A rigorous in silico genomic interrogation at 1p13.3 reveals 16 autosomal dominant candidate genes in syndromic neurodevelopmental disorders
Year: 2022
Type: article
Abstract: Genome-wide chromosomal microarray is extensively used to detect copy number variations (CNVs), which can diagnose microdeletion and microduplication syndromes. These small unbalanced chromosomal structural rearrangements ranging from 1 kb to 10 Mb comprise up to 15% of human mutations leading to monogenic or contiguous genomic disorders. Albeit rare, CNVs at 1p13.3 cause a variety of neurodevelopmental disorders (NDDs) including development delay (DD), intellectual disability (ID), autism, epilepsy, and craniofacial anomalies (CFA). Most of the 1p13.3 CNV cases reported in the pre-microarray era encompassed a large number of genes and lacked the demarcating genomic coordinates, hampering the discovery of positional candidate genes within the boundaries. In this study, we present four subjects with 1p13.3 microdeletions displaying DD, ID, autism, epilepsy, and CFA. In silico comparative genomic mapping with three previously reported subjects with CNVs and 22 unreported DECIPHER CNV cases has resulted in the identification of four different sub-genomic loci harboring five positional candidate genes for DD, ID, and CFA at 1p13.3. Most of these genes have pathogenic variants reported, and their interacting genes are involved in NDDs. RT-qPCR in various human tissues revealed a high expression pattern in the brain and fetal brain, supporting their functional roles in NDDs. Interrogation of variant databases and interacting protein partners led to the identification of another set of 11 potential candidate genes, which might have been dysregulated by the position effect of these CNVs at 1p13.3. Our studies define 1p13.3 as a genomic region harboring 16 NDD candidate genes and underscore the critical roles of small CNVs in in silico comparative genomic mapping for disease gene discovery. Our candidate genes will help accelerate the isolation of pathogenic heterozygous variants from exome/genome sequencing (ES/GS) databases.
Authors: Afif Ben-Mahmoud, Kyung Ran Jun, Vijay Gupta, Pinang Shastri, Alberto de la Fuente, Yongsoo Park, Kyung Chul Shin, Chong Ae Kim, Aparecido Divino da Cruz, Irene Plaza Pinto, Lysa Bernardes Minasi, Alex Silva da Cruz, Laurence Faivre, Patrick Callier, Caroline Racine, Lawrence C. Layman, Il-Keun Kong, Cheol-Hee Kim, Woo-Yang Kim, Hyung-Goo Kim
Institutions: Hamad bin Khalifa University, Inje University Haeundae Paik Hospital, Cape Fear Valley Health System, Cape Fear Valley Medical Center, Universidade de São Paulo, Chungnam National University, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Pontifícia Universidade Católica de Goiás, Inserm, Université de Bourgogne, CHU Dijon Bourgogne, Centre de recherche Translationnelle en Médecine moléculaire, Université Bourgogne Franche-Comté, Augusta University, Gyeongsang National University, Kent State University
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,950
Awards: G5402101301, G7135337194, G8196247942
OpenAlex ID: W4302286549