Novel Compound Heterozygous Mutation in TRAPPC9 Gene: The Relevance of Whole Genome Sequencing

Maria Isabel Alvarez-Mora,Irene Madrigal,Christian Gilissen,Jordi Corominas,Aurora Sanchez,Laia Rodriguez-Revenga

doi:10.3390/genes12040557

Abstract

Advances in high-throughput technologies and its implementation worldwide have had a considerable impact on the elucidation of the molecular causes underlying neurodevelopmental psychiatric disorders, especially for autism spectrum disorder and intellectual disability (ID). Nevertheless, etiology remains elusive in close to 50% of cases, even in those families with multiple affected individuals, strongly hinting at a genetic cause. Here we present a case report of two siblings affected with severe ID and other comorbidities, who embarked on a genetic testing odyssey until diagnosis was reached by using whole genome sequencing (WGS). WGS identified a maternally inherited novel missense variant (NM_031466.7:c.1037G > A; p.Gly346Glu) and a paternally inherited 90 kb intragenic deletion in TRAPPC9 gene. This report demonstrates the clinical utility of WGS in patients who remain undiagnosed after whole exome sequencing.

Highlights

Neurodevelopmental psychiatric disorders, including autism spectrum disorder (ASD), intellectual disability (ID), epilepsy, and schizophrenia (SZ), are a group of heterogeneous disorders associated mainly with the disruption of the tightly coordinated events that lead to brain development [1]
Since no second mutation was found on the other Trafficking protein particle complex 9 (TRAPPC9) allele, and copy number variations (CNVs) were previously discarded by array-CGH (44K), this variant was classified as a variant of unknown significance (VUS)
This was a novel deletion, intragenic deletions of TRAPPC9 gene were recently described as pathogenic variants as detected in six patients with ID [16]

Summary

Introduction

Neurodevelopmental psychiatric disorders, including autism spectrum disorder (ASD), intellectual disability (ID), epilepsy, and schizophrenia (SZ), are a group of heterogeneous disorders associated mainly with the disruption of the tightly coordinated events that lead to brain development [1]. This process results from highly complex and coordinated activity involving genetic and environmental processes. NDDs are clinically heterogeneous, with overlapping symptoms, and frequently co-occur, suggesting a common genetic etiology; this explains the high degree of comorbidity among them [4]. Insights from “The Psychiatric Cell Map Initiative” have evidenced three main molecular pathways involved in these disorders: protein synthesis, transcriptional or epigenetic regulation and synaptic signaling [6,7]

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