Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation.
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.
Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
Tahir Naeem
TN
Khan
Department of Immunology, Genetics and Pathology, Science for Life Laboratory at Uppsala University, Biomedical Center, Uppsala, Sweden.
Joakim
J
Klar
Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
Muhammad
M
Tariq
Department of Pathology, Children's Hospital, Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan.
Shehla
S
Anjum Baig
Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
Naveed Altaf
NA
Malik
Department of Neurology, Pakistan Institute of Medical Sciences (PIMS), Islamabad, Pakistan.
Raja
R
Yousaf
Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
Shahid Mahmood
SM
Baig
Department of Immunology, Genetics and Pathology, Science for Life Laboratory at Uppsala University, Biomedical Center, Uppsala, Sweden.
Niklas
N
Dahl
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D056426:Genetic Loci; D005820:Genetic Testing; D014644:Genetic Variation; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D017422:Sequence Analysis, DNA; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*
D008565:Membrane Proteins; C440006:ATL1 protein, human; D019204:GTP-Binding Proteins