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Catalog
2023 ACMG Annual Clinical Genetics Meeting Digital ...
A De Novo
Gain-of-Function
ANO5
...
A De Novo
Gain-of-Function
ANO5
Variant in a Patient with Anoctaminopathy5-related Muscular Dystrophy Challenges the Skeletal/Muscular Phenotype Dichotomy into Question
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Pdf Summary
Researchers from Indiana University School of Medicine and the Undiagnosed Rare Disease Clinic have identified a novel, de novo gain-of-function variant in the ANO5 gene in a patient with ANO5-related muscular dystrophy. ANO5 (also known as TMEM16E) is involved in phospholipid scrambling and sarcolemmal repair and is highly expressed in skeletal and cardiac muscle. Mutations in ANO5 can lead to autosomal dominant skeletal dysplasia or autosomal recessive muscular dystrophies. <br /><br />The 7-year-old female patient presented with a history of recurrent rhabdomyolysis, elevated creatine kinase levels, leg pain, myalgia, increased muscle fatiguability, episodic abdominal pain, and an antalgic gait. Muscle biopsy revealed primary myopathy with numerous ring fibers. Previous testing did not identify any pathogenic variants. However, exome re-analysis and trio-based genome sequencing identified a de novo heterozygous ANO5 variant of unknown significance (VUS) that has not been previously reported.<br /><br />Functional studies in HEK293A cells demonstrated a gain-of-function phenotype with mutant ANO5 overexpression, similar to other gain-of-function mutants. This further supports the existence of a novel autosomal dominant ANO5 subtype. The variant was found to be highly conserved and predicted to be deleterious by in silico studies. <br /><br />The findings challenge the current dichotomy between ANO5-related skeletal and muscle phenotypes and provide evidence for a new autosomal dominant condition consisting of both muscular and skeletal phenotypes. Further investigations are needed to understand the relationship between ANO5 gain-of-function variants and disease phenotypes. Larger cohort studies are also needed to examine the full spectrum of clinical manifestations and genotype-phenotype correlations.
Asset Subtitle
Presenting Author - Reynold Ly, PhD; Co-Author - Kayla Treat, MS, CGC; Co-Author - Brett H. Graham, MD, PhD; Co-Author - Erin E. Conboy, MD, FACMG; Co-Author - Anna Boccaccio, PhD; Co-Author - Francesco Vetrini, PhD, FACMG;
Meta Tag
Genetic Testing
Genome sequencing
Genotype-Phenotype Correlations
Inheritance Patterns
Molecular Pathophysiology
Musculoskeletal system
Sequencing
Co-Author
Kayla Treat, MS, CGC
Co-Author
Brett H. Graham, MD, PhD
Co-Author
Erin E. Conboy, MD, FACMG
Co-Author
Anna Boccaccio, PhD
Co-Author
Francesco Vetrini, PhD, FACMG
Presenting Author
Reynold Ly, PhD
Keywords
ANO5 gene
ANO5-related muscular dystrophy
skeletal muscle
cardiac muscle
autosomal dominant skeletal dysplasia
autosomal recessive muscular dystrophies
rhabdomyolysis
muscle biopsy
heterozygous ANO5 variant
gain-of-function phenotype
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