title: Small rare recurrent deletions and reciprocal duplications in 2q21.1, including brain-specific ARHGEF4 and GPR148.
abstract: We have identified a rare small (~450 kb unique sequence) recurrent deletion in a previously linked attention-deficit hyperactivity disorder (ADHD) locus at 2q21.1 in five unrelated families with developmental delay (DD)/intellectual disability (ID), ADHD, epilepsy and other neurobehavioral abnormalities from 17 035 samples referred for clinical chromosomal microarray analysis. Additionally, a DECIPHER (http://decipher.sanger.ac.uk) patient 2311 was found to have the same deletion and presented with aggressive behavior. The deletion was not found in either six control groups consisting of 13 999 healthy individuals or in the DGV database. We have also identified reciprocal duplications in five unrelated families with autism, developmental delay (DD), seizures and ADHD. This genomic region is flanked by large, complex low-copy repeats (LCRs) with directly oriented subunits of ~109 kb in size that have 97.7% DNA sequence identity. We sequenced the deletion breakpoints within the directly oriented paralogous subunits of the flanking LCR clusters, demonstrating non-allelic homologous recombination as a mechanism of formation. The rearranged segment harbors five genes: GPR148, FAM123C, ARHGEF4, FAM168B and PLEKHB2. Expression of ARHGEF4 (Rho guanine nucleotide exchange factor 4) is restricted to the brain and may regulate the actin cytoskeletal network, cell morphology and migration, and neuronal function. GPR148 encodes a G-protein-coupled receptor protein expressed in the brain and testes. We suggest that small rare recurrent deletion of 2q21.1 is pathogenic for DD/ID, ADHD, epilepsy and other neurobehavioral abnormalities and, because of its small size, low frequency and more severe phenotype might have been missed in other previous genome-wide screening studies using single-nucleotide polymorphism analyses.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room R809, Houston, TX 77030, USA.
authors.forename: Avinash V
authors.initials: AV
authors.lastname: Dharmadhikari
authors.forename: Sung-Hae L
authors.initials: SH
authors.lastname: Kang
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Szafranski
authors.forename: Richard E
authors.initials: RE
authors.lastname: Person
authors.forename: Srirangan
authors.initials: S
authors.lastname: Sampath
authors.forename: Siddharth K
authors.initials: SK
authors.lastname: Prakash
authors.forename: Patricia I
authors.initials: PI
authors.lastname: Bader
authors.forename: John A
authors.initials: JA
authors.lastname: Phillips
authors.forename: Vickie
authors.initials: V
authors.lastname: Hannig
authors.forename: Misti
authors.initials: M
authors.lastname: Williams
authors.forename: Sherry S
authors.initials: SS
authors.lastname: Vinson
authors.forename: Angus A
authors.initials: AA
authors.lastname: Wilfong
authors.forename: Tyler E
authors.initials: TE
authors.lastname: Reimschisel
authors.forename: William J
authors.initials: WJ
authors.lastname: Craigen
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: John
authors.initials: J
authors.lastname: Belmont
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.forename: Pawel
authors.initials: P
authors.lastname: Stankiewicz
mesh_terms: D000293:Adolescent; D001921:Brain / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics; D004827:Epilepsy / Q000235:genetics; D005260:Female; D020440:Gene Duplication; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors; D056916:Segmental Duplications, Genomic; D017384:Sequence Deletion
chemical_list: C576602:ARHGEF4 protein, human; C581862:GPR148 protein, human; D020662:Guanine Nucleotide Exchange Factors; D043562:Receptors, G-Protein-Coupled; D064067:Rho Guanine Nucleotide Exchange Factors