Genotype-phenotype correlation in seven motor neuron disease families with novel ALS2 mutations

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dc.contributor.authorSprute, Rosanne
dc.contributor.authorJergas, Hannah
dc.contributor.authorOelmez, Akguen
dc.contributor.authorAlawbathani, Salem
dc.contributor.authorKarasoy, Hatice
dc.contributor.authorDafsari, Hormos Salimi
dc.contributor.authorCirak, Sebahattin
dc.date.accessioned2020-12-01T11:57:44Z
dc.date.available2020-12-01T11:57:44Z
dc.date.issued2020
dc.departmentEge Üniversitesien_US
dc.description.abstractAutosomal-recessive mutations in the Alsin Rho guanine nucleotide exchange factor (ALS2) gene may cause specific subtypes of childhood-onset progressive neurodegenerative motor neuron diseases (MND). These diseases can manifest with a clinical continuum from infantile ascending hereditary spastic paraplegia (IAHSP) to juvenile-onset forms with or without lower motor neuron involvement, the juvenile primary lateral sclerosis (JPLS) and the juvenile amyotrophic lateral sclerosis (JALS). We report 11 patients from seven unrelated Turkish and Yemeni families with clinical signs of IAHSP or JPLS. We performed haplotype analysis or next-generation panel sequencing followed by Sanger Sequencing to unravel the genetic disease cause. We described their clinical phenotype and analyzed the pathogenicity of the detected variants with bioinformatics tools. We further reviewed all previously reported cases with ALS2-related MND. We identified five novel homozygous pathogenic variants in ALS2 at various positions: c.275_276delAT (p.Tyr92CysfsTer11), c.1044C>G (p.Tyr348Ter), c.1718C>A (p.Ala573Glu), c.3161T>C (p.Leu1054Pro), and c.1471+1G>A (NM_020919.3, NP_065970.2). in our cohort, disease onset was in infancy or early childhood with rapid onset of motor neuron signs. Muscle weakness, spasticity, severe dysarthria, dysphagia, and facial weakness were common features in the first decade of life. Frameshift and nonsense mutations clustered in the N-terminal Alsin domains are most prevalent. We enriched the mutational spectrum of ALS2-related disorders with five novel pathogenic variants. Our study indicates a high detection rate of ALS2 mutations in patients with a clinically well-characterized early onset MND. Intrafamilial and even interfamilial diversity in patients with identical pathogenic variants suggest yet unknown modifiers for phenotypic expression.en_US
dc.description.sponsorshipDeutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [CI 218/1-1]en_US
dc.description.sponsorshipDeutsche Forschungsgemeinschaft, Grant/Award Number: CI 218/1-1en_US
dc.identifier.doi10.1002/ajmg.a.61951en_US
dc.identifier.issn1552-4825
dc.identifier.issn1552-4833
dc.identifier.pmid33155358en_US
dc.identifier.urihttps://doi.org/10.1002/ajmg.a.61951
dc.identifier.urihttps://hdl.handle.net/11454/61782
dc.identifier.wosWOS:000585822000001en_US
dc.identifier.wosqualityQ3en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherWileyen_US
dc.relation.ispartofAmerican Journal of Medical Genetics Part Aen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectamyotrophic lateral sclerosis (ALS)en_US
dc.subjectfamilial ALSen_US
dc.subjectinfantile ascending hereditary spastic paraplegia (IAHSP)en_US
dc.subjectjuvenile amyotrophic lateral sclerosis (JALS)en_US
dc.subjectlinkage analysisen_US
dc.subjectwhole&#8208en_US
dc.subjectexome sequencingen_US
dc.titleGenotype-phenotype correlation in seven motor neuron disease families with novel ALS2 mutationsen_US
dc.typeArticleen_US

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