TY - JOUR
T1 - Pathogenic variants in three families with distal muscle involvement
AU - Weterman, Marian A.J.
AU - Bronk, Marieke
AU - Jongejan, Aldo
AU - Hoogendijk, Jessica E.
AU - Krudde, Judith
AU - Karjosukarso, Dyah
AU - Goebel, Hans H.
AU - Aronica, Eleonora
AU - Jöbsis, G. Joost
AU - van Ruissen, Fred
AU - van Spaendonck-Zwarts, Karin Y.
AU - de Visser, Marianne
AU - Baas, Frank
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
KW - CMT
KW - HMSN
KW - MYH7 myopathy
KW - Neuropathy
UR - http://www.scopus.com/inward/record.url?scp=85144790284&partnerID=8YFLogxK
U2 - 10.1016/j.nmd.2022.11.007
DO - 10.1016/j.nmd.2022.11.007
M3 - Article
C2 - 36539320
AN - SCOPUS:85144790284
SN - 0960-8966
VL - 33
SP - 58
EP - 64
JO - Neuromuscular Disorders
JF - Neuromuscular Disorders
IS - 1
ER -