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Am J Hum Genet DOI:10.1016/j.ajhg.2013.09.010

SCRIB and PUF60 are primary drivers of the multisystemic phenotypes of the 8q24.3 copy-number variant.

Publication TypeJournal Article
Year of Publication2013
AuthorsDauber, A, Golzio, C, Guenot, C, Jodelka, FM, Kibaek, M, Kjaergaard, S, Leheup, B, Martinet, D, Nowaczyk, MJM, Rosenfeld, JA, Zeesman, S, Zunich, J, Beckmann, JS, Hirschhorn, JN, Hastings, ML, Jacquemont, S, Katsanis, N
JournalAm J Hum Genet
Date Published2013 Nov 07
KeywordsAdolescent, Alleles, Animals, Child, Child, Preschool, Chromosome Mapping, Chromosomes, Human, Pair 8, Developmental Disabilities, DNA Copy Number Variations, Female, Gene Deletion, Gene Knockdown Techniques, HeLa Cells, Humans, Intellectual Disability, Male, Membrane Proteins, Microcephaly, Phenotype, Repressor Proteins, RNA Splicing Factors, RNA-Binding Proteins, Tumor Suppressor Proteins, Zebrafish

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.


Alternate JournalAm. J. Hum. Genet.
PubMed ID24140112
PubMed Central IDPMC3824129
Grant ListK23HD073351 / HD / NICHD NIH HHS / United States
K23 HD073351 / HD / NICHD NIH HHS / United States
P50 DK096415 / DK / NIDDK NIH HHS / United States
R01 NS069759 / NS / NINDS NIH HHS / United States
UL1 RR025758 / RR / NCRR NIH HHS / United States
UL1 RR 025758 / RR / NCRR NIH HHS / United States