SPAST mutations in Australian patients with hereditary spastic paraplegia

Abstract

We conclude that SPAST mutations are responsible for the majority of HSP in Australia. Most of the patients with SPAST mutations had pure forms of HSP and a positive family history to suggest autosomal dominant (AD) HSP. Not all mutations were identified by direct sequencing of the SPAST gene, necessitating further molecular analysis. Given that SPAST mutations cause AD-HSP, these findings are important when providing genetic counselling for affected patients.

Mutational Spectrum of Spast (Spg4) and Atl1 (Spg3a) Genes In Russian Patients With Hereditary Spastic Paraplegia

“…Mutations in SPAST gene identified here can be divided into 2 groups: large deletions/duplications detected by MLPA assay (29.1% of all SPAST mutations) and mutations detected via sequencing methods (70.9% of all SPAST mutations). The corresponding proportion of large deletions/duplications in SPAST gene in other cohorts was as follows: 37.5% in the Polish cohort 12 ; 2.5% in the Spanish cohort 9 ; 9.0% in The Republic of Bashkortostan cohort 15 ; and 13.5% in the Australian cohort 16 . The proportion of large deletions/duplications detected in this study and their mutational spectrum, were similar to the results obtained by Polish researchers.…”

Mutational Spectrum of Spast (Spg4) and Atl1 (Spg3a) Genes In Russian Patients With Hereditary Spastic Paraplegia

“…Mutations in SPAST gene identified here can be divided into 2 groups: large deletions/duplications detected by MLPA assay (29.1% of all SPAST mutations) and mutations detected via sequencing methods (70.9% of all SPAST mutations). The corresponding proportion of large deletions/duplications in SPAST gene in other cohorts was as follows: 37.5% in the Polish cohort 12 ; 2.5% in the Spanish cohort 9 ; 9.0% in The Republic of Bashkortostan cohort 15 ; and 13.5% in the Australian cohort 16 . The proportion of large deletions/duplications detected in this study and their mutational spectrum, were similar to the results obtained by Polish researchers.…”

Integration of Genome and Epigenetic Testing in the Diagnostic Evaluation of Developmental Delay: Differentiating Börjeson–Forssman–Lehmann (BFLS) and White–Kernohan (WHIKERS) Syndromes

“…The SPAST variant (c.1413+3_1413+6del) is listed in ClinVar (ID 536445) and classified as likely pathogenic or pathogenic (LP/P) [13]. The variant is well-described, having been published in over eight journals and seen in multiple cases of autosomal dominant hereditary spastic paraplegia (HSP) [14,15,16,17,18,19,20]. The variant is not present in population databases (gnomAD v4.1.0) [3].…”

“…The de novo SPAST variant (c.1413+3_1413+6del) has been reported in multiple patients with HSP with an age of onset starting in the 20s to 50s and presenting as both pure and complicated (additional neurological symptoms) HSP [ 14 , 15 , 16 , 18 ]. c.131C>T and c.134C>A are thought to be age of onset modifiers in SPAST , leading to very early onset of symptoms.…”

Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia

“…All patients involved in this study exhibited typical SPAST HSP clinical symptoms. Details of their clinical phenotypes are mentioned elsewhere 2 . Details of mutations and related patient information and also information related to healthy controls are listed in Table 1 .…”

Mutational Spectrum of Spast (Spg4) and Atl1 (Spg3a) Genes In Russian Patients With Hereditary Spastic Paraplegia

“…Mutations in SPAST gene identified here can be divided into 2 groups: large deletions/duplications detected by MLPA assay (29.1% of all SPAST mutations) and mutations detected via sequencing methods (70.9% of all SPAST mutations). The corresponding proportion of large deletions/duplications in SPAST gene in other cohorts was as follows: 37.5% in the Polish cohort 12 ; 2.5% in the Spanish cohort 9 ; 9.0% in The Republic of Bashkortostan cohort 15 ; and 13.5% in the Australian cohort 16 . The proportion of large deletions/duplications detected in this study and their mutational spectrum, were similar to the results obtained by Polish researchers.…”

Integration of Genome and Epigenetic Testing in the Diagnostic Evaluation of Developmental Delay: Differentiating Börjeson–Forssman–Lehmann (BFLS) and White–Kernohan (WHIKERS) Syndromes

“…The SPAST variant (c.1413+3_1413+6del) is listed in ClinVar (ID 536445) and classified as likely pathogenic or pathogenic (LP/P) [13]. The variant is well-described, having been published in over eight journals and seen in multiple cases of autosomal dominant hereditary spastic paraplegia (HSP) [14,15,16,17,18,19,20]. The variant is not present in population databases (gnomAD v4.1.0) [3].…”

“…The de novo SPAST variant (c.1413+3_1413+6del) has been reported in multiple patients with HSP with an age of onset starting in the 20s to 50s and presenting as both pure and complicated (additional neurological symptoms) HSP [ 14 , 15 , 16 , 18 ]. c.131C>T and c.134C>A are thought to be age of onset modifiers in SPAST , leading to very early onset of symptoms.…”

Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia

“…All patients involved in this study exhibited typical SPAST HSP clinical symptoms. Details of their clinical phenotypes are mentioned elsewhere 2 . Details of mutations and related patient information and also information related to healthy controls are listed in Table 1 .…”

Mutational Spectrum of Spast (Spg4) and Atl1 (Spg3a) Genes In Russian Patients With Hereditary Spastic Paraplegia

“…Mutations in SPAST gene identified here can be divided into 2 groups: large deletions/duplications detected by MLPA assay (29.1% of all SPAST mutations) and mutations detected via sequencing methods (70.9% of all SPAST mutations). The corresponding proportion of large deletions/duplications in SPAST gene in other cohorts was as follows: 37.5% in the Polish cohort 12 ; 2.5% in the Spanish cohort 9 ; 9.0% in The Republic of Bashkortostan cohort 15 ; and 13.5% in the Australian cohort 16 . The proportion of large deletions/duplications detected in this study and their mutational spectrum, were similar to the results obtained by Polish researchers.…”

Integration of Genome and Epigenetic Testing in the Diagnostic Evaluation of Developmental Delay: Differentiating Börjeson–Forssman–Lehmann (BFLS) and White–Kernohan (WHIKERS) Syndromes

“…The SPAST variant (c.1413+3_1413+6del) is listed in ClinVar (ID 536445) and classified as likely pathogenic or pathogenic (LP/P) [13]. The variant is well-described, having been published in over eight journals and seen in multiple cases of autosomal dominant hereditary spastic paraplegia (HSP) [14,15,16,17,18,19,20]. The variant is not present in population databases (gnomAD v4.1.0) [3].…”

“…The de novo SPAST variant (c.1413+3_1413+6del) has been reported in multiple patients with HSP with an age of onset starting in the 20s to 50s and presenting as both pure and complicated (additional neurological symptoms) HSP [ 14 , 15 , 16 , 18 ]. c.131C>T and c.134C>A are thought to be age of onset modifiers in SPAST , leading to very early onset of symptoms.…”

Mechanism of impaired microtubule-dependent peroxisome trafficking and oxidative stress in SPAST-mutated cells from patients with Hereditary Spastic Paraplegia

“…All patients involved in this study exhibited typical SPAST HSP clinical symptoms. Details of their clinical phenotypes are mentioned elsewhere 2 . Details of mutations and related patient information and also information related to healthy controls are listed in Table 1 .…”