American Journal of Medical Genetics 138A:75–78 (2005) Research Letter Probable Identity-by-Descent for a Mutation in the Dyggve–Melchior–Clausen/Smith–McCort Dysplasia (Dymeclin) Gene Among Patients From Guam, Chile, Argentina, and Spain Robert Pogue, 1 Nadia Ehtesham, 1 Gabriela M. Repetto, 2 Roque Carrero-Valenzuela, 3 Cristina Baza ´ n de Casella, 4,5 Silvia Pintos de Pons, 3 Maria Luisa Martı ´nez-Frı ´as, 6 Solange Heuertz, 7 Valerie Cormier-Daire, 7 and Daniel H. Cohn 1,8,9 * 1 Medical Genetics Institute, Steven Spielberg Pediatric Research Center, Los Angeles, California 2 Facultad de Medicina, Clinica Alemana-Universidad del Desarrollo, Santiago, Chile 3 Centro de Gene´tica Me´dica, Orientacio´n Gene´tica, Departamento Biome´dico, Universidad Nacional de Tucuma´n, Tucuma´n, Argentina 4 Orientacio´n Medicina Infanto-Juvenil, Departamento de Maternidad e Infancia, de la Facultad de Medicina de la Universidad Nacional de Tucuma´n, Tucuma´n, Argentina 5 Servicio de Endocrinologı´a Pedia´trica del Hospital del Nin ˜ o Jesu ´s, Tucuma´n, Argentina 6 Centro de Investigacio´n Sobre Anomalı´as Conge´nitas, Instituto de Salud Carlos III, Madrid, Spain 7 Department of Medical Genetics and INSERM U393, Hopital Necker Enfants Malades, Paris, France 8 Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California 9 Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California To the Editor: Dyggve–Melchior–Clausen dysplasia (DMC; OMIM 223800) [Dyggve et al., 1962] and Smith–McCort dysplasia (SMC; OMIM 607326) [Smith and McCort, 1958] are allelic, recessively-inherited osteochondrodysplasia phenotypes. Clinical features common to both conditions include short limbs and short trunk, a barrel shaped chest, kyphoscoliosis, microcephaly and brachydactyly. The two disorders are distinguished by the presence of mental retardation in DMC patients. Radiographically, patients with DMC and SMC ex- hibit platyspondyly, a characteristic double-humped appear- ance of the vertebrae with a central constriction, and both metaphyseal and epiphyseal irregularities [Burns et al., 2003]. The phenotypes thus fall within the spondyloepimetaphyseal dysplasia subgroup of the osteochondrodysplasias [Hall, 2002]. A lacy appearance of the iliac crests is a pathognomonic finding. Growth plate histology shows sparse chondrocytes, with disorganization and lack of column formation in the hypertrophic zone. Electron microscopy reveals that chondro- cytes have dilated endoplasmic reticulum containing amor- phous material of unknown constitution [Nakamura et al., 1997]. DMC and SMC are caused by mutations in the FLJ20071/ DYMECLIN gene [Cohn et al., 2003; El Ghouzzi et al., 2003]. Homozygosity or compound heterozygosity for null mutations was shown to be the primary cause of DMC, while two SMC patients from Guam were compound heterozygtes for an exon- skipping mutation and a missense mutation [Cohn et al., 2003]. The exon-skipping mutation was an A > G transition in the splice acceptor of intron 7 (IVS7-2A > G), producing a tran- script lacking exon 8. This resulted in an altered reading frame, predicting premature termination of protein synthesis. The same mutation was recently described in a Spanish DMC patient who was a compound heterozygote for this and another splicing mutation [Paupe et al., 2004]. We studied three DMC families, one each from Chile, Argentina, and Spain. Clinical information, radiographs, and blood samples were obtained under an IRB approved protocol. The clinical phenotypes of the two SMC patients from Guam (International Skeletal Dysplasia Registry reference numbers R94-126 and R98-116) were described previously [Cohn et al., 2003]. The DMC patient from Chile (R03-256), was a female born to consanguineous parents by C-section at 34 weeks gestation due to preeclampsia, and had a birth weight of 2,460 g (10th– 25th centile), and length of 45 cm (25th–50th centile). She manifested early onset growth retardation and bilateral hip subluxations. At 11 years of age her height was 84 cm (below 3rd centile), she had coarse facial features with prominent supraciliary arches, a short thorax with prominent ribs and sternum, coxa vara, genu valgum, and prominent wrists and ankles. She had severe mental retardation, with absent speech, communicating by whistling or hissing. She was ambulatory but required assistance for most activities of daily living. The DMC patient from Argentina (R03-318), was a male born at term to a consanguineous couple of Spanish descent. Birth weight, length, and head circumference were normal, but soon hypotonia, psychomotor delay, slow growth, and sternal prominence ensued. A skeletal survey at age 10 months led to the diagnosis. At 6 years, 7 months, he had a waddling gait, and was short, slim, borderline microcephalic (2nd centile), and mentally retarded; he also had a long and narrow face, bilateral superior epicanthal folds, small teeth, bifid uvula, prognath- ism, a short neck and trunk, prominent hips, dorsal-lumbar kyphosis, short limbs (especially the proximal segments), small hands and feet, and limited extension of the elbows and knees. Skeletal features apparent on radiographs included advanced bone age, dorsal-lumbar kyphosis, platyspondyly with notched upper and lower vertebral body surfaces, small iliac bones with irregularly calcified borders, subluxated hips, *Correspondence to: Daniel H. Cohn, Ph.D., Medical Genetics, SSB-3, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048. E-mail: dan.cohn@cshs.org Received 20 April 2005; Accepted 12 June 2005 DOI 10.1002/ajmg.a.30912 ß 2005 Wiley-Liss, Inc.