AI Article Synopsis
- Next-generation sequencing, like whole-exome sequencing (WES), is often used for studying Mendelian disorders but can yield "negative" results due to incorrect variant analysis.
- Noncoding variants, such as splicing mutations, are commonly overlooked, leading to missed molecular diagnoses.
- A case study of a family with four newborns suffering from severe congenital microcephaly reveals that a reanalysis of WES data uncovered a splice site variant in the asparagine synthetase gene as the likely cause, emphasizing the need to revisit exome data for better gene identification.
Article Abstract
Next-generation sequencing, such as whole-exome sequencing (WES), is increasingly used in the study of Mendelian disorders, yet many are reported as "negative." Inappropriate variant annotation and filtering steps are reasons for missing the molecular diagnosis. Noncoding variants, including splicing mutations, are examples of variants that can be overlooked. Herein, we report a family of four affected newborns, and all presented with severe congenital microcephaly. Initial research WES analysis identified a damaging homozygous variant in gene as a possible cause of primary microcephaly phenotype in these patients. However, reanalysis of the exome data uncovered a biallelic splice site variant in asparagine synthetase gene which seems to be the possible cause of the phenotype in these patients. This study highlights the importance of revisiting the exome data and the issue of "negative" exome and the afterward approaches to identify and prove new candidate genes.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10984708 | PMC |
| http://dx.doi.org/10.1055/s-0042-1757193 | DOI Listing |
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