title: A microdeletion at Xq22.2 implicates a glycine receptor GLRA4 involved in intellectual disability, behavioral problems and craniofacial anomalies.
abstract: BACKGROUND
  Among the 21 annotated genes at Xq22.2, PLP1 is the only known gene involved in Xq22.2 microdeletion and microduplication syndromes with intellectual disability. Using an atypical microdeletion, which does not encompass PLP1, we implicate a novel gene GLRA4 involved in intellectual disability, behavioral problems and craniofacial anomalies.
  
  
  METHODS
  We report a female patient (DGDP084) with a de novo Xq22.2 microdeletion of at least 110 kb presenting with intellectual disability, motor delay, behavioral problems and craniofacial anomalies. While her phenotypic features such as cognitive impairment and motor delay show overlap with Pelizaeus-Merzbacher disease (PMD) caused by PLP1 mutations at Xq22.2, this gene is not included in our patient's microdeletion and is not dysregulated by a position effect. Because the microdeletion encompasses only three genes, GLRA4, MORF4L2 and TCEAL1, we investigated their expression levels in various tissues by RT-qPCR and found that all three genes were highly expressed in whole human brain, fetal brain, cerebellum and hippocampus. When we examined the transcript levels of GLRA4, MORF4L2 as well as TCEAL1 in DGDP084's family, however, only GLRA4 transcripts were reduced in the female patient compared to her healthy mother. This suggests that GLRA4 is the plausible candidate gene for cognitive impairment, behavioral problems and craniofacial anomalies observed in DGDP084. Importantly, glycine receptors mediate inhibitory synaptic transmission in the brain stem as well as the spinal cord, and are known to be involved in syndromic intellectual disability.
  
  
  CONCLUSIONS
  We hypothesize that GLRA4 is involved in intellectual disability, behavioral problems and craniofacial anomalies as the second gene identified for X-linked syndromic intellectual disability at Xq22.2. Additional point mutations or intragenic deletions of GLRA4 as well as functional studies are needed to further validate our hypothesis.
authors: Department of Obstetrics & Gynecology, Section of Reproductive Endocrinology, Infertility & Genetics, Medical College of Georgia, 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.
authors: Jonathan D J
authors: JD
authors: Labonne
authors: Department of Obstetrics & Gynecology, Section of Reproductive Endocrinology, Infertility & Genetics, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA.
authors: Tyler D
authors: TD
authors: Graves
authors: Department of Laboratory Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
authors: Yiping
authors: Y
authors: Shen
authors: Greenwood Genetic Center, Greenwood, SC, 29646, USA.
authors: Julie R
authors: JR
authors: Jones
authors: Department of Animal Science, Division of Applied Life Science (BK21plus), Institute of Agriculture and Life Science, Gyeongsang National University, Jinju, Gyeongsangnam-do, South Korea.
authors: Il-Keun
authors: IK
authors: Kong
authors: Department of Obstetrics & Gynecology, Section of Reproductive Endocrinology, Infertility & Genetics, Medical College of Georgia, 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.
authors: Lawrence C
authors: LC
authors: Layman
authors: Department of Obstetrics & Gynecology, Section of Reproductive Endocrinology, Infertility & Genetics, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA. hkim@augusta.edu.|Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA. hkim@augusta.edu.
authors: Hyung-Goo
authors: HG
authors: Kim
mesh_terms: D001921:Brain / Q000378:metabolism; D002648:Child; D041321:Chromosomes, Human, X / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000150:complications / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000150:complications / Q000235:genetics*; D018991:Myelin Proteolipid Protein / Q000378:metabolism; D000066553:Problem Behavior; D018009:Receptors, Glycine / Q000096:biosynthesis / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis
chemical_list: D004268:DNA-Binding Proteins; C491669:MORF4L2 protein, human; D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human; D018009:Receptors, Glycine; C087628:TCEAL1 protein, human; D014157:Transcription Factors; C408089:glycine receptor, alpha4-subunit
keywords: Behavioral problems; Craniofacial anomalies; GLRA4; Intellectual disability; Microdeletion; Pseudogene; Xq22.2