期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 93, 期 5, 页码 798-811出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2013.09.010
关键词
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资金
- Harvard Catalyst, The Harvard Clinical and Translational Science Center (National Institutes of Health) [UL1 RR 025758]
- Harvard University
- Simons Foundation SFARI [239983]
- Eunice Kennedy Shriver National Institute of Child Health and Development [K23HD073351]
- Swiss National Fund professorship grant [PP00P3_144902]
- Swiss National Science Foundation (SNF) [PP00P3_144902] Funding Source: Swiss National Science Foundation (SNF)
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.
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