Dosage Changes of a Segment at 17p13.1 Lead to Intellectual Disability and Microcephaly as a Result of Complex Genetic Interaction of Multiple Genes

• Published in: American journal of human genetics Vol. 95; no. 5; pp. 565 - 578
• Main Authors: Carvalho, Claudia M.B., Vasanth, Shivakumar, Shinawi, Marwan, Russell, Chad, Ramocki, Melissa B., Brown, Chester W., Graakjaer, Jesper, Skytte, Anne-Bine, Vianna-Morgante, Angela M., Krepischi, Ana C.V., Patel, Gayle S., Immken, LaDonna, Aleck, Kyrieckos, Lim, Cynthia, Cheung, Sau Wai, Rosenberg, Carla, Katsanis, Nicholas, Lupski, James R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.11.2014; Cell Press; Elsevier
• Subjects: Abnormalities, Multiple - genetics; Acyl-CoA Dehydrogenase, Long-Chain - genetics; Adaptor Proteins, Signal Transducing - genetics; Animals; Asialoglycoprotein Receptor - genetics; Base Sequence; Cell Line; Chromosome Breakpoints; Chromosome Deletion; Chromosomes, Human, Pair 17 - genetics; Danio rerio; Dishevelled Proteins; Flow Cytometry; Gene Dosage - genetics; Genes; Genetic disorders; Genomics; Genotype & phenotype; Humans; Immunohistochemistry; Intellectual Disability - genetics; Microcephaly - genetics; Microtubule-Associated Proteins - genetics; Molecular Sequence Data; Phosphoproteins - genetics; Retrospective Studies; Sequence Analysis, DNA; Smith-Magenis Syndrome; Syndrome; Zebrafish
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2014.10.006

The 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation of more variable clinical features, most prominently microcephaly. We identified five subjects with copy-number variants (CNVs) on 17p13.1 for whom we performed detailed clinical and molecular studies. Breakpoint mapping and retrospective analysis of published cases refined the smallest region of overlap (SRO) for microcephaly to a genomic interval containing nine genes. Dissection of this phenotype in zebrafish embryos revealed a complex genetic architecture: dosage perturbation of four genes (ASGR1, ACADVL, DVL2, and GABARAP) impeded neurodevelopment and decreased dosage of the same loci caused a reduced mitotic index in vitro. Moreover, epistatic analyses in vivo showed that dosage perturbations of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO.