeson-Forssman-Lehmann syndrome. This gene encodes a transcriptional regulator which suppresses ribosomal RNA transcription. ERCC8, which causes Cockayne syndrome A, is part of the nucleotide excision repair/protein ubiquitination pathway. Several patients were found to have VUS results with autosomal dominant inheritance in genes found to cause similar symptoms to their phenotypes. Additionally, some patients were found to have multiple VUS results in several genes found to be associated with neurodevelopmental disorders and epilepsy raising question of compounding effects. No common pathway was identified in this small cohort of positive patients. We continue to evaluate for shared pathways among individuals with VUS results and additionally reanalyze rare variants. GS provides an opportunity to evaluate regions of the genome that are not picked up by traditional genetic testing. The genome harbors many rare variants with some likely contributing to these patients’ phenotypic findings. However, given the novelty of GS, a direct correlation requires additional patients with GS testing and phenotypic correlation to determine significance.