Comparative deletion mapping at 1p31.3-p32.2 implies NFIA responsible for intellectual disability coupled with macrocephaly and the presence of several other genes for syndromic intellectual disability

Jonathan D J Labonne; Yiping Shen; Il-Keun Kong; Michael P Diamond; Lawrence C Layman; Hyung-Goo Kim

doi:10.1186/s13039-016-0234-z

Comparative deletion mapping at 1p31.3-p32.2 implies NFIA responsible for intellectual disability coupled with macrocephaly and the presence of several other genes for syndromic intellectual disability

Mol Cytogenet. 2016 Mar 17:9:24. doi: 10.1186/s13039-016-0234-z. eCollection 2016.

Authors

Jonathan D J Labonne¹, Yiping Shen², Il-Keun Kong³, Michael P Diamond⁴, Lawrence C Layman⁵, Hyung-Goo Kim¹

Affiliations

¹ Department of Obstetrics & Gynecology, Augusta University, 1120 15th Street, Augusta, GA 30912 USA ; Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA 30912 USA.
² Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA.
³ Department of Animal Science, Division of Applied Life Science (BK21plus), Institute of Agriculture and Life Science, Gyeongsang National University, Jinju, Gyeongsangnam-do Korea.
⁴ Department of Obstetrics & Gynecology, Augusta University, 1120 15th Street, Augusta, GA 30912 USA.
⁵ Department of Obstetrics & Gynecology, Augusta University, 1120 15th Street, 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.

Abstract

Background: While chromosome 1 is the largest chromosome in the human genome, less than two dozen cases of interstitial microdeletions in the short arm have been documented. More than half of the 1p microdeletion cases were reported in the pre-microarray era and as a result, the proximal and distal boundaries containing the exact number of genes involved in the microdeletions have not been clearly defined.

Results: We revisited a previous case of a 10-year old female patient with a 1p32.1p32.3 microdeletion displaying syndromic intellectual disability. We performed microarray analysis as well as qPCR to define the proximal and distal deletion breakpoints and revised the karyotype from 1p32.1p32.3 to 1p31.3p32.2. The deleted chromosomal region contains at least 35 genes including NFIA. Comparative deletion mapping shows that this region can be dissected into five chromosomal segments containing at least six candidate genes (DAB1, HOOK1, NFIA, DOCK7, DNAJC6, and PDE4B) most likely responsible for syndromic intellectual disability, which was corroborated by their reduced transcript levels in RT-qPCR. Importantly, one patient with an intragenic microdeletion within NFIA and an additional patient with a balanced translocation disrupting NFIA display intellectual disability coupled with macrocephaly.

Conclusion: We propose NFIA is responsible for intellectual disability coupled with macrocephaly, and microdeletions at 1p31.3p32.2 constitute a contiguous gene syndrome with several genes contributing to syndromic intellectual disability.

Keywords: 1p microdeletion; Craniofacial anomalies; DAB1; DNAJC6; DOCK7; Delayed psychomotor development; HOOK1; Intellectual disability; NFIA; PDE4B.

Grants and funding

WT_/Wellcome Trust/United Kingdom