Whole‐exome sequencing identified a patient with TMCO1 defect syndrome and expands the phenotic spectrum

Çağlayan, Ahmet Okay; Per, Hüseyin; Akgumus, Gozde; Gümüş, Hakan; Baranoski, Jacob F; Canpolat, Mehmet; Çalık, Mustafa; Yıkılmaz, Ali; Bilgüvar, Kaya; Kumandaş, Sefer; Günel, Murat

doi:10.1111/cge.12088

Cited by 20 publications

(23 citation statements)

References 3 publications

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“…Phenotype comparison between Turkish and the Amish families demonstrates similar findings in individuals with TMCO1‐defect syndrome suggesting CFT as a possible diagnosis. Similarly, the patient reported recently by Cağlayan et al [] as an additional case of TMCO1‐defect syndrome has clinical findings compatible with CFT. Interestingly, this patient of Turkish origin shares the same founder mutation that is p.Arg87Ter (c.259 C>T) and the clinical assessment is from a medical center from the very same district with Families 2 and 3 in our cohort.…”

Section: Discussionsupporting

confidence: 60%

“…Prominence of ventricles was detected in those examined by CT or MRI in the original TMCO1‐defect cohort. Interestingly, the Turkish patient reported as TMCO1‐defect syndrome has corpus callosum agenesis and cerebellar herniation [Xin et al, ; Cağlayan et al, ]. Brachycephaly, flat face, narrow forehead and other previously noted dysmorphic findings are present in almost all patients with CFT and TMCO1‐defect syndrome.…”

Section: Discussionmentioning

confidence: 99%

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TMCO1 deficiency causes autosomal recessive cerebrofaciothoracic dysplasia

Alanay

Ergüner

Ütine

et al. 2013

American J of Med Genetics Pt A

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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.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

TMCO1 deficiency causes autosomal recessive cerebrofaciothoracic dysplasia

Alanay

Ergüner

Ütine

et al. 2013

American J of Med Genetics Pt A

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“…Combining our series of four patients with those previously reported (Alanay et al, ; Caglayan et al, ; Pehlivan et al, ; Xin et al, ) allows further delineation of the phenotypic spectrum of this rare condition (Table ). The majority of patients (22/23; 96%) were from consanguineous families.…”

Section: Discussionmentioning

confidence: 53%

“…Only 19 molecularly confirmed patients with CFTD have been reported to date (Alanay et al, ; Caglayan et al, ; Pehlivan et al, ; Xin et al, ). Here, we present three further familial patients together with an unrelated additional patient.…”

Section: Introductionmentioning

confidence: 99%

Cerebrofaciothoracic dysplasia: Four new patients with a recurrent TMCO1 pathogenic variant

Yates

Offiah

et al. 2018

American J of Med Genetics Pt A

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Biallelic loss of function variants in the TMCO1 gene have been previously demonstrated to result in cerebrofaciothoracic dysplasia (CFTD; MIM #213980). The phenotype of this condition includes severe intellectual disability, as well as distinctive craniofacial features, including brachycephaly, synophrys, arched eyebrows, “cupid's bow” upper lip, and microdontia. In addition, nonspecific skeletal anomalies are common, including bifid ribs, scoliosis, and spinal fusion. Only 19 molecularly confirmed patients have been previously described. Here, we present four patients with CFTD, including three brothers from a Pakistani background and an additional unrelated white Scottish patient. All share the characteristic craniofacial appearance, with severe intellectual disability and skeletal abnormalities. We further define the phenotype with comparison to the published literature, and present images to define the dysmorphic features in a previously unreported ethnic group. All of our patient series are homozygous for the same c.292_293del (p.Ser98*) TMCO1 pathogenic variant, which has been previously reported only in an isolated Amish population. Thus we provide evidence that CFTD may be more common than previously thought. The patients presented here further delineate the phenotypic spectrum of CFTD and provide evidence for a recurrent pathogenic variant in TMCO1.

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“…Caglayan et al 12 reported a different homozygous nonsense mutation in TMCO1 with similar clinical features in a singleton non-Amish case (Table 1). Neither report drew any inference regarding clinical overlap with CFTD.…”

Section: Introductionmentioning

confidence: 90%

Whole-exome sequencing links TMCO1 defect syndrome with cerebro-facio-thoracic dysplasia

et al. 2014

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Whole-exome sequencing (WES) is a type of disruptive technology that has tremendous influence on human and clinical genetics research. An efficient and cost-effective method, WES is now widely used as a diagnostic tool for identifying the molecular basis of genetic syndromes that are often challenging to diagnose. Here we report a patient with a clinical diagnosis of cerebro-facio-thoracic dysplasia (CFTD; MIM#213980) in whom we identified a homozygous splice-site mutation in the transmembrane and coiled-coil domains 1 (TMCO1) gene using WES. TMCO1 mutations cause craniofacial dysmorphism, skeletal anomalies characterized by multiple malformations of the vertebrae and ribs, and intellectual disability (MIM#614132). A retrospective review revealed that clinical manifestations of both syndromes are very similar and overlap remarkably. We propose that mutations of TMCO1 are not only responsible for craniofacial dysmorphism, skeletal anomalies and mental retardation syndrome but also for CFTD.

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Whole‐exome sequencing identified a patient with TMCO1 defect syndrome and expands the phenotic spectrum

Cited by 20 publications

References 3 publications

TMCO1 deficiency causes autosomal recessive cerebrofaciothoracic dysplasia

TMCO1 deficiency causes autosomal recessive cerebrofaciothoracic dysplasia

Cerebrofaciothoracic dysplasia: Four new patients with a recurrent TMCO1 pathogenic variant

Whole-exome sequencing links TMCO1 defect syndrome with cerebro-facio-thoracic dysplasia

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