Defining the genetic basis of early onset hereditary spastic paraplegia using whole genome sequencing.
We performed whole genome sequencing (WGS) in nine families from India with early-onset hereditary spastic paraplegia (HSP). We obtained a genetic diagnosis in 4/9 (44 %) families within known HSP genes (DDHD2 and CYP2U1), as well as perixosomal biogenesis disorders (PEX16) and GM1 gangliosidosis (GLB1). In the remaining patients, no candidate structural variants, copy number variants or predicted splice variants affecting an extended candidate gene list were identified. Our findings demonstrate the efficacy of using WGS for diagnosing early-onset HSP, particularly in consanguineous families (4/6 diagnosed), highlighting that two of the diagnoses would not have been made using a targeted approach.
Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St Leonards, 2065, Australia. kkum4618@uni.sydney.edu.au.|Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Australia. kkum4618@uni.sydney.edu.au.
Kishore R
KR
Kumar
Neurospecialities Centre, Belgaum, India.
G M
GM
Wali
Department of Paediatrics, KLE University's Jawaharlal Nehru J N Medical College, Belgaum, India.
Mahesh
M
Kamate
Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St Leonards, 2065, Australia.
Gautam
G
Wali
Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Australia.
André E
AE
Minoche
Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Australia.
Clare
C
Puttick
Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Australia.
Mark
M
Pinese
Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Australia.
Velimir
V
Gayevskiy
Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Australia.|St Vincent's Clinical School, University of New South Wales, Sydney, Australia.
Marcel E
ME
Dinger
Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St Leonards, 2065, Australia.|St Vincent's Clinical School, University of New South Wales, Sydney, Australia.|Department of Medical Genetics, Sydney Children's Hospital, Randwick, Australia.
Tony
T
Roscioli
Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St Leonards, 2065, Australia.
Carolyn M
CM
Sue
Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Australia.|St Vincent's Clinical School, University of New South Wales, Sydney, Australia.
Mark J
MJ
Cowley
D000072467:Cytochrome P450 Family 2 / Q000235:genetics; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007194:India; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D010740:Phospholipases / Q000235:genetics; D015419:Spastic Paraplegia, Hereditary / Q000175:diagnosis* / Q000235:genetics*; D000073336:Whole Genome Sequencing; D001616:beta-Galactosidase / Q000235:genetics
D008565:Membrane Proteins; C486345:PEX16 protein, human; C484320:CYP2U1 protein, human; D000072467:Cytochrome P450 Family 2; D010740:Phospholipases; C541017:DDHD2 protein, human; C061901:GLB1 protein, human; D001616:beta-Galactosidase
Gangliosidosis; Hereditary spastic paraplegia; Metabolic; SPG54; SPG56; Whole genome sequencing; Zellweger
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