Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation - PubMed (original) (raw)

Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation

Tahir Naeem Khan et al. Eur J Hum Genet. 2014 Oct.

Abstract

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 ∼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.

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Figures

Figure 1

Pedigree of the family segregating HSP and analysis of the ATL1 mutation. (a) The consanguineous family consists of two loops with two first-cousin marriages and six male individuals affected by pure HSP (filled symbols). The genotype at cDNA position 353 of ATL1 is shown below each symbol. Affected individuals are homozygous for the c.353G>A p.(Arg118Gln) mutation, whereas seven heterozygous family members are asymptomatic. The two females II:1 and II:4 are distantly related, but the precise relationship was unclear. (b) Sequence chromatogram showing part of ATL1 exon 4 (NM_001127713.1) obtained from a healthy control (top), individual III:6 (middle) and the affected individual III:1 (bottom). The ATL1 mutation c.353G>A p.(Arg118Gln) is indicated by an arrow. The asterisk denotes a synonymous SNP (rs1060197) with allele frequencies 0.19/0.81 (dbSNP) and without predicted effects. (c) Relative position of the p.(Arg118Gln) substitution in the GTPase domain of the atlastin-1 protein (top) and degree of conservation of the Arg118 residue (shaded) across different species. N, N-terminus; M, middle domain; TM, transmembrane domains.

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Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation - PubMed (original) (raw)