Comparative genomic mapping implicate LRRK2 for intellectual disability and autism at 12q12 and HDHD1 as well as PNPLA4 for X-linked intellectual disability at Xp22.31

---

Hyung-Goo Kim, Jonathan D J Labonne, Marvin E Harris, Lawrence C Layman, Terri M Driessen, Il-Keun Kong, Janghoo Lim, Omar El-Agnaf and Cheol-Hee Kim

Augusta University, USA
Yale University, USA
Gyeongsang National University, Republic of Korea
Hamad Bin Khalifa University, Qatar
Chungnam National University, Republic of Korea

: J Spine Neurosurg

Abstract

---

We report a genomic and phenotypic delineation for two chromosome regions with candidate genes for syndromic intellectual disability at 12q12 and Xp22.31. Fine mapping of six unreported small informative Copy Number Variations (CNVs) narrowed down the chromosomal interval to one gene LRRK2 at 12q12. Expression studies revealed high levels of LRRK2 transcripts in whole human brain, cerebral cortex and hippocampus. RT-qPCR assays revealed that LRRK2 transcripts were dramatically reduced in our micro deletion patient compared to his healthy grandfather with no deletion. The decreased expression of LRRK2 may affect proteinprotein interactions between LRRK2 and its binding partners, of which 8 have previously been linked to intellectual disability. These findings corroborate with a role for LRRK2 in cognitive development and thus, we propose that intellectual disability and autism displayed in the 12q12 micro deletion patient are likely caused by LRRK2. This is in stark contrast to the late-onset Parkinsonism caused by the same gene with an average onset age of 53 years. We identified one additional minimal candidate region demarcated by a micro deletion DCP250361 at 12q12. Among the four genes deleted, we propose TWF1 as a likely candidate gene for intellectual disability and craniofacial anomalies. Furthermore, we refined the known candidate gene region encompassing three genes to one gene NELL2 with one micro deletion patient DCP139. Through the genomic and clinical delineation of six reported and nine unreported cases at Xp22.31, we propose HDHD1 and PNPLA4 for X-linked intellectual disability. High transcript levels of these two genes in the human brain substantiate their role in intellectual functioning.

Biography

---

Hyung-Goo Kim is a Senior Scientist at Qatar Biomedical Research Institute. His current focus is in identifying new disease genes for neurological disorders to elucidate their underlying mechanism.

E-mail: hkim@hbku.edu.qa