Case report: Homozygous variants of NEB and KLHL40 in two Arab patients with nemaline myopathy

Cristina Skrypnyk; Aseel Ahmed Husain; Hisham Y Hassan; Jameel Ahmed; Abdulla Darwish; Latifa Almusalam; Noureddine Ben Khalaf; Fahad Al Qashar

doi:10.3389/fgene.2023.1098102

Case report: Homozygous variants of NEB and KLHL40 in two Arab patients with nemaline myopathy

Front Genet. 2023 Mar 21:14:1098102. doi: 10.3389/fgene.2023.1098102. eCollection 2023.

Authors

Cristina Skrypnyk^{1

2}, Aseel Ahmed Husain³, Hisham Y Hassan⁴, Jameel Ahmed⁵, Abdulla Darwish⁶, Latifa Almusalam⁶, Noureddine Ben Khalaf⁷, Fahad Al Qashar³

Affiliations

¹ Department of Molecular Medicine, Al-Jawhara Centre for Molecular Medicine, Arabian Gulf University, Manama, Bahrain.
² Department of Medical Genetics, University Medical Center, King Abdulla Medical City, Manama, Bahrain.
³ Department of Pediatrics, Bahrain Defence Force Hospital, Royal Medical Services, Riffa, Bahrain.
⁴ Banoon ART and Cytogenetics Centre, Bahrain Defence Force Hospital, Royal Medical Services, Riffa, Bahrain.
⁵ Radiology Department, University Medical Center, King Abdulla Medical City, Manama, Bahrain.
⁶ Department of Pathology, Bahrain Defence Force Hospital, Royal Medical Services, Riffa, Bahrain.
⁷ Life Sciences Department, Health Biotechnology Program, College of Graduate Studies, Arabian Gulf University, Manama, Bahrain.

Abstract

Objective: Nemaline myopathies are a heterogeneous group of congenital myopathies caused by mutations in different genes associated with the structural and functional proteins of thin muscular filaments. Most patients have congenital onset characterized by hypotonia, respiratory issues, and abnormal deep tendon reflexes, which is a phenotype encountered in a wide spectrum of neuromuscular disorders. Whole-exome sequencing (WES) contributes to a faster diagnosis and facilitates genetic counseling. Methods: Here, we report on two Arab patients from consanguineous families diagnosed with nemaline myopathy of different phenotype spectrum severities. Results: Clinical assessment and particular prenatal history raised suspicion of neuromuscular disease. WES identified homozygous variants in NEB and KLHL40. Muscle biopsy and muscle magnetic resonance imaging studies linked the genetic testing results to the clinical phenotype. The novel variant in the NEB gene resulted in a classical type 2 nemaline myopathy, while the KLHL40 gene variant led to a severe phenotype of nemaline myopathy, type 8. Both patients were identified as having other gene variants with uncertain roles in their complex phenotypes. Conclusions: This study enriches the phenotypic spectrum of nemaline myopathy caused by NEB and KLHL40 variants and highlights the importance of detailed prenatal, neonatal, and infancy assessments of muscular weakness associated with complex systemic features. Variants of uncertain significance in genes associated with nemaline myopathy may be correlated with the phenotype. Early, multidisciplinary intervention can improve the outcome in patients with mild forms of nemaline myopathies. WES is essential for clarifying complex clinical phenotypes encountered in patients from consanguineous families. Targeted carrier screening of extended family members would enable accurate genetic counseling and potential genetic prevention.

Keywords: KLHL40; NEB; WES; congenital; myopathy; nemaline.

Publication types

Case Reports