title: Recurrent HERV-H-mediated 3q13.2-q13.31 deletions cause a syndrome of hypotonia and motor, language, and cognitive delays.
abstract: We describe the molecular and clinical characterization of nine individuals with recurrent, 3.4-Mb, de novo deletions of 3q13.2-q13.31 detected by chromosomal microarray analysis. All individuals have hypotonia and language and motor delays; they variably express mild to moderate cognitive delays (8/9), abnormal behavior (7/9), and autism spectrum disorders (3/9). Common facial features include downslanting palpebral fissures with epicanthal folds, a slightly bulbous nose, and relative macrocephaly. Twenty-eight genes map to the deleted region, including four strong candidate genes, DRD3, ZBTB20, GAP43, and BOC, with important roles in neural and/or muscular development. Analysis of the breakpoint regions based on array data revealed directly oriented human endogenous retrovirus (HERV-H) elements of ~5 kb in size and of >95% DNA sequence identity flanking the deletion. Subsequent DNA sequencing revealed different deletion breakpoints and suggested nonallelic homologous recombination (NAHR) between HERV-H elements as a mechanism of deletion formation, analogous to HERV-I-flanked and NAHR-mediated AZFa deletions. We propose that similar HERV elements may also mediate other recurrent deletion and duplication events on a genome-wide scale. Observation of rare recurrent chromosomal events such as these deletions helps to further the understanding of mechanisms behind naturally occurring variation in the human genome and its contribution to genetic disease.
authors.affiliation: Signature Genomic Laboratories, PerkinElmer, Inc, Spokane, Washington.
authors.forename: Andrey
authors.initials: A
authors.lastname: Shuvarikov
authors.forename: Ian M
authors.initials: IM
authors.lastname: Campbell
authors.forename: Piotr
authors.initials: P
authors.lastname: Dittwald
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Neill
authors.forename: Martin G
authors.initials: MG
authors.lastname: Bialer
authors.forename: Christine
authors.initials: C
authors.lastname: Moore
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Wheeler
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Wallace
authors.forename: Mark C
authors.initials: MC
authors.lastname: Hannibal
authors.forename: Michael F
authors.initials: MF
authors.lastname: Murray
authors.forename: Monica A
authors.initials: MA
authors.lastname: Giovanni
authors.forename: Deborah
authors.initials: D
authors.lastname: Terespolsky
authors.forename: Sandi
authors.initials: S
authors.lastname: Sodhi
authors.forename: Matteo
authors.initials: M
authors.lastname: Cassina
authors.forename: David
authors.initials: D
authors.lastname: Viskochil
authors.forename: Billur
authors.initials: B
authors.lastname: Moghaddam
authors.forename: Kristin
authors.initials: K
authors.lastname: Herman
authors.forename: Chester W
authors.initials: CW
authors.lastname: Brown
authors.forename: Christine R
authors.initials: CR
authors.lastname: Beck
authors.forename: Anna
authors.initials: A
authors.lastname: Gambin
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.forename: Allen N
authors.initials: AN
authors.lastname: Lamb
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Shaffer
authors.forename: Jay W
authors.initials: JW
authors.lastname: Ellison
authors.forename: J Britt
authors.initials: JB
authors.lastname: Ravnan
authors.forename: Paweł
authors.initials: P
authors.lastname: Stankiewicz
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D056905:Chromosome Breakpoints; D002872:Chromosome Deletion; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D003072:Cognition Disorders / Q000175:diagnosis / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D020077:Endogenous Retroviruses / Q000235:genetics*; D019066:Facies; D005260:Female; D023061:Gene Order; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009123:Muscle Hypotonia / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D016415:Sequence Alignment; D013577:Syndrome; D055815:Young Adult
keywords: 3q13; HERV-H; NAHR; developmental delay; hypotonia; microarray; microdeletion; recurrent