Recessive Spondylocarpotarsal Synostosis Syndrome Due to Compound Heterozygosity for Variants in MYH3 Sophia R. Cameron-Christie, Constance F. Wells,

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Recessive Spondylocarpotarsal Synostosis Syndrome Due to Compound Heterozygosity for Variants in MYH3 Sophia R. Cameron-Christie, Constance F. Wells, Marleen Simon, Marja Wessels, Candy Z.N. Tang, Wenhua Wei, Riku Takei, Coranne Aarts-Tesselaar, Sarah Sandaradura, David O. Sillence, Marie-Pierre Cordier, Hermine E. Veenstra-Knol, Matteo Cassina, Kathrin Ludkig, Eva Trevisson, Melanie Bahlo, David M. Markie, Zandra A. Jenkins, Stephen P. Robertson The American Journal of Human Genetics Volume 102, Issue 6, Pages 1115-1125 (June 2018) DOI: 10.1016/j.ajhg.2018.04.008 Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree Structures and Phenotypes of Individuals with SCTS (A) Pedigrees of individuals 1–5, 7, and 8. (B) Individual 1 in the neonatal period demonstrates scoliosis but no radiological evidence of vertebral fusion. (C–E) Individual 2 shows scoliosis and vertebral fusions (C), capitate-hamate synostosis (D), and camptodactyly with mild interdigital webbing (E). (F) Individual 5 with scoliosis. (G and H) A 3D reconstructed computed tomography scan (G) and antero-posterior radiograph (H) of individual 6 with scoliosis and fusions involving the thoracic vertebrae. (I) Individuals 7 (left) and 8 (right) with scoliosis and fusions involving the thoracic vertebrae. The American Journal of Human Genetics 2018 102, 1115-1125DOI: (10.1016/j.ajhg.2018.04.008) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 2 Mapping and Identification of Pathogenic Variants in MYH3 (A) Scatterplot of all genomic regions that are identical by state (as measured by continuous sharing of at least one allele) between individuals 1 and 5. Points are filled if they are in the top five most extended regions, as measured by both the number of markers and genetic distance. Labels for these points report the chromosome and centiMorgan coordinates. Paternally inherited regions in individual 1 are represented in orange, and maternally inherited regions are in purple. (B) Shared haplotypes containing the two MYH3 variants in individuals 1, 2, and 5 via a large, shared paternal haplotype (orange) and a shared maternal haplotype (purple). The location of MYH3 and the truncating variant is represented by an X, and the 5′ UTR variant is represented by a circle. (C) Schematic of MYH3, MYHC-EMB, and published mutations6–10,23–26 leading to four different phenotypes. Abbreviations are as follows: DA1, distal arthrogrysosis type 1; DA2A, distal arthrogryposis type 2A; FSS, Freeman-Sheldon syndrome; DA2B, distal arthrogryposis type 2B; SHS, Sheldon-Hall syndrome; DA8, distal arthrogryposis type 8; SCTS, spondylocarpotarsal synostosis syndrome; †, mutation with c.−9+1G>A (rs557849165) on the other allele; N, neck; H, hinge; and aa, amino acid. The American Journal of Human Genetics 2018 102, 1115-1125DOI: (10.1016/j.ajhg.2018.04.008) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 3 Analysis of Splice Variants and Translational Efficiency for Wild-Type and c.−9+1G>A MYH3 Alleles (A) Diagram of exons 1–3, introns, and observed spice variants designated as A, B, or C; the position of the MYH3 c.−9+1G>A variant is indicated by a red star. (B) MiSeq data showing the proportions of observed splice variants A–C as a percentage of the total reads for both wild-type MYH3 (687 paired reads) and c.−9+1G>A MYH3 (749 paired reads; abbreviated as 9G>A). Variants were excluded if they represented ≤1% of the total reads. (C) Diagram of dual-expression plasmid constructs designed so that the variant MYH3 5′ UTRs are fused to the mCherry reporter and normalized to a dual-expressed EGFP. Construct A includes MYH3 exons 1 and 2 and 6 bp of exon 3 up to the ATG codon, and construct B includes MYH3 exon 1 spliced directly to 6 bp of exon 3. (D) Relative translational efficiency of MYH3 5′ UTR splice variants transfected into HEK293FT cells is represented as relative mCherry fluorescence normalized to that of EGFP. ∗∗∗p < 0.0001, two-tailed t test. Error bars represent standard deviation from the mean. The American Journal of Human Genetics 2018 102, 1115-1125DOI: (10.1016/j.ajhg.2018.04.008) Copyright © 2018 American Society of Human Genetics Terms and Conditions