A 40-year-old male visited our clinic for asymmetric upper and lower extremity weakness. The patient reported that he had suffered bilateral shoulder weakness since the age of 10 years. When he was 13-years-old, he presented with a right winged scapula. In addition, he reported bilateral leg weakness since he was 24 years old. Physical examination revealed a transverse smile; winged scapula; “Popeye” arm appearance; facial weakness; and asymmetric, proximal dominant arm and leg weakness (right side more severe than the left). Serum creatinine kinase levels were mildly elevated at 319 unit/L. His father and elder brother had similar symptoms (). His elder brother had been visiting another hospital for similar symptoms since he was 10 years old, and his muscle pathology showed severe chronic myopathic changes (marked increased size variability, hypertrophic fibers, degenerating and atrophic fibers, endomysial fibrosis and mild fatty infiltration, disruption of intermyofibrillar network, and lobulated fibers) with normal dystrophin immunoreactivity. The elder brother was diagnosed with FSHD based on clinical phenotype, but refused a genetic study. However, our patient agreed to undergo genetic analysis for diagnosis. Therefore, we performed conventional Southern blot analysis with EcoRI and BlnI enzymes, but the D4Z4 repeat size was 12, which is normal. Next, whole exome sequencing revealed a novel frameshift mutation (c.3801delG, p.Glu1267Aspfs*5) in SMCHD1 [, upper (patient) and lower (mother) panels], a mutation that has not been described in previous reports or public databases (ExAC, ESP6500, 1000 genome). Finally, methylation-sensitive Southern blot analysis with FseI showed mildly reduced D4Z4 repeat size on 4q (41kb/39kb) and reduced D4Z4 methylation ratio (14.6%). Accordingly, we could report our case 1 as “pathogenic” and carrying a novel variant, as indicated in ACMG-AMP guidelines.
A 38-year-old male visited our clinic for asymmetric upper extremity weakness. The patient reported that, at the age of nine, he had difficulty performing iron bar gymnastics. Since his third decade, he experienced prominent right shoulder and arm weakness, and he presented with facial asymmetry and weakness. Physical examination showed a transverse smile, positive Beevor's sign, and winged scapula (). In addition, he showed facial and bilateral arm and leg weakness with proximal dominance and asymmetricity (right side more severe than the left) on neurological examination. Serum creatinine kinase levels were mildly elevated at 224 unit/L. His mother and elder sister had similar symptoms (). We performed genetic analysis for FSHD. Southern blotting analysis by the EcoRI/BlnI digestion method using genomic DNA revealed that a fragment size of 37 kb, and the number of D4Z4 repeats was nine. Bisulfite sequencing to determine the haplotype of D4Z4 using digestion with HindIII and hybridized with 4qA probe and target sequencing analysis to screen for mutations in the SMCHD1 gene by a next-generation sequencer (Ion PGMTM) were performed for FSHD2 diagnosis. We found reduced DNA methylation ratio (16.8%), D4Z4 haplotype 4qA (homozygous), and c.1580C>T (p.T527M) SMCHD1 mutation, which was previously reported to be a pathogenic allele.\nInformed consent was obtained from the two patients regarding the reporting and publication of this case report.