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Nemaline Myopathy: Reclassification of Previously Reported Variants According to Acmg Guidelines, and Report of Novel Genetic Variants Publisher Pubmed



Haghighi A1, 2, 3, 4, 5 ; Alvandi Z6, 7 ; Nilipour Y8 ; Haghighi A1, 2, 3, 4, 5 ; Kornreich R10 ; Nafissi S11 ; Desnick RJ10
Authors
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Authors Affiliations
  1. 1. Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, 02115, MA, United States
  2. 2. Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, 02115, MA, United States
  3. 3. Department of Genetics, Harvard Medical School, Boston, 02115, MA, United States
  4. 4. Howard Hughes Medical Institute, Brigham and Women’s Hospital, Boston, 02115, MA, United States
  5. 5. The Broad Institute of MIT and Harvard, Cambridge, 02142, MA, United States
  6. 6. Department of Surgery, Harvard Medical School, Boston, 02115, MA, United States
  7. 7. Vascular Biology Program, Boston Children’s Hospital, Boston, 02115, MA, United States
  8. 8. Pediatric Pathology Research Center, Research Institute for Children’s Health, and Mofid Children Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  9. 9. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, 02115, MA, United States
  10. 10. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
  11. 11. Department of Neurology, Neuromuscular Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran

Source: European Journal of Human Genetics Published:2023


Abstract

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. © 2023, The Author(s), under exclusive licence to European Society of Human Genetics.
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