Whole exome sequencing in an Indian family links Coats plus syndrome and dextrocardia with a homozygous novel CTC1 and a rare HES7 variation

BMC Medical Genetics

Mohammed Faruq⁴  Arun Kumar³  Pramod Kumar Pal²  Parthasarathy Satishchandra²  Devaraddi Navalli²  Anil Ramakrishna²  Jitender Saini⁵  Paritosh Pandey⁶  Sumitabho Deb Roy¹  Manish Kumar Dwivedi⁴  Pushkar Dakle⁴  Saketh Kapoor³  Renu Kumari⁴  Manjunath Netravathi² 

[1] Proteomics and Structural Biology Unit, CSIR-Institute of Genomics and Integrative Biology, Mall Road, New Delhi, India;Department of Neurology, National Institute of mental health & Neurosciences (NIMHANS), Bangalore 560029, India;Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India;Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Mall Road, New Delhi, India;Department of Neuroimaging & Interventional Neuroradiology, National Institute of mental health & Neurosciences (NIMHANS), Bangalore 560034, India;Department of Neurosurgery, National Institute of mental health & Neurosciences (NIMHANS), Bangalore 560029, India

关键词: Notch signaling;    Dextrocardia;    Autosomal recessive disease;    Whole exome sequencing;    CRMCC;    Coats plus syndrome;    CTC1;   

Others  :  1122501
DOI  :  10.1186/s12881-015-0151-8

 received in 2014-07-17, accepted in 2015-01-30,  发布年份 2015

【 摘 要 】

Background

Coats plus syndrome is an autosomal recessive, pleiotropic, multisystem disorder characterized by retinal telangiectasia and exudates, intracranial calcification with leukoencephalopathy and brain cysts, osteopenia with predisposition to fractures, bone marrow suppression, gastrointestinal bleeding and portal hypertension. It is caused by compound heterozygous mutations in the CTC1 gene.

Case presentation

We encountered a case of an eight-year old boy from an Indian family with manifestations of Coats plus syndrome along with an unusual occurrence of dextrocardia and situs inversus. Targeted resequencing of the CTC1 gene as well as whole exome sequencing (WES) were conducted in this family to identify the causal variations. The identified candidate variations were screened in ethnicity matched healthy controls. The effect of CTC1 variation on telomere length was assessed using Southern blot. A novel homozygous missense mutation c.1451A > C (p.H484P) in exon 9 of the CTC1 gene and a rare 3′UTR known dbSNP variation (c.*556 T > C) in HES7 were identified as the plausible candidates associated with this complex phenotype of Coats plus and dextrocardia. This CTC1 variation was absent in the controls and we also observed a reduced telomere length in the affected individual’s DNA, suggesting its likely pathogenic nature. The reported p.H484P mutation is located in the N-terminal 700 amino acid regionthat is important for the binding of CTC1 to ssDNA through its two OB domains. WES data also showed a rare homozygous missense variation in the TEK gene in the affected individual. Both HES7 and TEK are targets of the Notch signaling pathway.

Conclusions

This is the first report of a genetically confirmed case of Coats plus syndrome from India. By means of WES, the genetic variations in this family with unique and rare complex phenotype could be traced effectively. We speculate the important role of Notch signaling in this complex phenotypic presentation of Coats plus syndrome and dextrocardia. The present finding will be useful for genetic diagnosis and carrier detection in the family and for other patients with similar disease manifestations.

【 授权许可】

   
2015 Netravathi et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

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