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Rajani Battu, Praveen Murthy, Priya Srinivasan, Rohit Shetty, Kavita Reddy; Next generation sequencing (NGS) of CHM, RPRG and RP2 genes identifies novel Indian mutations in two families with Choroideremia. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6430.
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To identify the genetic mutations in clinically identified Choroideremia families using NGS.
Choroideremia is caused by mutations in the CHM gene localized to the long arm of X-chromosome (Xq21.2). Two families who presented with clinical features of choroideremia and the unaffected female carriers underwent a complete ophthalmic evaluation including an optical coherence tomography and electroretinogram. The genomic DNA from the family members were isolated and quantified. The exons and promoter regions 1Kb 5’ prime of CHM, RPGR and RP2 genes were enriched by PCR and sequenced using Illumina HiSeq and MiSeq platform. The identified sequence variants were confirmed using Sanger sequencing.
Family 1: A c.653C>G mutation in exon 5 of CHM gene (Ref Seq id:NM 000390) on the X chromosome was found in the father (hemizygous affected) and the daughter ( heterozygous carrier). The variant is a nonsense mutation and at the protein level replaces the 218 amino acid serine with a STOP (S218X). The truncated protein lacked 436_aa at the C-terminal region that constitutes a part of the GDI (GDP dissociation inhibitor) domain. Family 2: A c820-1G>C mutation in intron 6 of CHM gene (Ref Seq id:NM000390) The proband was hemizygous affected and his mother was a heterozygous carrier for the mutation in an essential splice site of the CHM gene located on the X-chromosome. The mutation was a G to C substitution at position 85212981. This mutation is the likely cause of retinal abnormalities in the proband but his mother is protected on account of one good copy. The sister did not carry disease-associated mutations.
Choroideremia is a rare genetic disorder. Since there are no reported choroideremia mutations from the Indian subcontinent, NGS becomes the method of choice for genetic testing. Genetic counseling and screening other family members using Sanger sequencing can be done. It is also possible to enroll the affected individuals in stem cell/gene therapy clinical trials
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