Long read sequencing overcomes challenges in the diagnosis of SORD neuropathy.
Charcot-Marie-Tooth neuropathy
SORD
long-read sequencing
Journal
Journal of the peripheral nervous system : JPNS
ISSN: 1529-8027
Titre abrégé: J Peripher Nerv Syst
Pays: United States
ID NLM: 9704532
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
revised:
13
02
2022
received:
05
11
2021
accepted:
22
02
2022
pubmed:
1
3
2022
medline:
9
6
2022
entrez:
28
2
2022
Statut:
ppublish
Résumé
Biallelic mutations in sorbitol dehydrogenase (SORD) have been recently identified as a common cause of recessive axonal Charcot-Marie-Tooth neuropathy (CMT2). We aimed to assess a novel long-read sequencing approach to overcome current limitations in SORD neuropathy diagnostics due to the SORD2P pseudogene and the phasing of biallelic mutations in recessive disease. We conducted a screen of our Australian whole exome sequencing (WES) CMT cohort to identify individuals with homozygous or compound heterozygous SORD variants. Individuals detected with SORD mutations then underwent long-read sequencing, clinical assessment, and serum sorbitol analysis. An individual was detected with compound heterozygous truncating mutations in SORD exon 7, NM_003104.5:c.625C>T (p.Arg209Ter) and NM_003104.5:c.757del (p.Ala253GlnfsTer27). Subsequent Oxford Nanopore Tech (ONT) long-read sequencing was used to successfully differentiate SORD from the highly homologous non-functional SORD2P pseudogene and confirmed that the mutations were biallelic through haplotype-resolved analysis. The patient presented with axonal sensorimotor polyneuropathy (CMT2) and ulnar neuropathy without compression at the elbow. Burning neuropathic pain in the forearms and feet was also reported and was exacerbated by alcohol consumption and improved with alcohol cessation. UPLC-tandem mass spectrometry confirmed that the patient had elevated serum sorbitol levels (12.0 mg/L) consistent with levels previously observed in patients with biallelic SORD mutations. This represents a novel clinical presentation and expands the phenotype associated with biallelic SORD mutations causing CMT2. Our study is the first report of long-read sequencing for an individual with CMT and demonstrates the utility of this approach for clinical genomics.
Substances chimiques
Sorbitol
506T60A25R
L-Iditol 2-Dehydrogenase
EC 1.1.1.14
Types de publication
Case Reports
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
120-126Subventions
Organisme : Medical Research Council
ID : MR/T001712/1
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022 Peripheral Nerve Society.
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