RAPID COMMUNICATION TMCO1 Deficiency Causes Autosomal Recessive Cerebrofaciothoracic Dysplasia Yasemin Alanay, 1,2 Bekir Ergu ¨ner, 3 Eda Utine, 1 Orc ¸un Hac ¸arız, 4 Pelin Ozlem Simsek Kiper, 1 Ekim Zihni Tas ¸kıran, 5 Ferda Perc ¸in, 6 Elif Uz, 5,7 Mahmut S ¸amil Sag ˘ırog ˘lu, 3 Bayram Yuksel, 4 Koray Boduroglu, 1 and Nurten Ayse Akarsu 5 * 1 Department of Pediatrics, Pediatric Genetics, Hacettepe University Medical Faculty, Ankara, Turkey 2 Department of Pediatrics, Pediatric Genetics, Acıbadem University Medical Faculty, Istanbul, Turkey 3 Information Technologies Institute, TUBITAK Marmara Research Center, Kocaeli, Turkey 4 Genetic Engineering and Biotechnology Institute, TUBITAK Marmara Research Center, Kocaeli, Turkey 5 Department of Medical Genetics, Gene Mapping Laboratory, Hacettepe University Medical Faculty, Ankara, Turkey 6 Department of Medical Genetics, Gazi University Medical Faculty, Ankara, Turkey 7 Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Uludag University, Bursa, Turkey Manuscript Received: 19 June 2013; Manuscript Accepted: 19 August 2013 Cerebrofaciothoracic dysplasia (CFT) (OMIM #213980) is a multiple congenital anomaly and intellectual disability syn- drome involving the cranium, face, and thorax. The characteris- tic features are cranial involvement with macrocrania at birth, brachycephaly, various CT/MRI findings including hypoplasia of corpus callosum, enlargement of septum pellicidum, and diffuse hypodensity of the grey matter, flat face, hypertelorism, cleft lip and cleft palate, low-set, posteriorly rotated ears, short neck, and multiple costal and vertebral anomalies. The underlying genetic defect remains unknown. Using combination of homozygosity mapping and whole-exome sequencing, we identified a homozy- gous nonsense founder mutation, p.Arg87Ter (c.259 C>T), in the human transmembrane and coiled-coil domains protein 1 (TMCO1) in four out of five families of Turkish origin. The entire critical region on chromosome 1q24 containing TMCO1 was excluded in the fifth family with characteristic findings of CFT providing evidence for genetic heterogeneity of CFT spectrum. Another founder TMCO1 mutation has recently been reported to cause a unique genetic condition, TMCO1-defect syndrome (OMIM #614132). TMCO1-defect syndrome shares many fea- tures with CFT. This study supports the fact that “TMCO1-defect syndrome,” initially thought to represent a distinct disorder, indeed belongs to the genetically heterogeneous CFT dysplasia spectrum. Ó 2013 Wiley Periodicals, Inc. Key words: cerebrofaciothoracic dysplasia; TMCO1-defect; TMCO1; whole exome-sequencing INTRODUCTION Cerebrofaciothoracic dysplasia (CFT) (OMIM #213980) was first described by Pascual-Castroviejo et al. in 1975 in three unrelated children with psychomotor and intellectual disability, distinctive facial dysmorphic features, and multiple malformations of the ribs and vertebrae [Pascual-Castroviejo et al., 1975]. Report of two additional brothers designated CFT as a distinct entity [Philip et al., 1992]. Since then, clinical reports of nine additional individuals, including one reported by our group has enabled further delinea- How to Cite this Article: Alanay Y, Ergu ¨ner B, Utine E, Hac ¸arız O, Kiper POS, Tas ¸kıran EZ, Perc ¸in F, Uz E, Sag ˘ırog ˘lu MS ¸, Yuksel B, Boduroglu K, Akarsu NA. 2014. TMCO1 deficiency causes autosomal recessive cerebrofaciothoracic dysplasia. Am J Med Genet Part A 164A:291–304. Conflict of interest: No conflict of interest is declared. Grant sponsor: The Scientific and Technology Research Council of Turkey (TUBITAK); Grant number: 108S420; Grant sponsor: TUBI ˙ TAK- BI ˙ LGEM-UEKAE; Grant number: K030-T439; Grant sponsor: E-RARE network CRANIRARE consortium; Grant number: R07197KS; Grant sponsor: Ankara Development Agency; Grant number: TR51/11/ YEN/0119; Grant sponsor: Republic of Turkey Ministry of Development; Grant number: 2011K120020. Ã Correspondence to: Nurten Ayse Akarsu, M.D., Ph.D., Professor of Medical Genetics, Department of Medical Genetics, Gene Mapping Laboratory, Hacettepe University Medical Faculty, Sihhiye, 06100 Ankara, Turkey. E-mail: nakarsu@hacettepe.edu.tr, nakarsu9@gmail.com Article first published online in Wiley Online Library (wileyonlinelibrary.com): 5 November 2013 DOI 10.1002/ajmg.a.36248 Ó 2013 Wiley Periodicals, Inc. 291