Clinical features and molecular findings of a rare case of LGMDR18
Laboratory Genetics and Genomics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
Limb girdle muscular dystrophies are a group neuromuscular disorders characterized by proximal muscle weakness of variable severity and dystrophic changes on histology. There are currently more than 30 known subtypes of both autosomal dominant and recessive LGMDs associated with at least 34 reported genes. There is a wide spectrum of phenotypes among the LGMDs with clinical diagnosis conventionally guided by characteristic presentations of sub-types. However, the wide clinical and genetic heterogeneity as well as overlapping subtypes make precise diagnosis a challenge. High throughput sequencing technologies have facilitated the understanding of clinical patterns and expansion of phenotypes, identification of novel genes or rare variants and providing diagnosis for rare sub-types. In this study, we report a rare case of LGMDR18 patient and the molecular identification of gene variants to provide a definite diagnosis even before full presentation of expected symptoms.
Methods:
Immunohistochemical analysis was performed with primary antibodies against dystrophin and sarcoglycans. Genetics work-up included MLPA deletion/duplication analysis, exome sequencing and Sanger sequencing. Variant analysis was performed using standard protocols and interpreted according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. For confirmation, sanger sequencing of identified variants was performed on proband and parental samples.
Results:
A male Chinese patient presented with proximal muscle weakness with mild dysarthria and motor development delay at 17 months of age. Biochemical screening revealed elevated serum creatine kinase levels of 10,800 U/L. Initial suspicion of Duchenne muscular dystrophy directed MLPA screening for DMD gene deletions/duplications but was negative. Muscle biopsy showed mild loss of dystrophin and patchy loss of α-dystroglycan. Exome sequencing identified a splice site variant, c.2381-3T>C in DMD (NM_004006.3) and two compound heterozygous variants, c.142C>T and c.2938G>A in TRAPPC11 (NM_021942.6). The DMD variant was curated as likely benign with computational predictions (SpliceAI, BDGP, NetGene2) suggesting no change in splicing. On the other hand, the two TRAPPC11 variants were curated as pathogenic and confirmed to be inherited in trans. Follow-up of patient over the years showed progressive muscle weakness with positive Gower sign and manifestation of scapular winging, scoliosis and hepatic as well as ocular features in his teens. This is consistent with the molecular diagnosis of LGMDR18 although the main phenotypic features were not fully apparent at earlier age.
Conclusion:
LGMDR18 has a prevalence of less than 1/1,000,000. This is the first case identified in our population and shows how early and precise diagnosis before full presentation of symptoms is now possible with use of next-gen sequencing technologies. Such differential diagnosis is especially important due to the clinical heterogeneity and phenotype overlaps among LGMDs.
Limb girdle muscular dystrophies are a group neuromuscular disorders characterized by proximal muscle weakness of variable severity and dystrophic changes on histology. There are currently more than 30 known subtypes of both autosomal dominant and recessive LGMDs associated with at least 34 reported genes. There is a wide spectrum of phenotypes among the LGMDs with clinical diagnosis conventionally guided by characteristic presentations of sub-types. However, the wide clinical and genetic heterogeneity as well as overlapping subtypes make precise diagnosis a challenge. High throughput sequencing technologies have facilitated the understanding of clinical patterns and expansion of phenotypes, identification of novel genes or rare variants and providing diagnosis for rare sub-types. In this study, we report a rare case of LGMDR18 patient and the molecular identification of gene variants to provide a definite diagnosis even before full presentation of expected symptoms.
Methods:
Immunohistochemical analysis was performed with primary antibodies against dystrophin and sarcoglycans. Genetics work-up included MLPA deletion/duplication analysis, exome sequencing and Sanger sequencing. Variant analysis was performed using standard protocols and interpreted according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. For confirmation, sanger sequencing of identified variants was performed on proband and parental samples.
Results:
A male Chinese patient presented with proximal muscle weakness with mild dysarthria and motor development delay at 17 months of age. Biochemical screening revealed elevated serum creatine kinase levels of 10,800 U/L. Initial suspicion of Duchenne muscular dystrophy directed MLPA screening for DMD gene deletions/duplications but was negative. Muscle biopsy showed mild loss of dystrophin and patchy loss of α-dystroglycan. Exome sequencing identified a splice site variant, c.2381-3T>C in DMD (NM_004006.3) and two compound heterozygous variants, c.142C>T and c.2938G>A in TRAPPC11 (NM_021942.6). The DMD variant was curated as likely benign with computational predictions (SpliceAI, BDGP, NetGene2) suggesting no change in splicing. On the other hand, the two TRAPPC11 variants were curated as pathogenic and confirmed to be inherited in trans. Follow-up of patient over the years showed progressive muscle weakness with positive Gower sign and manifestation of scapular winging, scoliosis and hepatic as well as ocular features in his teens. This is consistent with the molecular diagnosis of LGMDR18 although the main phenotypic features were not fully apparent at earlier age.
Conclusion:
LGMDR18 has a prevalence of less than 1/1,000,000. This is the first case identified in our population and shows how early and precise diagnosis before full presentation of symptoms is now possible with use of next-gen sequencing technologies. Such differential diagnosis is especially important due to the clinical heterogeneity and phenotype overlaps among LGMDs.