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Abstract

July - September 2023 | Vol. 16 | Issue 3 | 03-07
GJC2 Variant Identification in Siblings with Pelizaeus-Merzbacher-Like Disease: Illustrative Report Highlighting the Limitations of Exome Sequencing
T Pragna Lakshmi1 Neelam Saini2, Prajnya Ranganath2, Ashwin Dalal1
1 Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India, 2 Department of Medical Genetics, Nizam’s Institute of Medical Sciences, Hyderabad, India
Address for Correspondence Email: ashwindalal@gmail.com
 
Abstract
Whole-exome sequencing (WES) has revolutionized genetic diagnosis and has become a powerful tool for identifying disease-causing variants. However, WES has limitations such as uneven read coverage, which can result in multiple low-coverage regions in the exome. Here, we report two affected siblings with a phenotype consistent with Pelizaeus-Merzbacher-like disease 1 (PMLD1), a rare early-onset autosomal recessive disorder caused by biallelic variants in the GJC2 gene. WES analysis of one affected child initially revealed only a single heterozygous nonsense variant in exon 2 of the GJC2 gene. However, on reanalysis with a local de novo assembly approach using the GATK HaplotypeCaller, a second variant - a frameshift insertion - was subsequently identified. This variant was found to be present in a low coverage region which is why it was missed in the initial analysis. Analysis of the segregation pattern of the variants in the affected sibling and parents through targeted Sanger sequencing confirmed that the variants were present in compound heterozygous form in both the affected siblings. Our study emphasizes the importance of considering the limitations of exome sequencing, especially in terms of low coverage of certain exonic regions.
 
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