Pathogenic variants in three families with distal muscle involvement

• Published in: Neuromuscular disorders : NMD Vol. 33; no. 1; pp. 58 - 64
• Main Authors: Weterman, Marian A.J., Bronk, Marieke, Jongejan, Aldo, Hoogendijk, Jessica E., Krudde, Judith, Karjosukarso, Dyah, Goebel, Hans H., Aronica, Eleonora, Jöbsis, G. Joost, van Ruissen, Fred, van Spaendonck-Zwarts, Karin Y., de Visser, Marianne, Baas, Frank
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 01.01.2023
• Subjects: Charcot-Marie-Tooth Disease - genetics; CMT; Genetic Testing; HMSN; Humans; Muscles; Mutation; MYH7 myopathy; Neuropathy; Phenotype; HMSN; MYH7 myopathy; CMT; Neuropathy
• ISSN: 0960-8966; 1873-2364; 1873-2364
• DOI: 10.1016/j.nmd.2022.11.007

•Identification of the cause of disease in three large families with distal muscle involvement.•MYH7 tail mutations cause a neuropathy-like phenotype.•MYH7 tail mutations may entail an increased risk for cardiomyopathies.•More variants in CMT -associated genes next to the pathogenic one may influence the phenotype. Three families suspected of distal hereditary motor neuropathy underwent genetic screening with the aim to identify the molecular defect underlying the disease. The description of the identification reflects the shift in molecular diagnostics that was made during the last decades. Our candidate gene approach yielded a known pathogenic variant in BSCL2 (p.Asn88Ser) in one family, and via a CMT-capture, in HSPB1 (p.Arg127Trp), in addition to five other variations in Charcot-Marie-Tooth-related genes in the proband of the second family. In the third family, using whole exome sequencing, followed by linkage-by-location, a three base pair deletion in exon 33 of MYH7 (p.Glu1508del) was found, a reported pathogenic allele albeit for a myopathy. After identification of the causative molecular defect, cardiac examination was performed for patients of the third family and this demonstrated abnormalities in three out of five affected family members. Heterogeneity and expansion of clinical phenotypes beyond known characteristics requires a wider set of genes to be screened. Whole exome/genome analysis with limited prior clinical information may therefore be used to precede a detailed clinical evaluation in cases of large families, preventing screening of a too narrow set of genes, and enabling the identification of novel disease-associated genes. In our cases, the variants had been reported, and co-segregation analysis confirmed the molecular diagnosis.