Homozygous Frameshift Mutation in TMCO1 Causes a Syndrome with Craniofacial Dysmorphism, Skeletal Anomalies, and Mental Retardation
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Homozygous frameshift mutation in TMCO1 causes a syndrome with craniofacial dysmorphism, skeletal anomalies, and mental retardation Baozhong Xina, Erik G. Puffenbergerb,c, Susan Turbena, Haiyan Tand, Aimin Zhoud, and Heng Wanga,e,f,1 aDDC Clinic for Special Needs Children, Middlefield, OH 44062; bThe Clinic for Special Children, Strasburg, PA 17579; cDepartment of Biology, Franklin and Marshall College, Lancaster, PA 17603; dDepartment of Chemistry, Cleveland State University, Cleveland, OH 44115; eDepartment of Pediatrics, Rainbow Babies and Children’s Hospital, Cleveland, OH 44106; and fDepartment of Molecular Cardiology, Cleveland Clinic, Cleveland, OH 44195 Edited by Albert de la Chapelle, Ohio State University Comprehensive Cancer Center, Columbus, OH, and approved November 18, 2009 (received for review July 27, 2009) We identified an autosomal recessive condition in 11 individuals Results in the Old Order Amish of northeastern Ohio. The syndrome was Clinical Phenotype. TMCO1 defect syndrome was diagnosed in 11 characterized by distinctive craniofacial dysmorphism, skeletal individuals (6 males, 5 females) ranging in age from 3 to 39 years. anomalies, and mental retardation. The typical craniofacial dys- All 11 patients demonstrated Old Order Amish ancestry, and morphism included brachycephaly, highly arched bushy eye- genealogical analyses revealed multiple lines of common descent brows, synophrys, long eyelashes, low-set ears, microdontism of between all parents of affected children (Fig. 1). The phenotype primary teeth, and generalized gingival hyperplasia, whereas was not observed in the parents or 23 unaffected siblings. Sprengel deformity of scapula, fusion of spine, rib abnormities, A history of first trimester spontaneous abortions was reported pectus excavatum, and pes planus represented skeletal anomalies. by four mothers with an overall incidence of 10 of 45 pregnancies The genome-wide homozygosity mapping using six affected indi- (22%). The abnormalities in affected individuals were observed viduals localized the disease gene to a 3.3-Mb region on chromo- from prenatal period (Table 1). Ventriculomegaly, cleft lip and fi some 1q23.3-q24.1. Candidate gene sequencing identi ed a palate were noted through prenatal ultrasound in one patient, homozygous frameshift mutation, c.139_140delAG, in the trans- TMCO1) although this procedure was not routinely performed in this membrane and coiled-coil domains 1 ( gene, as the patho- ethnic group. All affected individuals were born with normal genic change in all affected members of the extended pedigree. birth weight for their gestational age (10 of 11 being full term), This mutation is predicted to result in a severely truncated protein and five exhibited length exceeding the 90th percentile. Nine (p.Ser47Ter) of only one-fourth the original length. The TMCO1 infants were reportedly macrocephlic at birth, probably secon- gene product is a member of DUF841 superfamily of several dary to their dysmorphic craniofacial features because their oc- eukaryotic proteins with unknown function. The gene has highly cipitofrontal circumference in fact was not significantly increased conserved amino acid sequence and is universally expressed in all – human tissues examined. The high degree of conservation and the (range 3 95%, average 33%) (Table 1 and Table 2). Hypotonia ubiquitous expression pattern in human adult and fetal tissues and poor feeding were found in all newborns. Routine hemato- suggest a critical role for TMCO1. This report shows a TMCO1 logic and metabolic assays were generally within normal ranges. sequence variant being associated with a genetic disorder in hu- The standard karyotype analysis was performed on at least four man. We propose “TMCO1 defect syndrome” as the name of this patients and reported as normal. condition. The craniofacial dysmorphism was noticeable at birth and included brachycephaly, flat face, low hairline, low-set ears, high- Amish | transmembrane and coiled-coil domains 1 gene | genotyping and arched palate, and cleft lip and palate. Other characteristic mapping | homozygosity | SNP arrays dysmorphic features, such as highly arched bushy eyebrows, synophrys, orbital hypertelorism, long eyelashes, wide nose bridge, short nose with anteverted nares, and microdontism of lthough there are a significant number of autosomal primary teeth appeared later, generally before they reached Aphenotypes associated with syndromic and nonsyndromic fi preschool age. Generalized gingival hyperplasia usually mental retardation, the identi cation of these genes has been appeared after the eruption of permanent teeth (Fig. 2, Fig. S1, relatively slow, and the underlying pathophysiology of mental and Table 1). retardation remains unexplained in most cases (1). The use of Skeletal dysmorphism, such as pectus excavatum and club feet, homozygosity mapping in consanguineous families and isolated was noted during early infancy, whereas scoliosis and long, populations is a powerful tool for revealing genetic lesions in hyperextensible fingers developed when the patients reached various recessive conditions (2–6). Yet, this approach, as with puberty. Fusion of the cervical or thoracic spine, rib anomalies conventional linkage mapping, requires that the clinical phe- (including fusion, hypoplasia, or broad or missing ribs), and notype be well defined and easily recognizable. Unfortunately, Sprengel deformity of scapula, were usually incidental findings mental retardation as a clinical descriptor is nonspecific unless during routine imaging studies for other purposes. The actual found in association with other features. Here, we describe a incidence of these abnormalities in TMCO1 defect syndrome unique genetic condition characterized by craniofacial dys- morphism, skeletal anomalies, and mental retardation in the Old Order Amish of northeastern Ohio. Through a genome- Author contributions: H.W. designed research; B.X., E.G.P., S.T., H.T., A.Z., and H.W. per- formed research; B.X., E.G.P., and H.W. analyzed data; B.X. and H.W. wrote the paper; wide mapping study, we localized the disease gene to chromo- and S.T. and H.W. evaluated patients. fi some 1q23.3-q24.1 and identi ed a homozygous frameshift The authors declare no conflict of interest. mutation in the transmembrane and coiled-coil domains 1 gene This article is a PNAS Direct Submission. TMCO1 ( ) as the cause of this autosomal recessive condition, 1To whom correspondence should be addressed: E-mail: [email protected]. “ ” thus we propose TMCO1 defect syndrome as the name for This article contains supporting information online at www.pnas.org/cgi/content/full/ this disease. 0908457107/DCSupplemental. 258–263 | PNAS | January 5, 2010 | vol. 107 | no. 1 www.pnas.org/cgi/doi/10.1073/pnas.0908457107 Downloaded by guest on October 1, 2021 I II III IV V Fig. 1. Partial pedigree of the family with VI TMCO1 defect syndrome. Filled symbols represent affected individuals, and open VII symbols represent unaffected individuals. Circles and squares denote females and fi VIII ? males, respectively. A double line identi es consanguinity. Arrows indicate affected IX individuals included in genetic mapping study and sequence analysis. might be higher if systematic osseous surveys were performed in erozygous for the c.139_140delAG mutation (estimated carrier all patients (Table 1, Table 2, Fig. 2, and Fig. S1). The skeletal frequency of 0.7%). anomalies found in this condition mostly involve the axial skel- To determine the distribution of the TMCO1 mutation in eton, which embryologically originates from somites. There was other Amish populations, we screened 75 Old Order Amish from significant divergence in patients’ stature, two of them having tall southeastern Pennsylvania for c.139_140delAG mutation. This stature with height >95th percentile, whereas three exhibited sample included normal controls and undiagnosed patients. We short stature with height in less than the 3rd percentile. Global found five c.139_140delAG heterozygotes for an estimated car- developmental delay was found in all affected individuals, al- rier frequency of 6.6%. Surprisingly, among the undiagnosed though regression was not observed. patients, we identified a single mutation homozygote. Review of Neurological examination revealed depressed deep tendon his clinical history revealed a phenotype strikingly similar to the reflexes and unstable gait, and intention tremor developed in affected children from Ohio. Further testing of undiagnosed fi some older patients. Imaging studies demonstrated mild prom- children at the Clinic for Special Children identi ed a total of fi inence of ventricles viewed through CT or MRI (Fig. 2H). ve affected c.139_140delAG homozygotes. Review of the SNP fi Sluggish speech with a loud and hoarse voice was found in all genotype data generated previously showed that all ve patients from Pennsylvania were indeed homozygous for SNPs spanning verbal patients. Anatomical abnormalities of the genito-urinary TMCO1 B system were noted, including renal agenesis, hydronephrosis, the locus, but the haplotypes were different (Fig. 3 ). vesicoureteral reflux, hypoplastic labia minora, hydrocele, and The three homozygotes from the Lancaster County Amish set- undescended testes. Other clinical features with high incidence tlement were homozygous for a different background haplotype than the other two homozygotes, who lived in Somerset County were frequent otitis media, sinusitis, strabismus, and constipation of Pennsylvania. The Somerset County Amish haplotype although