TY - JOUR
T1 - SCRIB and PUF60 are primary drivers of the multisystemic phenotypes of the 8q24.3 copy-number variant
AU - Dauber, Andrew
AU - Golzio, Christelle
AU - Guenot, Cécile
AU - Jodelka, Francine M
AU - Kibaek, Maria
AU - Kjaergaard, Susanne
AU - Leheup, Bruno
AU - Martinet, Danielle
AU - Nowaczyk, Malgorzata J M
AU - Rosenfeld, Jill A
AU - Zeesman, Susan
AU - Zunich, Janice
AU - Beckmann, Jacques S
AU - Hirschhorn, Joel N
AU - Hastings, Michelle L
AU - Jacquemont, Sebastien
AU - Katsanis, Nicholas
N1 - Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
PY - 2013/11/7
Y1 - 2013/11/7
N2 - 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.
AB - 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.
KW - Adolescent
KW - Alleles
KW - Animals
KW - Child
KW - Child, Preschool
KW - Chromosome Mapping
KW - Chromosomes, Human, Pair 8
KW - DNA Copy Number Variations
KW - Developmental Disabilities
KW - Female
KW - Gene Deletion
KW - Gene Knockdown Techniques
KW - HeLa Cells
KW - Humans
KW - Intellectual Disability
KW - Male
KW - Membrane Proteins
KW - Microcephaly
KW - Phenotype
KW - RNA-Binding Proteins
KW - Repressor Proteins
KW - Tumor Suppressor Proteins
KW - Zebrafish
U2 - 10.1016/j.ajhg.2013.09.010
DO - 10.1016/j.ajhg.2013.09.010
M3 - Journal article
C2 - 24140112
SN - 1537-6605
VL - 93
SP - 798
EP - 811
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -