@article {446,
	title = {WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.},
	journal = {Am J Hum Genet},
	volume = {102},
	year = {2018},
	month = {2018 01 04},
	pages = {27-43},
	abstract = {<p>Locus heterogeneity characterizes a variety of skeletal dysplasias often due to interacting or overlapping signaling pathways. Robinow syndrome is a skeletal disorder historically refractory to molecular diagnosis, potentially stemming from substantial genetic heterogeneity. All current known pathogenic variants reside in genes within the noncanonical Wnt signaling pathway including ROR2, WNT5A, and more recently, DVL1 and DVL3. However, \~{}70\% of autosomal-dominant Robinow syndrome cases remain molecularly unsolved. To investigate this missing heritability, we recruited 21 families with at least one family member clinically diagnosed with Robinow or Robinow-like phenotypes and performed genetic and genomic studies. In total, four families with variants in FZD2 were identified as well as three individuals from two families with biallelic variants in NXN that co-segregate with the phenotype. Importantly, both FZD2 and NXN are relevant protein partners in the WNT5A interactome, supporting their role in skeletal development. In addition to confirming that clustered -1 frameshifting variants in DVL1 and DVL3 are the main contributors to dominant Robinow syndrome, we also found likely pathogenic variants in candidate genes GPC4 and RAC3, both linked to the Wnt signaling pathway. These data support an initial hypothesis that Robinow syndrome results from perturbation of the Wnt/PCP pathway, suggest specific relevant domains of the proteins involved, and reveal key contributors in this signaling cascade during human embryonic development. Contrary to the view that non-allelic genetic heterogeneity hampers gene discovery, this study demonstrates the utility of rare disease genomic studies to parse gene function in human developmental pathways.</p>},
	keywords = {Adolescent, Adult, Base Sequence, Child, Child, Preschool, Chromosome Segregation, Craniofacial Abnormalities, Diagnosis, Differential, Dwarfism, Female, Genes, Dominant, Genetic Association Studies, Genetic Heterogeneity, Humans, Limb Deformities, Congenital, Male, Middle Aged, Mutation, Missense, Phenotype, Urogenital Abnormalities, Wnt Signaling Pathway},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2017.10.002},
	author = {White, Janson J and Mazzeu, Juliana F and Coban-Akdemir, Zeynep and Bayram, Yavuz and Bahrambeigi, Vahid and Hoischen, Alexander and van Bon, Bregje W M and Gezdirici, Alper and Gulec, Elif Yilmaz and Ramond, Francis and Touraine, Renaud and Thevenon, Julien and Shinawi, Marwan and Beaver, Erin and Heeley, Jennifer and Hoover-Fong, Julie and Durmaz, Ceren D and Karabulut, Halil Gurhan and Marzioglu-Ozdemir, Ebru and Cayir, Atilla and Duz, Mehmet B and Seven, Mehmet and Price, Susan and Ferreira, Barbara Merfort and Vianna-Morgante, Angela M and Ellard, Sian and Parrish, Andrew and Stals, Karen and Flores-Daboub, Josue and Jhangiani, Shalini N and Gibbs, Richard A and Brunner, Han G and Sutton, V Reid and Lupski, James R and Carvalho, Claudia M B}
}
@article {209,
	title = {Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes.},
	journal = {Am J Hum Genet},
	volume = {95},
	year = {2014},
	month = {2014 Nov 06},
	pages = {565-78},
	abstract = {<p>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. </p>},
	keywords = {Abnormalities, Multiple, Acyl-CoA Dehydrogenase, Long-Chain, Adaptor Proteins, Signal Transducing, Animals, Asialoglycoprotein Receptor, Base Sequence, Cell Line, Chromosome Breakpoints, Chromosome Deletion, Chromosomes, Human, Pair 17, Dishevelled Proteins, Flow Cytometry, Gene Dosage, Humans, Immunohistochemistry, Intellectual Disability, Microcephaly, Microtubule-Associated Proteins, Molecular Sequence Data, Phosphoproteins, Retrospective Studies, Sequence Analysis, DNA, Smith-Magenis Syndrome, Syndrome, Zebrafish},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2014.10.006},
	author = {Carvalho, Claudia M B and Vasanth, Shivakumar and Shinawi, Marwan and Russell, Chad and Ramocki, Melissa B and Brown, Chester W and Graakjaer, Jesper and Skytte, Anne-Bine and Vianna-Morgante, Angela M and Krepischi, Ana C V and Patel, Gayle S and Immken, LaDonna and Aleck, Kyrieckos and Lim, Cynthia and Cheung, Sau Wai and Rosenberg, Carla and Katsanis, Nicholas and Lupski, James R}
}
