Xin et al. (2010) described a mental retardation syndrome in 11 patients from the Old Order Amish population of Geauga County in northeastern Ohio. Some abnormalities, such as cleft lip and palate and ventriculomegaly, could be observed from ... Xin et al. (2010) described a mental retardation syndrome in 11 patients from the Old Order Amish population of Geauga County in northeastern Ohio. Some abnormalities, such as cleft lip and palate and ventriculomegaly, could be observed from the prenatal period, although not all patients had prenatal ultrasound. Features at birth included hypotonia, poor feeding, and craniofacial dysmorphisms, including brachycephaly, flat face, low hairline, low-set ears, high-arched palate, and cleft lip and palate. Features that appeared later included highly arched bushy eyebrows, synophrys, hypertelorism, long eyelashes, wide nasal bridge, short nose with anteverted nares, microdontism, and gingival hyperplasia. Skeletal dysmorphisms tended to involve the axial skeleton, with pectus excavatum, scoliosis, vertebral fusion, and rib anomalies. Two patients had tall stature, whereas 3 had short stature. All had global developmental delay. Neurologic examination showed hyporeflexia, unsteady gait, and intention tremor in some older patients. Some had variable genitourinary anomalies, such as renal agenesis, hydronephrosis, vesicoureteral reflux, and undescended testes. First trimester spontaneous abortions occurred in 22% of pregnancies. Caglayan et al. (2013) reported a 7-year-old Turkish boy, born of first-cousin parents, who was hypotonic at birth and had feeding difficulties, hypothyroidism, and significant neurodevelopmental delay. His family reported that he was anxious and exhibited self-mutilating behavior such as chewing his fingers. Examination at 7 years of age revealed dysmorphic features including short neck, low hairline, low-set ears, synophrys, hypertelorism, anteverted nares, high-arched palate, prognathism, hyperextensible fingers, pectus carinatum, scoliosis, and genu varus. He was awake but unable to speak, walk, or feed himself. Brain MRI showed dysgenesis of the corpus callosum and cerebellar herniation.
By genomewide homozygosity mapping followed by candidate gene sequencing, Xin et al. (2010) identified homozygosity for a 2-bp deletion in the TMCO1 gene (614123.0001) in 9 of 11 northeastern Ohio Amish patients with a mental retardation syndrome and ... By genomewide homozygosity mapping followed by candidate gene sequencing, Xin et al. (2010) identified homozygosity for a 2-bp deletion in the TMCO1 gene (614123.0001) in 9 of 11 northeastern Ohio Amish patients with a mental retardation syndrome and skeletal anomalies. Two patients were deceased, and their genotype was not confirmed. Screening of ethnically matched controls from the same community showed a carrier frequency of 0.7%. Screening of Old Order Amish from southeastern Pennsylvania yielded a carrier frequency of 6.6%. Further analysis identified 6 more patients from Pennsylvania with a similar phenotype who were also homozygous for the 2-bp deletion. Two patients from Somerset County, Pennsylvania, were on the same haplotype as the Ohio Amish patients, and 3 patients from Lancaster County, Pennsylvania, were on a different haplotype. Xin et al. (2010) proposed the designation 'TMCO1 defect syndrome.' In a 7-year-old Turkish boy with mental retardation and craniofacial and skeletal anomalies, Caglayan et al. (2013) performed homozygosity mapping followed by exome sequencing and identified homozygosity for a nonsense mutation in the TMCO1 gene (R87X; 614123.0002). The mutation was found in heterozygosity in the available parent. In contrast to patients previously described with TMOC1 deficiency, Caglayan et al. (2013) noted that this patient had more profound developmental impairment and did not show craniosynostosis or spinal fusion, which occurred in 18% and 55% of the original cases, respectively.