Exome sequencing of a Pakistani family with spastic paraplegia identified an 18 bp deletion in the cytochrome B5 domain of FA2H

Abstract Hereditary spastic paraplegias refer to a heterogeneous group of neurodegenerative disorders resulting from degeneration of the corticospinal tract. Clinical characterization of patients with hereditary spastic paraplegias represents progressive spasticity, exaggerated reflexes and muscular weakness. Here, to expand on the increasingly broad pools of previously unknown hereditary spastic paraplegia causative genes and subtypes, we performed whole exome sequencing for six affected and two unaffected individuals from two unrelated Chinese families with an autosomal dominant hereditary spastic paraplegia and lacking mutations in known hereditary spastic paraplegia implicated genes. The exome sequencing revealed two stop-gain mutations, c.247_248insGTGAATTC (p.I83Sfs*11) and c.526G>T (p.E176*), in the ubiquitin-associated protein 1 (UBAP1) gene, which co-segregated with the spastic paraplegia. We also identified two UBAP1 frameshift mutations, c.324_325delCA (p.H108Qfs*10) and c.425_426delAG (p.K143Sfs*15), in two unrelated families from an additional 38 Chinese pedigrees with autosomal dominant hereditary spastic paraplegias and lacking mutations in known causative genes. The primary disease presentation was a pure lower limb predominant spastic paraplegia. In vivo downregulation of Ubap1 in zebrafish causes abnormal organismal morphology, inhibited motor neuron outgrowth, decreased mobility, and shorter lifespan. UBAP1 is incorporated into endosomal sorting complexes required for transport complex I and binds ubiquitin to function in endosome sorting. Patient-derived truncated form(s) of UBAP1 cause aberrant endosome clustering, pronounced endosome enlargement, and cytoplasmic accumulation of ubiquitinated proteins in HeLa cells and wild-type mouse cortical neuron cultures. Biochemical and immunocytochemical experiments in cultured cortical neurons derived from transgenic Ubap1flox mice confirmed that disruption of UBAP1 leads to dysregulation of both early endosome processing and ubiquitinated protein sorting. Strikingly, deletion of Ubap1 promotes neurodegeneration, potentially mediated by apoptosis. Our study provides genetic and biochemical evidence that mutations in UBAP1 can cause pure autosomal dominant spastic paraplegia.

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Whole-exome sequencing identifies a novel mutation in spermine synthase gene (SMS) associated with Snyder-Robinson Syndrome

10.21203/rs.3.rs-23574/v4 ◽

2020 ◽

Author(s):

Talal J. Qazi ◽

Qiao Wu ◽

Ailikemu Aierken ◽

Daru Lu ◽

Ihtisham Bukhari ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Mutational Analysis ◽

Novel Mutation ◽

Pathogenic Variant ◽

Facial Dysmorphism ◽

Pakistani Family ◽

Spermine Synthase ◽

Whole Exome

Abstract Background: Loss of function mutations in the spermine synthase gene (SMS) have been reported to cause a rare X-linked intellectual disability known as Snyder-Robinson Syndrome (SRS). Besides intellectual disability, SRS is also characterized by reduced bone density, osteoporosis and facial dysmorphism. SRS phenotypes evolve with age from childhood to adulthood. Methods: Whole exome sequencing was performed to know the causative gene/pathogenic variant. Later we confirmed the pathogenic variant through Sanger sequencing. Furthermore, we also performed the mutational analysis through HOPE SERVER and SWISS-MODEL. Also, radiographs were also obtained for affected individual to confirm the disease features. Results: In this article, we report the first Pakistani family consisting of three patients with SRS and a novel missense pathogenic variant in the SMS gene (c.905 C>T p.(Ser302Leu)). In addition to the typical phenotypes, one patient presented with early-onset seizures. Clinical features, genetic and in-silico analysis linked the affected patients of the family with Snyder-Robinson and suggest that this novel mutation affects the spermine synthase activity Conclusion: A novel missense variant in the SMS, c.905C >T p. (Ser302Leu), causing Snyder- Robinson Syndrome (SRS) is reported in three members of Pakistani Family.

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Whole exome sequencing identifies a novel mutation in spermine synthase gene (SMS) associated with Snyder-Robinson Syndrome

10.21203/rs.3.rs-23574/v3 ◽

2020 ◽

Author(s):

Talal J. Qazi ◽

Qiao Wu ◽

Ailikemu Aierken ◽

Daru Lu ◽

Ihtisham Bukhari ◽

...

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Mutational Analysis ◽

Novel Mutation ◽

Pathogenic Variant ◽

Facial Dysmorphism ◽

Pakistani Family ◽

Spermine Synthase ◽

Whole Exome

Abstract Background: Loss of function mutations in the spermine synthase gene (SMS) have been reported to cause a rare X-linked intellectual disability known as Snyder-Robinson Syndrome (SRS). Besides intellectual disability, SRS is also characterized by reduced bone density, osteoporosis and facial dysmorphism. SRS phenotypes evolve with age from childhood to adulthood. Methods: Whole exome sequencing was performed to know the causative gene/pathogenic variant. Later we confirmed the pathogenic variant through Sanger sequencing. Furthermore, we also performed the mutational analysis through HOPE SERVER and SWISS-MODEL. Also, radiographs were also obtained for affected individual to confirm the disease features. Results: In this article, we report the first Pakistani family consisting of three patients with SRS and a novel missense pathogenic variant in the SMS gene (c.905 C>T p.(Ser302Leu)). In addition to the typical phenotypes, one patient presented with early-onset seizures. Clinical features, genetic and in-silico analysis linked the affected patients of the family with Snyder-Robinson and suggest that this novel mutation affects the spermine synthase activityConclusion: A novel missense variant in the SMS, c.905C >T p. (Ser302Leu), causing Snyder- Robinson Syndrome (SRS) is reported in three members of Pakistani Family.

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Whole exome sequencing identified two novel homozygous missense variants in the same codon of CLCN7 underlying autosomal recessive infantile malignant osteopetrosis in a Pakistani family

Molecular Biology Reports ◽

10.1007/s11033-018-4194-8 ◽

2018 ◽

Vol 45 (4) ◽

pp. 565-570 ◽

Cited By ~ 1

Author(s):

Muhammad Aman Khan ◽

Aman Ullah ◽

Muhammad Naeem

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Recessive ◽

Pakistani Family ◽

Missense Variants ◽

Whole Exome ◽

Malignant Osteopetrosis ◽

Infantile Malignant Osteopetrosis

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A novel SPAST gene mutation identified in a Chinese family with hereditary spastic paraplegia

10.21203/rs.3.rs-26296/v1 ◽

2020 ◽

Author(s):

Weiwei Yu ◽

Haiqiang Jin ◽

Jianwen Deng ◽

Ding Nan ◽

Yining Huang

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Hereditary Spastic Paraplegia ◽

Dna Isolation ◽

Tertiary Structure ◽

Novel Mutation ◽

Chinese Family ◽

Spastic Paraplegia ◽

Whole Exome ◽

And Function

Abstract Background: Hereditary spastic paraplegia is a heterogeneous group of clinically and genetically neurodegenerative diseases characterized by progressive gait disorder. Hereditary spastic paraplegia can be inherited in various ways, and all modes of inheritance are associated with multiple genes or loci. At present, more than 76 disease-causing loci have been identified in hereditary spastic paraplegia patients. Here, we report a novel mutation in SPAST gene associated with hereditary spastic paraplegia in a Chinese family, further enriching the hereditary spastic paraplegia spectrum. Methods: Whole genomic DNA was extracted from peripheral blood of the 15 subjects from a Chinese family using DNA Isolation Kit. The Whole Exome Sequencing of the proband was analyzed and the result was identified in the rest individuals. RaptorX prediction tool and Protein Variation Effect Analyzer were used to predict the effects of the mutation on protein tertiary structure and function.Results: Spastic paraplegia has been inherited across at least four generations in this family, during which only four HSP patients were alive. The results obtained by analyzing the Whole Exome Sequencing of the proband exhibited a novel disease-associated in-frame deletion in the SPAST gene, and the this mutation also existed in the rest three HSP patients in this family. This in-frame deletion consists of three nucleotides deletion (c.1710_1712delGAA) within the exon 16, resulting in lysine deficiency at the position 570 of the protein (p.K570del). This novel mutation was also predicted to result in the synthesis of misfolded SPAST protein and have the deleterious effect on the function of SPAST protein.Conclusion: In this case, we reported a novel mutation in the known SPAST gene that segregated with HSP disease, which can be inherited in each generation. Simultaneously, this novel discovery significantly enriches the mutation spectrum, which provides an opportunity for further investigation of genetic pathogenesis of HSP.

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Whole-exome sequencing in a consanguineous Pakistani family identifies a mutational hotspot in the COL7A1 gene, causing recessive dystrophic epidermolysis bullosa

Clinical Dysmorphology ◽

10.1097/mcd.0000000000000299 ◽

2020 ◽

Vol 29 (2) ◽

pp. 86-89

Author(s):

Atta Ur Rehman ◽

Virginie G. Peter ◽

Mathieu Quinodoz ◽

Muhammad Dawood ◽

Carlo Rivolta

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Epidermolysis Bullosa ◽

Pakistani Family ◽

Dystrophic Epidermolysis Bullosa ◽

Whole Exome ◽

Recessive Dystrophic Epidermolysis Bullosa ◽

Col7a1 Gene

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CAPN1 mutations broadening the hereditary spastic paraplegia/spinocerebellar ataxia phenotype

Practical Neurology ◽

10.1136/practneurol-2017-001842 ◽

2018 ◽

Vol 18 (5) ◽

pp. 369-372 ◽

Cited By ~ 7

Author(s):

Jeffrey Lambe ◽

Bernadette Monaghan ◽

Tudor Munteanu ◽

Janice Redmond

Keyword(s):

Exome Sequencing ◽

Spinocerebellar Ataxia ◽

Hereditary Spastic Paraplegia ◽

Diagnostic Testing ◽

Next Generation ◽

Spastic Paraplegia ◽

Sequencing Technologies ◽

Disease Entities ◽

Mixed Phenotype ◽

Generation Sequencing

Increasing availability of next-generation sequencing technologies has revealed several limitations of diagnosis-driven traditional clinicogenetic disease classifications, particularly among patients with an atypical or mixed phenotype. Hereditary spastic paraplegia (HSP) and spinocerebellar ataxia (SCA) are two such disease entities with an often overlapping presentation, in which next generation exome sequencing has played a key role in identification of genes causing disease along a continuum of ataxia and spasticity. We describe a patient who presented with features of both ataxia and spasticity, in whom initial diagnostic testing was inconclusive. Ultimately next generation exome sequencing identified homozygosity for a pathogenic variant in exon 13 of the CAPN1 gene c.1534C>T(p.Arg512Cys). This case supports consideration of a less discriminatory classification system among such patients, potentially allowing for more expedient diagnosis through testing of a larger gene panel along the ‘ataxia-spasticity spectrum’.

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