Exome Sequencing Identifies DYNC1H1 Variant Associated With Vertebral Abnormality and Spinal Muscular Atrophy With Lower Extremity Predominance.
BACKGROUND
Molecular diagnosis of the distal spinal muscular atrophies or distal hereditary motor neuropathies remains challenging because of clinical and genetic heterogeneity. Next generation sequencing offers potential for identifying de novo mutations of causative genes in isolated cases.


PATIENT DESCRIPTION
We present a 3.6-year-old girl with congenital scoliosis, equinovarus, and L5/S1 left hemivertebra who demonstrated delayed walking and lower extremities atrophy. She was negative for SMN1 deletion testing, and parents show no sign of disease.


RESULTS
Whole exome sequencing of the affected girl showed a novel de novo heterozygous missense mutation c.1792C>T (p.Arg598Cys) in the tail domain of the DYNC1H1 gene encoding for cytoplasmic dynein heavy chain 1. The mutation changed a highly conserved amino acid and was absent from both parents.


CONCLUSION
De novo mutations of DYNC1H1 have been found in individuals with autosomal dominant mental retardation with neuronal migration defects. Dominantly inherited mutations of DYNC1H1 have been reported to cause spinal muscular atrophy with predominance of lower extremity involvement and Charcot-Marie-Tooth type 2O. This is the first report of a de novoDYNC1H1 mutation associated with the spinal muscular atrophy with predominance of lower extremity phenotype with a spinal deformity (lumbar hemivertebrae). This case also demonstrates the power of next generation sequencing to discover de novo mutations on a genome-wide scale.
['Punetha|Jaya|J|', 'Monges|Soledad|S|', 'Franchi|Maria Emilia|ME|', 'Hoffman|Eric P|EP|', 'Cirak|Sebahattin|S|', 'Tesi-Rocha|Carolina|C|']
D002675:Child, Preschool D056445:Cytoplasmic Dyneins D005260:Female D006801:Humans D038061:Lower Extremity Deformities, Congenital D009134:Muscular Atrophy, Spinal D009154:Mutation
DYNC1H1 spinal muscular atrophy with lower extremity predominance distal spinal muscular atrophy whole exome sequencing Charcot-Marie-Tooth SMA-LED dSMA