A rigorous in silico genomic interrogation at 1p13.3 reveals 16 autosomal dominant candidate genes in syndromic neurodevelopmental disorders

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

doi:10.3389/fnmol.2022.979061

A rigorous in silico genomic interrogation at 1p13.3 reveals 16 autosomal dominant candidate genes in syndromic neurodevelopmental disorders

Front Mol Neurosci. 2022 Oct 6:15:979061. doi: 10.3389/fnmol.2022.979061. eCollection 2022.

Authors

Afif Ben-Mahmoud¹, Kyung Ran Jun², Vijay Gupta¹, Pinang Shastri³, Alberto de la Fuente⁴, Yongsoo Park¹, Kyung Chul Shin¹, Chong Ae Kim⁵, Aparecido Divino da Cruz^{6

7}, Irene Plaza Pinto^{6

7}, Lysa Bernardes Minasi^{6

7}, Alex Silva da Cruz^{6

7}, Laurence Faivre^{8

9}, Patrick Callier¹⁰, Caroline Racine¹⁰, Lawrence C Layman^{11

12}, Il-Keun Kong¹³, Cheol-Hee Kim¹⁴, Woo-Yang Kim¹⁵, Hyung-Goo Kim¹

Affiliations

¹ Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar.
² Department of Laboratory Medicine, Inje University Haeundae Paik Hospital, Busan, South Korea.
³ Department of Cardiovascular Medicine, Cape Fear Valley Medical Center, Fayetteville, NC, United States.
⁴ Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar.
⁵ Faculdade de Medicina, Unidade de Genética do Instituto da Criança - Hospital das Clínicas HCFMUSP, Universidade de São Paulo, São Paulo, Brazil.
⁶ School of Medical and Life Sciences, Genetics Master Program, Replicon Research Group, Pontifical Catholic University of Goiás, Goiânia, Brazil.
⁷ Genetics Master Program, Replicon Research Nucleus, School of Agrarian and Biological Sciences, Pontifical Catholic University of Goias, Goiás, Brazil.
⁸ Inserm UMR 1231 GAD, Genetics of Developmental Disorders, Université de Bourgogne-Franche Comté, Dijon, France.
⁹ Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, Dijon, France.
¹⁰ UMR 1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France.
¹¹ Section of Reproductive Endocrinology, Infertility and Genetics, Department of Obstetrics and Gynecology, Augusta University, Augusta, GA, United States.
¹² Department of Neuroscience and Regenerative Medicine, Augusta University, Augusta, GA, United States.
¹³ Department of Animal Science, Division of Applied Life Science (BK21 Four), Gyeongsang National University, Jinju, South Korea.
¹⁴ Department of Biology, Chungnam National University, Daejeon, South Korea.
¹⁵ Department of Biological Sciences, Kent State University, Kent, OH, United States.

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.

Keywords: 1p13.3 deletion; ELAPOR1; GSTM5; LRIF1; VAV3; WDR47; autism; intellectual disability.