Abstract
sBackgroundDuchenne muscular dystrophies (DMDs) are X-linked recessive neuromuscular disorders with malfunction or absence of the Dystrophin protein. Precise genetic diagnosis is critical for proper planning of patient care and treatment. In this study, we described a Chinese family with mosaic DMD mutations and discussed the best method for prenatal diagnosis and genetic counseling of X-linked familial disorders.MethodsWe investigated all variants of the whole dystrophin gene using multiple DNA samples isolated from the affected family and identified two variants of the DMD gene in a sick boy and two female carriers by targeted next generation sequencing (TNGS), Sanger sequencing, and haplotype analysis.ResultsWe identified the hemizygous mutation c.6794delG (p.G2265Efs*6) of DMD in the sick boy, which was inherited from his mother. Unexpectedly, a novel heterozygous mutation c.6796delA (p.I2266Ffs*5) of the same gene, which was considered to be a de novo variant, was detected from his younger sister instead of his mother by Sanger sequencing. However, further NGS analysis of the mother and her amniotic fluid samples revealed that the mother carried a low-level mosaic c.6796delA mutation.ConclusionsWe reported two different mutations of the DMD gene in two siblings, including the novel mutation c.6796delA (p.I2266Ffs*5) inherited from the asymptomatic mosaic-carrier mother. This finding has enriched the knowledge of the pathogenesis of DMD. If no mutation is detected in obligate carriers, the administration of intricate STR/NGS/Sanger analysis will provide new ideas on the prenatal diagnosis of DMD.
Highlights
Duchenne muscular dystrophies (DMDs) are X-linked recessive neuromuscular disorders with malfunction or absence of the Dystrophin protein
We investigated all variants of the whole dystrophin gene using multiple DNA samples isolated from the affected family and identified two variants of the DMD gene in a sick boy and two female carriers by targeted generation sequencing (TNGS), Sanger sequencing, and haplotype analysis
We identified the hemizygous mutation c.6794delG (p.G2265Efs*6) of DMD in the sick boy, which was inherited from his mother
Summary
Duchenne muscular dystrophy (DMD, OMIM #310200) is a fatal X-linked recessive, inherited neuromuscular disorder characterized by muscle inflammation and progressive deterioration of muscle function [1,2,3]. The result of targeted sequencing indicated that the amniotic fluid carried another heterozygous mutation c.6796delA (p.I2266Ffs*5) (Fig. 2e), and a low frequency (18/447, 3.87%) of this mutation was detected in the peripheral blood of the mother in mid-pregnancy (Fig. 2f). We found that the amniotic fluid sample (later born as a daughter) carried another frameshift mutation c.6796delA (p.I2266Ffs*5) in exon 47, which was a different heterozygous mutation from the mother and the proband (Fig. 3d). It is worth noting that the proband carried a c.6794delG mutation in exon 47 of the Dystrophin gene, resulting in a frameshift and a premature stop codon (p.G2265Efs*6), while the amniotic fluid sample (later born as daughter) displayed different mutant site c.6796delA (p.I2266Ffs*5) in the same exon. The fact that the first reported c.6796delA mutation was initially undetected
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