Daimagüler, Hülya-Sevcan, Akpulat, Ugur, Özdemir, Özkan, Yis, Uluc, Güngör, Serdal, Talim, Beril, Diniz, Gülden, Baydan, Figen, Thiele, Holger, Altmüller, Janine, Nürnberg, Peter, Cirak, SebahattinDaimagüler H.S., Akpulat U., Özdemir Ö., Yis U., Güngör S., Talim B., Diniz G., Baydan F., Thiele H., Altmüller J., Nürnberg P., Cirak S.Daimaguler, HS, Akpulat, U, Ozdemir, O, Yis, U, Gungor, S, Talim, B, Diniz, G, Baydan, F, Thiele, H, Altmuller, J, Nurnberg, P, Cirak, S2023-05-092023-05-092021-06-012021-06-012021.01.011552-4825https://hdl.handle.net/20.500.12597/12343Congenital myopathies (CMs) are a heterogeneous group of inherited muscle disorders characterized by muscle weakness at birth, while limb-girdle muscular dystrophies (LGMD) have a later onset and slower disease progression. Thus, detailed clinical phenotyping of genetically defined disease entities are required for the full understanding of genotype-phenotype correlations. A recently defined myopathic genetic disease entity is caused by bi-allelic variants in a gene coding for pyridine nucleotide-disulfide oxidoreductase domain 1 (PYROXD1) with unknown substrates. Here, we present three patients from two consanguineous Turkish families with mild LGMD, facial weakness, normal CK levels, and slow progress. Genomic analyses revealed a homozygous known pathogenic missense variant (c.464A>G, p.Asn155Ser) in family 1 with two affected females. In the affected male of family 2, we found this variant in a compound heterozygous state together with a novel frameshift variant (c.329_332delTCTG, p.Leu112Valfs*8), which is the second frameshift variant known so far in PYROXD1. We have been able to define a large homozygous region in family 1 sharing a common haplotype with family 2 in the critical region. Our data suggest that c.464A>G is a Turkish founder mutation. To gain deeper insights, we performed a systematic review of all published PYROXD1-related myopathy cases. Our analysis showed that the c.464A > G variant was found in 87% (20/23) of the patients and that it may cause either a childhood- or adult-onset phenotype, irrespective of its presence in a homozygous or compound heterozygous state. Interestingly, only four patients had elevated CK levels (up to 1000 U/L), and cardiac involvement was found in few compound heterozygous cases.Congenital myopathies (CMs) are a heterogeneous group of inherited muscle disorders characterized by muscle weakness at birth, while limb-girdle muscular dystrophies (LGMD) have a later onset and slower disease progression. Thus, detailed clinical phenotyping of genetically defined disease entities are required for the full understanding of genotype–phenotype correlations. A recently defined myopathic genetic disease entity is caused by bi-allelic variants in a gene coding for pyridine nucleotide-disulfide oxidoreductase domain 1 (PYROXD1) with unknown substrates. Here, we present three patients from two consanguineous Turkish families with mild LGMD, facial weakness, normal CK levels, and slow progress. Genomic analyses revealed a homozygous known pathogenic missense variant (c.464A>G, p.Asn155Ser) in family 1 with two affected females. In the affected male of family 2, we found this variant in a compound heterozygous state together with a novel frameshift variant (c.329_332delTCTG, p.Leu112Valfs*8), which is the second frameshift variant known so far in PYROXD1. We have been able to define a large homozygous region in family 1 sharing a common haplotype with family 2 in the critical region. Our data suggest that c.464A>G is a Turkish founder mutation. To gain deeper insights, we performed a systematic review of all published PYROXD1-related myopathy cases. Our analysis showed that the c.464A > G variant was found in 87% (20/23) of the patients and that it may cause either a childhood- or adult-onset phenotype, irrespective of its presence in a homozygous or compound heterozygous state. Interestingly, only four patients had elevated CK levels (up to 1000 U/L), and cardiac involvement was found in few compound heterozygous cases.trueLGMDMendeliomePYROXD1congenital myopathyhaplotype analysiswhole exome sequencingcongenital myopathy | haplotype analysis | LGMD | Mendeliome | PYROXD1 | whole exome sequencingJournal Article10.1002/ajmg.a.6214810.1002/ajmg.a.621482-s2.0-85102266424WOS:00062717230000133694278167816901851552-4833