Christian Gilissen, Heleen H

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Exome Sequencing Identifies WDR35 Variants Involved in Sensenbrenner Syndrome Christian Gilissen, Heleen H. Arts, Alexander Hoischen, Liesbeth Spruijt, Dorus A. Mans, Peer Arts, Bart van Lier, Marloes Steehouwer, Jeroen van Reeuwijk, Sarina G. Kant, Ronald Roepman, Nine V.A.M. Knoers, Joris A. Veltman, Han G. Brunner The American Journal of Human Genetics Volume 87, Issue 3, Pages 418-423 (September 2010) DOI: 10.1016/j.ajhg.2010.08.004 Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 1 Two Patients with Sensenbrenner Syndrome for Whom Exome Sequencing Was Performed (A) Patient 1: small thorax, pectus excavatum, rhizomelic shortening of limbs. (B) Shortening of proximal second phalanx. The proximal phalanx is indicated by “P”; the middle phalanx is indicated by “M.” (C) Syndactyly 2-3 right foot, 2-3-4 left foot. (D) Hypertelorism, unilateral ptosis of left eye, low-set ears, everted lower lip. (E) Patient 2: small thorax, pectus excavatum, rhizomelic shortening of limbs. (F) Short, broad hands. (G) Bilateral sandal gap between first and second toe. (H) Hypertelorism, low-set simple ears, thin hair. The American Journal of Human Genetics 2010 87, 418-423DOI: (10.1016/j.ajhg.2010.08.004) Copyright © 2010 The American Society of Human Genetics Terms and Conditions

Figure 2 Splice-Site Mutation in Patient 1 (A) Gene and protein structure of WDR35. WD domains are indicated by triangles; the box indicates a low-complexity region. (B) Sequencing reads showing the heterozygous splice-site mutation at the splice-acceptor site of exon 2 as well as a nearby exonic polymorphism (rs1060742). (C) Maternal inheritance of the splice-site mutation in patient 1 shown by Sanger sequencing. (D) Effect of the splice-site mutation on the RNA shows two different products of equal intensity in lane 1 (523 bp and 465 bp for the upper and lower band, respectively). Lane 2 shows the product of an unrelated control (465 bp). (E) Sequence of the two WDR35 RT-PCR products from Figure 2D, showing that the polymorphism (rs1060742) is predominantly present in the normal spliced product as a C (Figure 2D, lane 1, arrow a), whereas this is a T in the alternatively spliced product (Figure 2D, lane 1, arrow b). The sequence of the RT-PCR product of an unrelated individual with the same heterozygous SNP (rs1060742) is shown as a control (Figure 2D, lane 3, arrow c). The American Journal of Human Genetics 2010 87, 418-423DOI: (10.1016/j.ajhg.2010.08.004) Copyright © 2010 The American Society of Human Genetics Terms and Conditions