title: TMCO1 deficiency causes autosomal recessive cerebrofaciothoracic dysplasia.
abstract: Cerebrofaciothoracic dysplasia (CFT) (OMIM #213980) is a multiple congenital anomaly and intellectual disability syndrome involving the cranium, face, and thorax. The characteristic 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 homozygous 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 features 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.
authors.affiliation: Department of Pediatrics, Pediatric Genetics, Hacettepe University Medical Faculty, Ankara, Turkey; Department of Pediatrics, Pediatric Genetics, Acıbadem University Medical Faculty, Istanbul, Turkey.
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Alanay
authors.forename: Bekir
authors.initials: B
authors.lastname: Ergüner
authors.forename: Eda
authors.initials: E
authors.lastname: Utine
authors.forename: Orçun
authors.initials: O
authors.lastname: Haçariz
authors.forename: Pelin Ozlem Simsek
authors.initials: PO
authors.lastname: Kiper
authors.forename: Ekim Zihni
authors.initials: EZ
authors.lastname: Taşkıran
authors.forename: Ferda
authors.initials: F
authors.lastname: Perçin
authors.forename: Elif
authors.initials: E
authors.lastname: Uz
authors.forename: Mahmut Şamil
authors.initials: MŞ
authors.lastname: Sağiroğlu
authors.forename: Bayram
authors.initials: B
authors.lastname: Yuksel
authors.forename: Koray
authors.initials: K
authors.lastname: Boduroglu
authors.forename: Nurten Ayse
authors.initials: NA
authors.lastname: Akarsu
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology; D001921:Brain / Q000473:pathology; D015220:Calcium Channels; D002675:Child, Preschool; D002874:Chromosome Mapping; D003241:Consanguinity; D004252:DNA Mutational Analysis; D059472:Exome; D019066:Facies; D017809:Fatal Outcome; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011247:Pregnancy; D011256:Pregnancy Outcome; D011859:Radiography; D014421:Turkey
chemical_list: D015220:Calcium Channels; D008565:Membrane Proteins; C575495:TMCO1 protein, human
keywords: TMCO1; TMCO1-defect; cerebrofaciothoracic dysplasia; whole exome-sequencing