SCRIB and PUF60 are primary drivers of the multisystemic phenotypes of the 8q23.4 CNV. C. Golzio1, A. Dauber2, F. M. Jodelka3, C. Guenot4, J. S. Beckmann4, J. N. Hirschhorn5,6,7, M. L. Hastings3, S. Jacquemont4, N. Katsanis1,8 1) Center for Human Disease Modeling and Department of Cell Biology, Duke University, Durham, NC; 2) Boston Childrens Hospital, Boston, MA; 3) Chicago Medical School, Department of Cell Biology and Anatomy, IL; 4) Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; 5) Program in Medical and Population Genetics, Broad Institute, Boston, MA; 6) Division of Endocrinology, Boston Childrens Hospital, Boston, MA; 7) Departments of Genetics and Pediatrics, Harvard Medical School, Boston, MA; 8) Department of Pediatrics, Duke University, Durham, NC.

   Copy number variants (CNVs) are frequent contributors to human genetic disorders. These lesions also represent a significant interpretative challenge, given that each CNV typically affects the dosage of multiple genes. Here we report five patients with coloboma, microcephaly, short stature, craniofacial, cardiac, and renal defects who harbor overlapping microdeletions on 8q23.4. Fine mapping localized a commonly-deleted 78kb region that contains three genes: SCRIB, NRBP2, and PUF60. In vivo dissection of the CNV showed discrete contributions of SCRIB and PUF60 to the observed syndromic phenotype, while the combinatorial suppression of both genes exacerbated some, but not all, phenotypic components. Consistent with these findings, we identified a patient with microcephaly, short stature, intellectual disability and heart defects with a de novo p.H169Y change in the splicing factor 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 of binary genetic interactions.

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