An atypical 12q24.31 microdeletion implicates six genes including a histone demethylase KDM2B and a histone methyltransferase SETD1B in syndromic intellectual disability.
Microdeletion syndromes are frequent causes of neuropsychiatric disorders leading to intellectual disability as well as autistic features accompanied by epilepsy and craniofacial anomalies. From comparative deletion mapping of the smallest microdeletion to date at 12q24.31, found in a patient with overlapping clinical features of 12q24.31 microdeletion syndrome, we narrowed the putative critical region to 445 kb containing seven genes, one microRNA, and one non-coding RNA. Zebrafish in situ hybridization and comprehensive transcript analysis of annotated genes in the panels of human organ and brain suggest that these are all candidates for neurological phenotypes excluding the gene HPD. This is also corroborated by synteny analysis revealing the conservation of the order of these six candidate genes between humans and zebrafish. Among them, we propose histone demethylase KDM2B and histone methyltransferase SETD1B as the two most plausible candidate genes involved in intellectual disability, autism, epilepsy, and craniofacial anomalies. These two chromatin modifiers located approximately 224 kb apart were both commonly deleted in six patients, while two additional patients had either KDM2B or SETD1B deleted. The four additional candidate genes (ORAI1, MORN3, TMEM120B, RHOF), a microRNA MIR548AQ, and a non-coding RNA LINC01089 are localized between KDM2B and SETD1B. The 12q24.31 microdeletion syndrome with syndromic intellectual disability extends the growing list of microdeletion syndromes and underscores the causative roles of chromatin modifiers in cognitive and craniofacial development.
Section of Reproductive Endocrinology, Infertility and Genetics, Department of Obstetrics and Gynecology, Augusta University, Augusta, GA, 30912, USA.|Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA.
Jonathan D J
JD
Labonne
Department of Biology, Chungnam National University, Daejeon, 34134, Korea.
Kang-Han
KH
Lee
Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA.
Shigeki
S
Iwase
Division of Applied Life Science (BK21plus), Department of Animal Science, Institute of Agriculture and Life Science, Gyeongsang National University, Jinju, Gyeongsangnam-do, Korea.
Il-Keun
IK
Kong
Section of Reproductive Endocrinology, Infertility and Genetics, Department of Obstetrics and Gynecology, Augusta University, Augusta, GA, 30912, USA.
Michael P
MP
Diamond
Section of Reproductive Endocrinology, Infertility and Genetics, Department of Obstetrics and Gynecology, Augusta University, Augusta, GA, 30912, USA.|Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA.|Neuroscience Program, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
Lawrence C
LC
Layman
Department of Biology, Chungnam National University, Daejeon, 34134, Korea.
Cheol-Hee
CH
Kim
Section of Reproductive Endocrinology, Infertility and Genetics, Department of Obstetrics and Gynecology, Augusta University, Augusta, GA, 30912, USA. kimfarang@gmail.com.|Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA. kimfarang@gmail.com.
Hyung-Goo
HG
Kim
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000503:physiopathology; D002872:Chromosome Deletion; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D004195:Disease Models, Animal; D004827:Epilepsy / Q000235:genetics* / Q000503:physiopathology; D044783:F-Box Proteins / Q000235:genetics*; D005260:Female; D005333:Fetus; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015027:Zebrafish
D044783:F-Box Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human