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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Reduced penetrance in hereditary motor neuropathy caused by TRPV4 Arg269Cys mutation
José Berciano1, Jonathan Baets, Elena Gallardo
1Service of Neurology, University Hospital "Marqués de Valdecilla" (IFIMAV), "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas" (CIBERNED), University of Cantabria (UC), 39008 Santander, Spain. jaberciano@humv.es
Abstract:
Incomplete penetrance has rarely been reported in Charcot-Marie-Tooth disease. Our aim is to describe reduced penetrance in a hereditary motor neuropathy pedigree due to mutation in the transient receptor potential vallinoid 4 (TRPV4) gene. The pedigree comprised two affected members, the proband aged 44 years and her affected daughter aged 7 years, and seven additional related subjects, three of whom were subclinical gene mutation carriers aged 9, 40 and 70 years. Clinico-electrophysiological studies, MRI of lower-limb musculature and genetic testing of the TRPV4 were performed. The proband presented with a moderate facio-scapulo-peroneal syndrome, whereas her symptomatic daughter suffered from severe congenital spinal muscular atrophy with arthrogryposis, laryngomalacia, and vocal cord paresis. Electrophysiological evaluation revealed a pure motor axonal neuropathy. In the proband, MRI showed extensive and widespread fatty atrophy of lower-leg musculature, whereas in thigh musculature there was just mild distal fatty infiltration of vastus lateralis. Genetic testing revealed a heterozygous Arg269Cys mutation in the TPRV4 gene. In all three mutation carriers results from clinical and electrophysiological examination, and MRI of foot and lower-leg musculature were normal. We conclude that non-penetrance may be an integral feature of neuropathic syndromes associated with TRPV4 gene mutation.
Insights
Reduced penetrance of Charcot-Marie-Tooth disease was observed in a hereditary motor neuropathy family with a TRPV4 gene mutation. Some gene carriers showed no symptoms, indicating non-penetrance is a feature of TRPV4-related neuropathies.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Charcot-Marie-Tooth disease (CMT) is a group of inherited peripheral nervous system disorders.
- Incomplete penetrance, where a genetic mutation does not manifest phenotypically, is rarely documented in CMT.
- The transient receptor potential vallinoid 4 (TRPV4) gene is implicated in various neuromuscular disorders.
Observation:
- A multi-generational family with a hereditary motor neuropathy was studied.
- Two members exhibited distinct phenotypes: moderate facio-scapulo-peroneal syndrome in the proband and severe congenital spinal muscular atrophy with arthrogryposis in her daughter.
- Three asymptomatic relatives were identified as carriers of a heterozygous Arg269Cys mutation in the TRPV4 gene.
Findings:
- Clinico-electrophysiological studies and lower-limb MRI confirmed a pure motor axonal neuropathy in affected individuals.
- Genetic testing identified a heterozygous Arg269Cys mutation in the TRPV4 gene in the affected proband and three asymptomatic carriers.
- Asymptomatic mutation carriers showed normal clinical, electrophysiological, and imaging results.
Implications:
- This study highlights reduced penetrance as a significant feature in neuropathic syndromes associated with TRPV4 gene mutations.
- Understanding non-penetrance is crucial for accurate genetic counseling and diagnosis of hereditary neuropathies.
- Further research is needed to elucidate the mechanisms underlying variable expressivity and reduced penetrance in TRPV4-related disorders.
