Whole-Exome Sequencing Identifies Novel Variants that Co-segregates with Autosomal Recessive Retinal Degeneration in a Pakistani Pedigree

Pooja Biswas; Muhammad Asif Naeem; Muhammad Hassaan Ali; Muhammad Zaman Assir; Shaheen N Khan; Sheikh Riazuddin; J Fielding Hejtmancik; S Amer Riazuddin; Radha Ayyagari

doi:10.1007/978-3-319-75402-4_27

Whole-Exome Sequencing Identifies Novel Variants that Co-segregates with Autosomal Recessive Retinal Degeneration in a Pakistani Pedigree

Adv Exp Med Biol. 2018:1074:219-228. doi: 10.1007/978-3-319-75402-4_27.

Authors

Affiliations

¹ Shiley Eye Institute, University of California San Diego, La Jolla, CA, USA.
² National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
³ Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan.
⁴ National Centre for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, Pakistan.
⁵ Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, MD, USA.
⁶ Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. riazuddin@ncemb.org.
⁷ Shiley Eye Institute, University of California San Diego, La Jolla, CA, USA. rayyagari@ucsd.edu.

PMID: 29721947
DOI: 10.1007/978-3-319-75402-4_27

Abstract

Purpose: To identify the molecular basis of inherited retinal degeneration (IRD) in a familial case of Pakistani origin using whole-exome sequencing.

Methods: A thorough ophthalmic examination was completed, and genomic DNA was extracted using standard protocols. Whole exome(s) were captured with Agilent V5 + UTRs probes and sequenced on Illumina HiSeq genome analyzer. The exomeSuite software was used to filter variants, and the candidate causal variants were prioritized, examining their allele frequency and PolyPhen2, SIFT, and MutationTaster predictions. Sanger dideoxy sequencing was performed to confirm the segregation with disease phenotype and absence in ethnicity-matched control chromosomes.

Results: Ophthalmic examination confirmed retinal degeneration in all affected individuals that segregated as an autosomal recessive trait in the family. Whole-exome sequencing identified two homozygous missense variants: c.1304G > A; p.Arg435Gln in ZNF408 (NM_024741) and c.902G > A; p.Gly301Asp in C1QTNF4 (NM_031909). Both variants segregated with the retinal phenotype in the PKRD320 and were absent in ethnically matched control chromosomes.

Conclusion: Whole-exome sequencing coupled with bioinformatics analysis identified potential novel variants that might be responsible for IRD.

Keywords: C1QTNF4; Novel variants; Retinal degeneration; Whole-exome sequencing; ZNF408.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Chromosomes, Human, Pair 11 / genetics
Consanguinity
Conserved Sequence
DNA Mutational Analysis
DNA-Binding Proteins / chemistry
DNA-Binding Proteins / genetics*
Exome Sequencing*
Genes, Recessive*
Genetic Linkage
Humans
INDEL Mutation
Pakistan
Pedigree
Polymorphism, Single Nucleotide*
Retinal Degeneration / genetics*
Sequence Alignment
Sequence Homology, Amino Acid
Species Specificity
Transcription Factors / chemistry
Transcription Factors / genetics*

Substances

DNA-Binding Proteins
Transcription Factors
ZNF408 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding