De novo duplication on chromosome 19 observed in nuclear family displaying neurodevelopmental disorders

• Published in: Cold Spring Harbor molecular case studies 2020-06, Vol.6 (3), p.a004721
• Main Authors: Sjaarda, Calvin P, Kaiser, Beatrice, McNaughton, Amy Jm, Hudson, Melissa L, Harris-Lowe, Liam, Lou, Kyle, Guerin, Andrea, Ayub, Muhammad, Liu, Xudong
• Format: Article
• Language: English
• Subjects: Attention deficit hyperactivity disorder; Autism; Cell proliferation; Chromosome 19; Chromosomes; Disorders; Dysbacteriosis; Endoplasmic reticulum; Epithelial cells; Etiology; Gene duplication; Gene expression; Gene mapping; Genes; Genetic diversity; Genetic variance; Immune response; Intellectual disabilities; Intestinal microflora; Mapping; Mental disorders; Microbiomes; Neurodevelopmental disorders; Peripheral blood; Pleiotropy; Polymerase chain reaction; Reproduction (copying); Ribonucleic acid; Risk analysis; Risk factors; RNA; Transcription
• ISSN: 2373-2865; 2373-2873
• DOI: 10.1101/MCS.A004721

Pleiotropy and variable expressivity have been cited to explain the seemingly distinct neurodevelopmental disorders due to a common genetic etiology within the same family. Here we present a family with a de novo 1 Mb duplication involving 18 genes on chromosome 19. Within the family there are multiple cases of neurodevelopmental disorders including: Autism Spectrum Disorder, Attention Deficit/Hyperactivity Disorder, Intellectual Disability, and psychiatric disease in individuals carrying this Copy Number Variant (CNV). Quantitative PCR confirmed the CNV was de novo in the mother and inherited by both sons. Whole exome sequencing did not uncover further genetic risk factors segregating within the family. Transcriptome analysis of peripheral blood demonstrated a ~1.5-fold increase in RNA transcript abundance in 12 of the 15 detected genes within the CNV region for individuals carrying the CNV compared with their non-carrier relatives. Examination of transcript abundance across the rest of the transcriptome identified 407 differentially expressed genes (p-value < 0.05; adjusted p-value < 0.1) mapping to immune response, response to endoplasmic reticulum stress, and regulation of epithelial cell proliferation pathways. 16S microbiome profiling demonstrated compositional difference in the gut bacteria between the half-brothers. These results raise the possibility that the observed CNV may contribute to the varied phenotypic characteristics in family members through alterations in gene expression and/or dysbiosis of the gut microbiome. More broadly, there is growing evidence that different neurodevelopmental and psychiatric disorders can share the same genetic variant which lays a framework for later neurodevelopmental and psychiatric manifestations.