DVL3 Alleles Resulting in a −1 Frameshift of the Last Exon Mediate Autosomal- Dominant Robinow Syndrome Janson J. White, Juliana F. Mazzeu, Alexander.

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DVL3 Alleles Resulting in a −1 Frameshift of the Last Exon Mediate Autosomal- Dominant Robinow Syndrome Janson J. White, Juliana F. Mazzeu, Alexander Hoischen, Yavuz Bayram, Marjorie Withers, Alper Gezdirici, Virginia Kimonis, Marloes Steehouwer, Shalini N. Jhangiani, Donna M. Muzny, Richard A. Gibbs, Bregje W.M. van Bon, V. Reid Sutton, James R. Lupski, Han G. Brunner, Claudia M.B. Carvalho The American Journal of Human Genetics Volume 98, Issue 3, Pages 553-561 (March 2016) DOI: 10.1016/j.ajhg.2016.01.005 Copyright © 2016 The American Society of Human Genetics Terms and Conditions

Figure 1 Locations of All Currently Described Variants Resulting in DVL1-Mediated Robinow Syndrome (A) Depiction of the resulting mutant transcript in BAB8062. Black represent regions identical to the wild-type DVL1, and red indicates the mutant coding region. (B) Locations of all variants currently described in the literature. Orange indicates nucleotides deleted in individuals reported by Bunn et al.,6 green represents those from White et al.,7 and yellow indicates those in BAB8062, reported here. All the variants are located within a stretch of ∼110 nucleotides in the penultimate exon, and all are deletions that result in a −1 frameshift. The American Journal of Human Genetics 2016 98, 553-561DOI: (10.1016/j.ajhg.2016.01.005) Copyright © 2016 The American Society of Human Genetics Terms and Conditions

Figure 2 Robinow-Associated DVL3 Variants Overview of the variants identified in DVL3 in individuals with autosomal-dominant Robinow syndrome. (A) Location of the identified variants within the final two exons, including three frameshifts in coding regions and two splice acceptor variants. The red bar within exon 15 represents the shared premature termination codon of all individuals within our cohort. (B) Representation of the predicted mutant C-terminal tail from Robinow-syndrome-affected individuals in our cohort. Black regions represent amino acids encoded by exons of the wild-type DVL3. Red regions represent mutant amino acids predicted to result from translation in the −1 frame. The American Journal of Human Genetics 2016 98, 553-561DOI: (10.1016/j.ajhg.2016.01.005) Copyright © 2016 The American Society of Human Genetics Terms and Conditions

Figure 3 mRNA Expression of DVL1 and DVL3 Transcripts in Robinow Syndrome (A) Chromatograms display Sanger sequencing results of cloned cDNA transcripts in BAB8062 (DVL1) and BAB4569 (DVL3). Mutant and reference alleles were cloned and sequenced independently for confirming mutant mRNA expression. (B) Depiction of the relative change in gene expression according to a TaqMan gene-expression assay for DVL1 and DVL3 with exon-spanning probes Hs00737028_m1 and Hs00610263_m1, respectively. For evaluating relative expression, the ΔΔct method19 was used with TBP as the endogenous control and unaffected individual BAB8063 as the control subject. The American Journal of Human Genetics 2016 98, 553-561DOI: (10.1016/j.ajhg.2016.01.005) Copyright © 2016 The American Society of Human Genetics Terms and Conditions

Figure 4 Facial Features of the Individuals with DRS in This Study Individuals BAB4569, BAB7982, BAB7990, and 015902 have DVL3 variants, and BAB8062 has a de novo variant in DVL1. The American Journal of Human Genetics 2016 98, 553-561DOI: (10.1016/j.ajhg.2016.01.005) Copyright © 2016 The American Society of Human Genetics Terms and Conditions