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

ABSTRACT: 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.

SUBMITTER: Pehlivan D

PROVIDER: S-EPMC4135405 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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

Pehlivan Davut D Karaca Ender E Aydin Hatip H Beck Christine R CR Gambin Tomasz T Muzny Donna M DM Bilge Geckinli B B Karaman Ali A Jhangiani Shalini N SN Gibbs Richard A RA Lupski James R JR

European journal of human genetics : EJHG 20140115 9

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 a ...[more]

PMID: 24424126

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Project description:ObjectiveTo report a new phenotype caused by mutations in the CRB1 gene in a family with 2 affected siblings.DesignMolecular genetics and observational case studies.ParticipantsTwo affected siblings and 3 unaffected family members.MethodsEach subject received a complete ophthalmic examination together with color fundus photography, fundus autofluorescence (FAF), and spectral-domain optical coherence tomography (SD-OCT). Microperimetry 1 (MP-1) mapping and electroretinogram (ERG) analysis were performed on the proband. Screening for disease-causing mutations was performed by whole exome sequencing in 3 family members followed by segregation analyses in the entire family.Main outcome measuresAppearance of the macula as examined by clinical examination, fundus photography, FAF imaging, SD-OCT, and visual function by MP-1 and ERG.ResultsThe proband and her affected brother exhibited unusual, previously unreported, findings of a macular dystrophy with relative sparing of the retinal periphery beyond the vascular arcades. The FAF imaging showed severely affected areas of hypoautofluorescence that extended nasally beyond the optic disc in both eyes. A central macular patch of retinal pigment epithelium (RPE) sparing was evident in both eyes on FAF, whereas photoreceptor sparing was documented in the right eye only using SD-OCT. The affected brother presented with irregular patterns of autofluorescence in both eyes characterized by concentric rings of alternating hyper- and hypoautofluorescence, and foveal sparing of photoreceptors and RPE, as seen on SD-OCT, bilaterally. After negative results in screening for mutations in candidate genes including ABCA4 and PRPH2, DNA from 3 members of the family, including both affected siblings and their mother, was screened by whole exome sequencing resulting in identification of 2 CRB1 missense mutations, c.C3991T:p.R1331C and c.C4142T:p.P1381L, which segregated with the disease in the family. Of the 2, the p.R1331C CRB1 mutation has not been described before and the p.P1381L variant has been described in 1 patient with Leber congenital amaurosis.ConclusionsThis report illustrates a novel presentation of a macular dystrophy caused by CRB1 mutations. Both affected siblings exhibited a relatively well-developed retinal structure and preservation of generalized retinal function. An unusual 5-year progression of macular atrophy alone was observed that has not been described in any other CRB1-associated phenotypes.

Project description:Cerebro-oculo-facio-skeletal (COFS) syndrome is a recessively inherited rapidly progressive neurologic disorder leading to brain atrophy, with calcifications, cataracts, microcornea, optic atrophy, progressive joint contractures, and growth failure. Cockayne syndrome (CS) is a recessively inherited neurodegenerative disorder characterized by low to normal birth weight, growth failure, brain dysmyelination with calcium deposits, cutaneous photosensitivity, pigmentary retinopathy and/or cataracts, and sensorineural hearing loss. Cultured CS cells are hypersensitive to UV radiation, because of impaired nucleotide-excision repair (NER) of UV-induced damage in actively transcribed DNA, whereas global genome NER is unaffected. The abnormalities in CS are caused by mutated CSA or CSB genes. Another class of patients with CS symptoms have mutations in the XPB, XPD, or XPG genes, which result in UV hypersensitivity as well as defective global NER; such patients may concurrently have clinical features of another NER syndrome, xeroderma pigmentosum (XP). Clinically observed similarities between COFS syndrome and CS have been followed by discoveries of cases of COFS syndrome that are associated with mutations in the XPG and CSB genes. Here we report the first involvement of the XPD gene in a new case of UV-sensitive COFS syndrome, with heterozygous substitutions-a R616W null mutation (previously seen in patients in XP complementation group D) and a unique D681N mutation-demonstrating that a third gene can be involved in COFS syndrome. We propose that COFS syndrome be included within the already known spectrum of NER disorders: XP, CS, and trichothiodystrophy. We predict that future patients with COFS syndrome will be found to have mutations in the CSA or XPB genes, and we document successful use of DNA repair for prenatal diagnosis in triplet and singleton pregnancies at risk for COFS syndrome. This result strongly underlines the need for screening of patients with COFS syndrome, for either UV sensitivity or DNA-repair abnormalities.

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

Publications

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

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