SAMS, a Syndrome of Short Stature, Auditory-Canal Atresia, Mandibular Hypoplasia, and Skeletal Abnormalities Is a Unique Neurocristopathy Caused by Mutations.

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SAMS, a Syndrome of Short Stature, Auditory-Canal Atresia, Mandibular Hypoplasia, and Skeletal Abnormalities Is a Unique Neurocristopathy Caused by Mutations in Goosecoid David A. Parry, Clare V. Logan, Alexander P.A. Stegmann, Zakia A. Abdelhamed, Alistair Calder, Shabana Khan, David T. Bonthron, Virginia Clowes, Eamonn Sheridan, Neeti Ghali, Albert E. Chudley, Angus Dobbie, Constance T.R.M. Stumpel, Colin A. Johnson The American Journal of Human Genetics Volume 93, Issue 6, Pages 1135-1142 (December 2013) DOI: 10.1016/j.ajhg.2013.10.027 Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical Features of SAMS in Individual C (A–C) At the age of 1 month, individual C presented with malar hypoplasia, severe micrognathia, scaphocephaly with a prominent forehead, downward-slanting palpebral fissures, and rhizomelic shortening of the upper limbs (A). Rudimentary pinnae with bilateral atresia of the (B) right and (C) left external auditory canals with small preauricular tags (arrowheads) can be seen. (D) Pedigree of individual C (arrow) and unaffected family members. (E and F) Left humeroscapular synostosis (E, arrowhead) but normal right shoulder joint (F), with bilateral shortening of the humeri and flaring of the distal metaphyses. (G) Immature ossification of the pelvis, with a flattened acetabulum and bilaterally dislocated hips, and absence of ossification of the pubic rami. (H) Fixed talipes equinovarus of the right foot. The American Journal of Human Genetics 2013 93, 1135-1142DOI: (10.1016/j.ajhg.2013.10.027) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 2 Homozygous-Null Mutations and Microdeletion of GSC Cause SAMS (A) fancyGENE representation9 of human GSC and homozygous point mutations identified in SAMS individuals A, C, and D. The homeobox domain is shown in green. Mutations are marked on the gene in red, and corresponding electropherograms are shown in the top panels, as indicated (red arrows). Wild-type normal sequence is shown below for comparison. (B) Affymetrix CytoScan HD Microarray SNP genotyping of individual B for chromosome 14. The top track identifies a copy-number segment (brown, indicated by a red arrowhead). Other tracks show the log2 ratio signal intensity (blue), genes (pink), and stretches of contiguous loss of heterozygosity (LoH; purple) consistent with identity-by-descent from the consanguineous parents. (C) Array result for individual B of chromosomal region 14q32.13 shows a 306 kb copy-number segment loss arr 14q32.13(95,204,793-95,511,597)x0 (brown, indicated by a red arrowhead) with a copy-number state (light purple) of CN = 0, indicating a homozygous deletion. The Goosecoid gene (GSC) is indicated on the gene track (pink arrowhead), and the physical location in kb is shown at the bottom. The American Journal of Human Genetics 2013 93, 1135-1142DOI: (10.1016/j.ajhg.2013.10.027) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 3 Goosecoid Colocalizes with Pax3 in Neural-Crest Derivatives and the Developing Pelvis (A) Mouse embryonic midline sagittal and horizontal sections showing Goosecoid (green) and Pax3 (red) colocalization in neural-crest-tissue derivatives in the frontonasal prominence (fnp) and the first branchial arch (BA1) and bony attachment points in the embryonic shoulder joint (arrowheads). Scale bars represent 20 μm. Abbreviations are as follows: gc, glenoid cavity; and hu, humerus. (B) Goosecoid and Pax3 colocalization in the developing pubic bone for a midline sagittal section of an E14.5 mouse embryo. The scale bar represents 20 μm. A magnified inset (bottom) is indicated by a white frame. The American Journal of Human Genetics 2013 93, 1135-1142DOI: (10.1016/j.ajhg.2013.10.027) Copyright © 2013 The American Society of Human Genetics Terms and Conditions