title: SCRIB and PUF60 are primary drivers of the multisystemic phenotypes of the 8q24.3 copy-number variant.
abstract: Copy-number variants (CNVs) represent a significant interpretative challenge, given that each CNV typically affects the dosage of multiple genes. Here we report on five individuals with coloboma, microcephaly, developmental delay, short stature, and craniofacial, cardiac, and renal defects who harbor overlapping microdeletions on 8q24.3. Fine mapping localized a commonly deleted 78 kb region that contains three genes: SCRIB, NRBP2, and PUF60. In vivo dissection of the CNV showed discrete contributions of the planar cell polarity effector SCRIB and the splicing factor PUF60 to the syndromic phenotype, and the combinatorial suppression of both genes exacerbated some, but not all, phenotypic components. Consistent with these findings, we identified an individual with microcephaly, short stature, intellectual disability, and heart defects with a de novo c.505C>T variant leading to a p.His169Tyr change in PUF60. Functional testing of this allele in vivo and in vitro showed that the mutation perturbs the relative dosage of two PUF60 isoforms and, subsequently, the splicing efficiency of downstream PUF60 targets. These data inform the functions of two genes not associated previously with human genetic disease and demonstrate how CNVs can exhibit complex genetic architecture, with the phenotype being the amalgam of both discrete dosage dysfunction of single transcripts and also of binary genetic interactions.
authors.affiliation: Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02115, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Dauber
authors.forename: Christelle
authors.initials: C
authors.lastname: Golzio
authors.forename: Cécile
authors.initials: C
authors.lastname: Guenot
authors.forename: Francine M
authors.initials: FM
authors.lastname: Jodelka
authors.forename: Maria
authors.initials: M
authors.lastname: Kibaek
authors.forename: Susanne
authors.initials: S
authors.lastname: Kjaergaard
authors.forename: Bruno
authors.initials: B
authors.lastname: Leheup
authors.forename: Danielle
authors.initials: D
authors.lastname: Martinet
authors.forename: Malgorzata J M
authors.initials: MJ
authors.lastname: Nowaczyk
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.forename: Susan
authors.initials: S
authors.lastname: Zeesman
authors.forename: Janice
authors.initials: J
authors.lastname: Zunich
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Hastings
authors.forename: Sebastien
authors.initials: S
authors.lastname: Jacquemont
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
mesh_terms: D000293:Adolescent; D000483:Alleles; D000818:Animals; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D056915:DNA Copy Number Variations; D002658:Developmental Disabilities / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008831:Microcephaly / Q000235:genetics; D010641:Phenotype; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C480591:SCRIB protein, human; D025521:Tumor Suppressor Proteins; C410595:poly-U binding splicing factor 60KDa