High genetic heterogeneity of leukodystrophies in Iranian children: the first report of Iranian Leukodystrophy Registry.

Humans Child Iran Genetic Heterogeneity Demyelinating Diseases Magnetic Resonance Imaging Brain Neurodegenerative Diseases Alcohol Oxidoreductases

Consanguinity Leukodystrophy Magnetic resonance imaging Single gene test Variants Whole-exome sequencing

Journal

Neurogenetics

ISSN: 1364-6753

Titre abrégé: Neurogenetics

Pays: United States

ID NLM: 9709714

Informations de publication

Date de publication:
Oct 2023

Historique:

received: 05 02 2023

accepted: 09 08 2023

medline: 23 10 2023

pubmed: 19 8 2023

entrez: 19 8 2023

Statut: ppublish

Résumé

Leukodystrophies (LDs) are a heterogeneous group of progressive neurological disorders and characterized by primary involvement of white matter of the central nervous system (CNS). This is the first report of the Iranian LD Registry database to describe the clinical, radiological, and genomic data of Persian patients with leukodystrophies. From 2016 to 2019, patients suspicious of LDs were examined followed by a brain magnetic resonance imaging (MRI). A single gene testing or whole-exome sequencing (WES) was used depending on the neuroradiologic phenotypes. In a few cases, the diagnosis was made by metabolic studies. Based on the MRI pattern, diagnosed patients were divided into cohorts A (hypomyelinating LDs) versus cohort B (Other LDs). The most recent LD classification was utilized for classification of diagnosed patients. For novel variants, in silico analyses were performed to verify their pathogenicity. Out of 680 registered patients, 342 completed the diagnostic evaluations. In total, 245 patients met a diagnosis which in turn 24.5% were categorized in cohort A and the remaining in cohort B. Genetic tests revealed causal variants in 228 patients consisting of 213 variants in 110 genes with 78 novel variants. WES and single gene testing identified a causal variant in 65.5% and 34.5% cases, respectively. The total diagnostic rate of WES was 60.7%. Lysosomal disorders (27.3%; GM2-gangliosidosis-9.8%, MLD-6.1%, KD-4.5%), amino and organic acid disorders (17.15%; Canavan disease-4.5%, L-2-HGA-3.6%), mitochondrial leukodystrophies (12.6%), ion and water homeostasis disorders (7.3%; MLC-4.5%), peroxisomal disorders (6.5%; X-ALD-3.6%), and myelin protein disorders (3.6%; PMLD-3.6%) were the most commonly diagnosed disorders. Thirty-seven percent of cases had a pathogenic variant in nine genes (ARSA, HEXA, ASPA, MLC1, GALC, GJC2, ABCD1, L2HGDH, GCDH). This study highlights the most common types as well as the genetic heterogeneity of LDs in Iranian children.

Identifiants

DOI: 10.1007/s10048-023-00730-y PMID: 37597066

pubmed: 37597066

doi: 10.1007/s10048-023-00730-y

pii: 10.1007/s10048-023-00730-y

doi:

Substances chimiques

L2HGDH protein, human EC 1.1.99.2

Alcohol Oxidoreductases EC 1.1.-

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

279-289

Subventions

Organisme : National Institute for Medical Research Development

ID : 983886

Organisme : Tehran University of Medical Sciences and Health Services

ID : 96-02-30-35551

Commentaires et corrections

Type : ErratumIn

Informations de copyright

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