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GGC Repeat Expansion in the NOTCH2NLC Gene Is Associated With a Phenotype of Predominant Motor-Sensory and Autonomic Neuropathy.

ABSTRACT: There is still a considerable proportion of patients with inherited peripheral neuropathy (IPN) whose pathogenic genes are unknown. This study was intended to investigate whether the GGC repeat expansion in the NOTCH2NLC is presented in some patients with IPN. A total of 142 unrelated mainland Chinese patients with highly suspected diagnosis of IPN without any known causative gene were recruited. Repeat-primed polymerase chain reaction (RP-PCR) was performed to screen GGC repeat expansion in NOTCH2NLC, followed by fluorescence amplicon length analysis-PCR (AL-PCR) to determine the GGC repeat size. Detailed clinical data as well as nerve, muscle, and skin biopsy were reviewed and analyzed in the NOTCH2NLC-related IPN patients. In total, five of the 142 patients (3.52%) were found to have pathogenic GGC expansion in NOTCH2NLC, with repeat size ranging from 126 to 206 repeats. All the NOTCH2NLC-related IPN patients presented with adult-onset motor-sensory and autonomic neuropathy that predominantly affected the motor component of peripheral nerves. While tremor and irritating dry cough were noted in four-fifths of the patients, no other signs of the central nervous system were presented. Electrophysiological studies revealed both demyelinating and axonal changes of polyneuropathy that were more severe in lower limbs and asymmetrically in upper limbs. Sural nerve pathology was characterized by multiple fibers with thin myelination, indicating a predominant demyelinating process. Muscle pathology was consistent with neuropathic changes. P62-positive intranuclear inclusions were observed in nerve, skin, and muscle tissues. Our study has demonstrated that GGC expansion in NOTCH2NLC is associated with IPN presenting as predominant motor-sensory and autonomic neuropathy, which expands the phenotype of the NOTCH2NLC-related repeat expansion spectrum. Screening of GGC repeat expansions in the NOTCH2NLC should be considered in patients presenting with peripheral neuropathy with tremor and irritating dry cough.

SUBMITTER: Wang H

PROVIDER: S-EPMC8293674 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The extracellular matrix comprises a network of macromolecules such as collagens, proteoglycans and glycoproteins. VWA1 (von Willebrand factor A domain containing 1) encodes a component of the extracellular matrix that interacts with perlecan/collagen VI, appears to be involved in stabilizing extracellular matrix structures, and demonstrates high expression levels in tibial nerve. Vwa1-deficient mice manifest with abnormal peripheral nerve structure/function; however, VWA1 variants have not previously been associated with human disease. By interrogating the genome sequences of 74 180 individuals from the 100K Genomes Project in combination with international gene-matching efforts and targeted sequencing, we identified 17 individuals from 15 families with an autosomal-recessive, non-length dependent, hereditary motor neuropathy and rare biallelic variants in VWA1. A single disease-associated allele p.(G25Rfs*74), a 10-bp repeat expansion, was observed in 14/15 families and was homozygous in 10/15. Given an allele frequency in European populations approaching 1/1000, the seven unrelated homozygote individuals ascertained from the 100K Genomes Project represents a substantial enrichment above expected. Haplotype analysis identified a shared 220 kb region suggesting that this founder mutation arose >7000 years ago. A wide age-range of patients (6-83 years) helped delineate the clinical phenotype over time. The commonest disease presentation in the cohort was an early-onset (mean 2.0 ± 1.4 years) non-length-dependent axonal hereditary motor neuropathy, confirmed on electrophysiology, which will have to be differentiated from other predominantly or pure motor neuropathies and neuronopathies. Because of slow disease progression, ambulation was largely preserved. Neurophysiology, muscle histopathology, and muscle MRI findings typically revealed clear neurogenic changes with single isolated cases displaying additional myopathic process. We speculate that a few findings of myopathic changes might be secondary to chronic denervation rather than indicating an additional myopathic disease process. Duplex reverse transcription polymerase chain reaction and immunoblotting using patient fibroblasts revealed that the founder allele results in partial nonsense mediated decay and an absence of detectable protein. CRISPR and morpholino vwa1 modelling in zebrafish demonstrated reductions in motor neuron axonal growth, synaptic formation in the skeletal muscles and locomotive behaviour. In summary, we estimate that biallelic variants in VWA1 may be responsible for up to 1% of unexplained hereditary motor neuropathy cases in Europeans. The detailed clinical characterization provided here will facilitate targeted testing on suitable patient cohorts. This novel disease gene may have previously evaded detection because of high GC content, consequential low coverage and computational difficulties associated with robustly detecting repeat-expansions. Reviewing previously unsolved exomes using lower QC filters may generate further diagnoses.

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GGC Repeat Expansion in the NOTCH2NLC Gene Is Associated With a Phenotype of Predominant Motor-Sensory and Autonomic Neuropathy.

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