AUTHOR=Meyer Stefanie , Kaulfuß Silke , Zechel Sabrina , Kummer Karsten , Seif Amir Hosseini Ali , Ernst Marielle Sophie , Schmidt Jens , Pauli Silke , Zschüntzsch Jana 

TITLE=Evidence of Two Novel LAMA2 Variants in a Patient With Muscular Dystrophy: Facing the Challenges of a Certain Diagnosis

JOURNAL=Frontiers in Neurology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2022.893605

DOI=10.3389/fneur.2022.893605

ISSN=1664-2295

ABSTRACT=Background: Benefits and challenges resulting from advances in genetic diagnostics are two sides of the same coin. Facilitation of a correct and timely diagnosis is paralleled by challenges in interpretation of variants of unknown significance (VUS). Focusing on an individual VUS-re-classification pipeline, this study offers a diagnostic approach beyond the state of the art for clinically suspected hereditary muscular dystrophy by combining the expertise of an interdisciplinary team. 

Methods:  In a multi-step approach, a thorough phenotype assessment including clinical examination, laboratory work, muscle MRI and histopathological evaluation of muscle was performed in combination with advanced Next Generation Sequencing (NGS).  Different in-silico tools and prediction programs like Alamut, SIFT, Polyphen, MutationTaster and M-Cap as well as 3D- modelling of protein structure and RNA-sequencing were employed to determine clinical significance of the LAMA2 variants. 

Results: Two previously unknown sequence alterations in LAMA2 were detected, one of them was classified according to ACMG guidelines as a VUS class 3 whereas the second variant was deemed as likely pathogenic (class 4). Pathogenicity of VUS class 4 was confirmed through mRNA-Sequencing and 3D modelling of resulting protein structure. Combination of the detected variants could be associated to the LGMDR23-phenotype based on the MRI matching and literature research.

Discussion: Two novel variants in LAMA2 associated with LGMDR23-phenotype are described. This study illustrates challenges of the genetic findings due to their VUS classification and elucidates how individualized diagnostic procedure has contributed to the accurate diagnosis in the spectrum of LGMD. This case underlines the necessity of interdisciplinary workup and the use of AI-based methods in diagnostics of hereditary neuromuscular disease.