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30-09-2023 | Original Communication

Phenotype-driven reanalysis reveals five novel pathogenic variants in 40 exome-negative families with Charcot–Marie–Tooth Disease

Authors: Zhiqiang Lin, Lei Liu, Xiaobo Li, Shunxiang Huang, Huadong Zhao, Sen Zeng, Honglan Yang, Yongzhi Xie, Ruxu Zhang

Published in: Journal of Neurology | Issue 1/2024

Abstract

Background

To identify genetic causes in 40 whole exome sequencing (WES)-negative Charcot–Marie–Tooth (CMT) families and provide a summary of the clinical and genetic features of the diagnosed patients.

Methods

The clinical information and sequencing data of 40 WES-negative families out of 131 CMT families were collected, and phenotype-driven reanalysis was conducted using the Exomiser software.

Results

The molecular diagnosis was regained in 4 families, increasing the overall diagnosis rate by 3.0%. One family with adolescent-onset pure CMT1 was diagnosed [POLR3B: c.2810G>A (p.R937Q)] due to the novel genotype–phenotype association. One infantile-onset, severe CMT1 family with deep sensory disturbance was diagnosed by screening the BAM file and harbored c.1174C>T (p.R392*) and 875_927delinsCTGCCCACTCTGCCCACTCTGCCCACTCTG (p.V292Afs53) of PRX. Two families were diagnosed due to characteristic phenotypes, including an infantile-onset ICMT family with renal dysfunction harboring c.213_233delinsGAGGAGCA (p.S72Rfs34) of INF2 and an adolescent-onset CMT2 family with optic atrophy harboring c.560C>T (p.P187L) and c.616A>G (p.K206E) of SLC25A46. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the variants of POLR3B and SLC25A46 were classified as likely pathogenic, and the variants of INF2 and PRX were pathogenic. All these variants were first reported worldwide except for p.R392* of PRX.

Conclusions

We identified five novel pathogenic variants in POLR3B, PRX, INF2, and SLC25A46, which broaden their phenotypic and genotypic spectrums. Regular phenotype-driven reanalysis is a powerful strategy for increasing the diagnostic yield of WES-negative CMT patients, and long-term follow-up and screening BAM files for contiguous deletion and missense variants are both essential for reanalysis.

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Skre H (1974) Genetic and clinical aspects of Charcot–Marie–Tooth’s disease. Clin Genet 6:98–118. https://doi.org/10.1111/j.1399-0004.1974.tb00638.xCrossRefPubMed

Harding AE, Thomas PK (1980) The clinical features of hereditary motor and sensory neuropathy types I and II. Brain 103:259–280. https://doi.org/10.1093/brain/103.2.259CrossRefPubMed

Davis CJ, Bradley WG, Madrid R (1978) The peroneal muscular atrophy syndrome: clinical, genetic, electrophysiological and nerve biopsy studies. I. Clinical, genetic and electrophysiological findings and classification. J Genet Hum 26:311–349PubMed

Wenger AM, Guturu H, Bernstein JA, Bejerano G (2017) Systematic reanalysis of clinical exome data yields additional diagnoses: implications for providers. Genet Med 19:209–214. https://doi.org/10.1038/gim.2016.88CrossRefPubMed

Smedley D, Jacobsen JO, Jäger M et al (2015) Next-generation diagnostics and disease-gene discovery with the Exomiser. Nat Protoc 10:2004–2015. https://doi.org/10.1038/nprot.2015.124CrossRefPubMedPubMedCentral

Thompson R, Papakonstantinou Ntalis A, Beltran S et al (2019) Increasing phenotypic annotation improves the diagnostic rate of exome sequencing in a rare neuromuscular disorder. Hum Mutat 40:1797–1812. https://doi.org/10.1002/humu.23792CrossRefPubMed

Cipriani V, Pontikos N, Arno G et al (2020) An improved phenotype-driven tool for rare mendelian variant prioritization: benchmarking exomiser on real patient whole-exome data. Genes. https://doi.org/10.3390/genes11040460CrossRefPubMedPubMedCentral

Bourinaris T, Smedley D, Cipriani V et al (2020) Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project. Eur J Hum Genet 28:1763–1768. https://doi.org/10.1038/s41431-020-00720-wCrossRefPubMedPubMedCentral

Štěrbová K, Vlčková M, Hansíková H et al (2021) Novel variants in the NARS2 gene as a cause of infantile-onset severe epilepsy leading to fatal refractory status epilepticus: case study and literature review. Neurogenetics 22:359–364. https://doi.org/10.1007/s10048-021-00659-0CrossRefPubMed

10.

Shang S, Zhou Y, Chen K et al (2022) A novel gene CDC27 causes SLE and is associated with the disease activity. Front Immunol 13:876963. https://doi.org/10.3389/fimmu.2022.876963CrossRefPubMedPubMedCentral

11.

Tábuas-Pereira M, Santana I, Gibbons E et al (2022) Exome sequencing of a Portuguese cohort of frontotemporal dementia patients: looking into the ALS-FTD continuum. Front Neurol 13:886379. https://doi.org/10.3389/fneur.2022.886379CrossRefPubMedPubMedCentral

12.

Schon KR, Horvath R, Wei W et al (2021) Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study. BMJ (Clinical Research ed) 375:e066288. https://doi.org/10.1136/bmj-2021-066288CrossRefPubMed

13.

Smedley D, Smith KR, Martin A et al (2021) 100,000 genomes pilot on rare-disease diagnosis in health care—preliminary report. N Engl J Med 385:1868–1880. https://doi.org/10.1056/NEJMoa2035790CrossRefPubMed

14.

Murphy SM, Herrmann DN, McDermott MP et al (2011) Reliability of the CMT neuropathy score (second version) in Charcot–Marie–Tooth disease. J Peripher Nerv System JPNS 16:191–198. https://doi.org/10.1111/j.1529-8027.2011.00350.xCrossRef

15.

Richards S, Aziz N, Bale S et al (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424. https://doi.org/10.1038/gim.2015.30CrossRefPubMedPubMedCentral

16.

Tan NB, Stapleton R, Stark Z et al (2020) Evaluating systematic reanalysis of clinical genomic data in rare disease from single center experience and literature review. Mol Genet Genomic Med 8:e1508. https://doi.org/10.1002/mgg3.1508CrossRefPubMedPubMedCentral

17.

Djordjevic D, Pinard M, Gauthier MS et al (2022) De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy. Am J Hum Genet 109:759–763. https://doi.org/10.1016/j.ajhg.2022.03.006CrossRefPubMedPubMedCentral

18.

Tétreault M, Choquet K, Orcesi S et al (2011) Recessive mutations in POLR3B, encoding the second largest subunit of Pol III, cause a rare hypomyelinating leukodystrophy. Am J Hum Genet 89:652–655. https://doi.org/10.1016/j.ajhg.2011.10.006CrossRefPubMedPubMedCentral

19.

Ando M, Higuchi Y, Yuan JH et al (2022) Novel de novo POLR3B mutations responsible for demyelinating Charcot–Marie–Tooth disease in Japan. Ann Clin Transl Neurol 9:747–755. https://doi.org/10.1002/acn3.51555CrossRefPubMedPubMedCentral

20.

Xie Y, Lin Z, Liu L et al (2021) Genotype and phenotype distribution of 435 patients with Charcot–Marie–Tooth disease from central south China. Eur J Neurol 28:3774–3783. https://doi.org/10.1111/ene.15024CrossRefPubMed

21.

Guilbot A, Williams A, Ravisé N et al (2001) A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease. Hum Mol Genet 10:415–421. https://doi.org/10.1093/hmg/10.4.415CrossRefPubMed

22.

Madrid R, Aranda JF, Rodríguez-Fraticelli AE et al (2010) The formin INF2 regulates basolateral-to-apical transcytosis and lumen formation in association with Cdc42 and MAL2. Dev Cell 18:814–827. https://doi.org/10.1016/j.devcel.2010.04.001CrossRefPubMed

23.

Andrés-Delgado L, Antón OM, Bartolini F et al (2012) INF2 promotes the formation of detyrosinated microtubules necessary for centrosome reorientation in T cells. J Cell Biol 198:1025–1037. https://doi.org/10.1083/jcb.201202137CrossRefPubMedPubMedCentral

24.

Brown EJ, Schlöndorff JS, Becker DJ et al (2010) Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis. Nat Genet 42:72–76. https://doi.org/10.1038/ng.505CrossRefPubMed

25.

Boyer O, Nevo F, Plaisier E et al (2011) INF2 mutations in Charcot–Marie–Tooth disease with glomerulopathy. N Engl J Med 365:2377–2388. https://doi.org/10.1056/NEJMoa1109122CrossRefPubMed

26.

Janer A, Prudent J, Paupe V et al (2016) SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome. EMBO Mol Med 8:1019–1038. https://doi.org/10.15252/emmm.201506159CrossRefPubMedPubMedCentral

27.

Abrams AJ, Hufnagel RB, Rebelo A et al (2015) Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder. Nat Genet 47:926–932. https://doi.org/10.1038/ng.3354CrossRefPubMedPubMedCentral

28.

Braunisch MC, Gallwitz H, Abicht A et al (2018) Extension of the phenotype of biallelic loss-of-function mutations in SLC25A46 to the severe form of pontocerebellar hypoplasia type I. Clin Genet 93:255–265. https://doi.org/10.1111/cge.13084CrossRefPubMed

Title: Phenotype-driven reanalysis reveals five novel pathogenic variants in 40 exome-negative families with Charcot–Marie–Tooth Disease
Authors: Zhiqiang Lin
Lei Liu
Xiaobo Li
Shunxiang Huang
Huadong Zhao
Sen Zeng
Honglan Yang
Yongzhi Xie
Ruxu Zhang
Publication date: 30-09-2023
Publisher: Springer Berlin Heidelberg
Published in: Journal of Neurology / Issue 1/2024
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-023-11991-w

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Phenotype-driven reanalysis reveals five novel pathogenic variants in 40 exome-negative families with Charcot–Marie–Tooth Disease

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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