Genetic analysis of a patient with Rod-shaped myopathy due to variants of NEB gene

Objective: To explore the genetic etiology of a child with Nemaline myopathy (NM).

Methods: A child who had visited Fujian Children's Hospital on January 28, 2023 due to "phlegm in the throat for more than a month" was selected as the study subject. Clinical data of the child was collected, in addition with peripheral blood samples from her and her parents. Following extraction of genomic DNA, trio-whole exome sequencing (WES) was carried out. Candidate variants was verified by Sanger sequencing and bioinformatic analysis. This study has been approved by the Medical Ethics Committee of Fujian Children's Hospital (Ethic No. 2023ETKLRK2004).

Results: The patient, a 2-month-old female, had presented with persistent phlegm in the throat, recurrent severe pneumonia, swallowing difficulty, and decreased muscle tone. WES results revealed that she has harbored compound heterozygous variants of the NEB (NM_001271208.1) gene, namely c.4611+2T>A and c.12961del (p.Ser4321ALafs*21), and the associated disease is rod-like myopathy. Sanger sequencing confirms that the variants were respectively inherited from her mother and father, both of whom had normal phenotypes. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were rated as likely pathogenic (PVS1_Moderate+PM2_Supporting+PM3; PVS1+PM2_Supporting).

Conclusions: The c.4611+2T>A/c.12961del (p.Ser4321ALafs*21) compound heterozygous variants of the NEB gene probably underlay the pathogenesis in this child. Above findings has facilitated the diagnosis, genetic counseling, and guidance for reproductive decision of her family.