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An atypical 12q24.31 microdeletion implicates six genes including a histone demethylase KDM2B and a histone methyltransferase SETD1B in syndromic intellectual disability

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Abstract

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.

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Acknowledgments

We would like to thank the patient and family members who kindly consented to participate in our study. We wish to extend our thanks to Paul Browne. We are also thankful to Bronwyn Kerr, Alex Henderson and Joris Andrieux who provided phenotypes for DCDP251274, DCP259210, and DCP272960, respectively. This genetics study was performed following the standards established by the Institutional Review Board (IRB) at AU. S.I. has been collectively supported by NIH: NS089896 and Cooley’s Anemia Foundation. C.H.K. was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science, ICT & Future (NRF-2015M3A9A8029261). We also gratefully wish to acknowledge the support of funding provided by Caroline Jones-Carrick and Collin Carrick.

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Authors and Affiliations

  1. Section of Reproductive Endocrinology, Infertility and Genetics, Department of Obstetrics and Gynecology, Augusta University, Augusta, GA, 30912, USA

    Jonathan D. J. Labonne, Michael P. Diamond, Lawrence C. Layman & Hyung-Goo Kim

  2. Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA

    Jonathan D. J. Labonne, Lawrence C. Layman & Hyung-Goo Kim

  3. Department of Biology, Chungnam National University, Daejeon, 34134, Korea

    Kang-Han Lee & Cheol-Hee Kim

  4. Department of Human Genetics, University of Michigan, Ann Arbor, MI, 48109, USA

    Shigeki Iwase

  5. 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 Kong

  6. Neuroscience Program, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA

    Lawrence C. Layman

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Correspondence to Hyung-Goo Kim.

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Labonne, J.D.J., Lee, KH., Iwase, S. et al. An atypical 12q24.31 microdeletion implicates six genes including a histone demethylase KDM2B and a histone methyltransferase SETD1B in syndromic intellectual disability. Hum Genet 135, 757–771 (2016). https://doi.org/10.1007/s00439-016-1668-4

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