Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation
2014 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 22, no 10, 1180-1184 p.Article in journal (Refereed) Published
Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of disorders characterized by progressive spasticity and weakness of the lower limbs. Autosomal dominant and 'pure' forms of HSP account for similar to 80% of cases in Western societies of whom 10% carry atlastin-1 (ATL1) gene mutations. We report on a large consanguineous family segregating six members with early onset HSP. The pedigree was compatible with both autosomal dominant and autosomal recessive inheritance. Whole-exome sequencing and segregation analysis revealed a homozygous novel missense variant c.353G>A, p.(Arg118Gln) in ATL1 in all six affected family members. Seven heterozygous carriers, five females and two males, showed no clinical signs of HSP with the exception of sub-clinically reduced vibration sensation in one adult female. Our combined findings show that homozygosity for the ATL1 missense variant remains the only plausible cause of HSP, whereas heterozygous carriers are asymptomatic. This apparent autosomal recessive inheritance adds to the clinical complexity of spastic paraplegia 3A and calls for caution using directed genetic screening in HSP.
Place, publisher, year, edition, pages
2014. Vol. 22, no 10, 1180-1184 p.
SPG3A, autosomal recessive, ATL1 gene
Biochemistry and Molecular Biology Genetics
IdentifiersURN: urn:nbn:se:uu:diva-235312DOI: 10.1038/ejhg.2014.5ISI: 000342476100005PubMedID: 24473461OAI: oai:DiVA.org:uu-235312DiVA: diva2:761177