title: Inside the 8p23.1 duplication syndrome; eight microduplications of likely or uncertain clinical significance.
abstract: The 8p23.1 duplication syndrome (8p23.1 DS) is a recurrent genomic condition with an estimated prevalence of 1 in 58,000. The core 3.68 Mb duplication contains 32 genes of which five are currently candidates for the phenotypic features. Here we describe four patients and five families with eight microduplications of 8p23.1 ranging from 187 to 1082 kb in size and one atypical duplication of 4 Mb. These indicate that a minimal region of overlap (MRO) in medial 8p23.1 can give rise to features of 8p23.1 DS including developmental delay, dysmorphism, macrocephaly and otitis media, but not congenital heart disease (CHD). This MRO spans 776 kb (chr8:10,167,881-10,943,836 hg19) and contains SOX7 and seven of the other 32 core 8p23.1 DS genes. In centromeric 8p23.1, microduplications including GATA4 can give rise to non-syndromic CHD but the clinical significance of two smaller centromeric microduplications without GATA4 was uncertain due to severe neurological profiles not usually found in 8p23.1 DS. The clinical significance of three further 8p23.1 microduplications was uncertain due to additional genetic factors without which the probands might not have come to medical attention. Variable expressivity was indicated by the almost entirely unaffected parents in all five families and the mildly affected sibling in one. Intronic interruptions of six genes by microduplication breakpoint intervals had no apparent additional clinical consequences. Our results suggest that 8p23.1 DS is an oligogenetic condition largely caused by the duplication and interactions of the SOX7 and GATA4 transcription factors.
authors.affiliation: Department of Human Genetics and Genomic Medicine, University of Southampton, Southampton, UK.
authors.forename: John C K
authors.initials: JC
authors.lastname: Barber
authors.affiliation: Signature Genomic Laboratories, PerkinElmer Inc., Spokane, Washington.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Medical Genetics Institute, Cedars Sinai Medical Center, Los Angeles, California.
authors.forename: John M
authors.initials: JM
authors.lastname: Graham
authors.affiliation: Medical Genetics Institute, Cedars Sinai Medical Center, Los Angeles, California.
authors.forename: Nancy
authors.initials: N
authors.lastname: Kramer
authors.affiliation: Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Lachlan
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Bateman
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK.
authors.forename: Morag N
authors.initials: MN
authors.lastname: Collinson
authors.affiliation: Department of Medical Genetics, Rikshospitalet, Oslo University Hospital, Oslo, Norway.
authors.forename: Barbro Fossøy
authors.initials: BF
authors.lastname: Stadheim
authors.affiliation: Department of Clinical Genetics, Royal Devon and Exeter Hospital (Heavitree), Exeter, UK.
authors.forename: Claire L S
authors.initials: CL
authors.lastname: Turner
authors.affiliation: Division of Developmental Medicine and the Centre for Child Development, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Jacqueline N
authors.initials: JN
authors.lastname: Gauthier
authors.affiliation: Division of Developmental Medicine and the Centre for Child Development, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Tyler E
authors.initials: TE
authors.lastname: Reimschisel
authors.affiliation: Center for Pediatric and Congenital Heart Disease, The Cleveland Clinic, Cleveland, Ohio.
authors.forename: Athar M
authors.initials: AM
authors.lastname: Qureshi
authors.affiliation: Medical Genetics Department, Belfast Health and Social Care Trust, Belfast City Hospital, Belfast, Northern Ireland.
authors.forename: Tabib A
authors.initials: TA
authors.lastname: Dabir
authors.affiliation: Northern Ireland Regional Genetics Centre, Belfast Health and Social Care Trust, Belfast City Hospital, Belfast, Northern Ireland.
authors.forename: Mervyn W
authors.initials: MW
authors.lastname: Humphreys
authors.affiliation: Children's Hospital of New Orleans, New Orleans, Louisiana.
authors.forename: Michael
authors.initials: M
authors.lastname: Marble
authors.affiliation: School of Medicine, University of California, Irvine, California.
authors.forename: Taosheng
authors.initials: T
authors.lastname: Huang
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Beal
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Massiah
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury, UK.
authors.forename: Emma-Jane
authors.initials: EJ
authors.lastname: Taylor
authors.affiliation: Unique, Caterham, UK.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Wynn
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D050991:GATA4 Transcription Factor / Q000235:genetics; D020440:Gene Duplication / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D013577:Syndrome
chemical_list: D050991:GATA4 Transcription Factor
keywords: 8p23.1; DNA array; GATA4; SOX7; candidate genes; clinical significance; microduplication; variable penetrance