Nemaline myopathy: reclassification of previously reported variants according to ACMG guidelines, and report of novel genetic variants

• Published in: European journal of human genetics : EJHG Vol. 31; no. 11; pp. 1237 - 1250
• Main Authors: Haghighi, Alireza, Alvandi, Zahra, Nilipour, Yalda, Haghighi, Amirreza, Kornreich, Ruth, Nafissi, Shahriar, Desnick, Robert J.
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.11.2023; Springer International Publishing
• Subjects: Genetic analysis; Genetic diversity; Genetic screening; Genetic Testing - methods; Heterozygote; Humans; Laboratories; Medical laboratories; Mutation; Myopathies, Nemaline - diagnosis; Myopathies, Nemaline - genetics; Myopathies, Nemaline - pathology; Myopathy; Nemaline myopathy; Reclassification; RNA Splicing; Splicing
• ISSN: 1018-4813; 1476-5438; 1476-5438
• DOI: 10.1038/s41431-023-01378-w

Nemaline myopathy (NM) is a heterogeneous genetic neuromuscular disorder characterized by rod bodies in muscle fibers resulting in multiple complications due to muscle weakness. NM patients and their families could benefit from genetic analysis for early diagnosis, carrier and prenatal testing; however, clinical classification of variants is subject to change as further information becomes available. Reclassification can significantly alter the clinical management of patients and their families. We used the newly published data and ACMG/AMP guidelines to reassess NM-associated variants previously reported by clinical laboratories (ClinVar). Our analyses on rare variants that were not canonical loss-of-function (LOF) resulted in the downgrading of ~29% (28/97) of variants from pathogenic or likely-pathogenic (P/LP) to variants of uncertain significance (VUS). In addition, we analyzed the splicing effect of variants identified in NM patients by clinical laboratories or research, using an accurate in silico prediction tool that applies a deep-learning network. We identified 55 rare variants that may impact splicing (cryptic splicing). We also analyzed six new NM families and identified eight variants in NEB and ACTA1, including three novel variants: homozygous pathogenic c.164A > G (p.Tyr55Cys), and homozygous likely pathogenic c.980T > C (p.Met327Thr) in ACTA1, and heterozygous VUS c.18694-3T > G in NEB. This study demonstrates the importance of reclassifying variants to facilitate more definitive "calls" on causality or no causality in clinical genetic testing of patients with NM. Reclassification of ~150 variants is now available for improved clinical management, risk counseling and screening of NM patients.