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


METHODS
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.
Department of Neurology, National Institute of mental health & Neurosciences (NIMHANS), Bangalore, 560029, India. sundernetra@yahoo.co.in.
Manjunath
M
Netravathi
Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Mall Road, New Delhi, India. renu.kumari@igib.in.
Renu
R
Kumari
Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, 560012, India. kapoor.saketh@gmail.com.
Saketh
S
Kapoor
Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Mall Road, New Delhi, India. pushkar.dakle@igib.in.
Pushkar
P
Dakle
Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Mall Road, New Delhi, India. mk.dwivedi@igib.in.
Manish Kumar
MK
Dwivedi
Proteomics and Structural Biology Unit, CSIR-Institute of Genomics and Integrative Biology, Mall Road, New Delhi, India. sumitabhodebroy@gmail.com.
Sumitabho Deb
SD
Roy
Department of Neurosurgery, National Institute of mental health & Neurosciences (NIMHANS), Bangalore, 560029, India. paritosh2000@gmail.com.
Paritosh
P
Pandey
Department of Neuroimaging & Interventional Neuroradiology, National Institute of mental health & Neurosciences (NIMHANS), Bangalore, 560034, India. jsaini76@gmail.com.
Jitender
J
Saini
Department of Neurology, National Institute of mental health & Neurosciences (NIMHANS), Bangalore, 560029, India. anilramakrishna78@yahoo.co.in.
Anil
A
Ramakrishna
Department of Neurology, National Institute of mental health & Neurosciences (NIMHANS), Bangalore, 560029, India. devaraddi.navalli@rediffmail.com.
Devaraddi
D
Navalli
Department of Neurology, National Institute of mental health & Neurosciences (NIMHANS), Bangalore, 560029, India. drpsatishchandra@yahoo.com.
Parthasarathy
P
Satishchandra
Department of Neurology, National Institute of mental health & Neurosciences (NIMHANS), Bangalore, 560029, India. pal.pramod@rediffmail.com.
Pramod Kumar
PK
Pal
Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, 560012, India. karun@mrdg.iisc.ernet.in.
Arun
A
Kumar
Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Mall Road, New Delhi, India. faruq.mohd@igib.res.in.
Mohammed
M
Faruq
D000818:Animals; D001259:Ataxia / Q000150:complications / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D001932:Brain Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002114:Calcinosis / Q000150:complications / Q000235:genetics* / Q000473:pathology; D020863:Central Nervous System Cysts / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002648:Child; D003914:Dextrocardia / Q000150:complications*; D059472:Exome / Q000235:genetics*; D023281:Genomics; D006720:Homozygote; D006801:Humans; D007194:India; D056784:Leukoencephalopathies / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008297:Male; D009128:Muscle Spasticity / Q000150:complications / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D051880:Receptors, Notch / Q000378:metabolism; D012164:Retinal Diseases / Q000150:complications / Q000235:genetics* / Q000473:pathology; D012640:Seizures / Q000150:complications / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D016615:Telomere / Q000235:genetics; D034501:Telomere-Binding Proteins / Q000235:genetics*
D051792:Basic Helix-Loop-Helix Proteins; D051880:Receptors, Notch; D034501:Telomere-Binding Proteins; C544945:Ctc1 protein, human; C486601:HES7 protein, human