Revisiting Exome Data Identified Missed Splice Site Variant of the Asparagine Synthetase (ASNS) Gene

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 NME1 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.

Keywords

whole-exome sequencing - candidate genes - microcephaly - ASNS - NME1

Authors' Contribution

G.K. contributed to conceptualization, organization, and execution of the research project. She designed and executed the experiments. She also wrote the first draft of the manuscript. F.M. and A.F. contributed to conceptualization of the research project, patient care, and clinical phenotype characterization. T.J. contributed to organization and execution of the research project. He reviewed and critiqued the manuscript. F.Z. contributed to conceptualization, organization of the research project. S.Y. and A.M. contributed to conceptualization, organization, and execution of the research project, design the experiments, wrote the first draft of the manuscript, and review and critique the manuscript.

Data Availability

Data available on request from the authors.

^* These authors have equal contributions.

Publikationsverlauf

Eingereicht: 10. Mai 2022

Angenommen: 21. August 2022

Artikel online veröffentlicht:
13. Oktober 2022

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