High Frequency of Pathogenic Rearrangements in <i>SPG11</i>
 and Extensive Contribution of Mutational Hotspots and Founder Alleles

Günther, Sven; Elert‐Dobkowska, Ewelina; Soehn, Anne S.; Hinreiner, Sophie; Yoon, Grace; Heller, Raoul; Hellenbroich, Yorck; Hübner, Christian A.; Ray, Peter N.; Hehr, Ute; Bauer, Péter; Sulek, Anna; Beetz, Christian

doi:10.1002/humu.23000

Cited by 12 publications

(8 citation statements)

References 41 publications

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“…Eleven variants (Table 1) in seven known genes related to HSP were identified in eight index patients (Table 2). Seven variants were novel and four (p.M245 fs, p.L950 fs in SPG11 , p.R112X in CYP7B1 , c.759 + 1G > A in CAPN1 ) were previously reported [19–22]. According to the American College of Medical Genetics and Genomics (ACMG) standards [23], two SPG11 variants (p.V1979_L1980delinsX and p.F2343 fs), one GBA2 variant (p.D597fs), and one ATP13A2 variant (p.Q486X) were classified as pathogenic mutations, whereas two AP5Z1 variants (p.T55 M and p.S308 T) and one ALDH18A1 variant (p.S242 N) were classified as uncertain significance variants.…”

Section: Resultsmentioning

confidence: 99%

Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia

Wei

Dong

Pan

et al. 2019

Transl Neurodegener

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Background Although many causative genes of hereditary spastic paraplegia (HSP) have been uncovered in recent years, there are still approximately 50% of HSP patients without genetically diagnosis, especially in autosomal recessive (AR) HSP patients. Rare studies have been performed to determine the genetic spectrum and clinical profiles of recessive HSP patients in the Chinese population. Methods In this study, we investigated 24 Chinese index AR/sporadic patients by targeted next-generation sequencing (NGS), Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Further functional studies were performed to identify pathogenicity of those uncertain significance variants. Results We identified 11 mutations in HSP related genes including 7 novel mutations, including two (p.V1979_L1980delinsX, p.F2343 fs) in SPG11 , two (p.T55 M, p.S308 T) in AP5Z1 , one (p.S242 N) in ALDH18A1, one (p.D597fs) in GBA2 , and one (p.Q486X) in ATP13A2 in 8 index patients and their family members. Mutations in ALDH18A1, AP5Z1, CAPN1 and ATP13A2 genes were firstly reported in the Chinese population. Furthermore, the clinical phenotypes of the patients carrying mutations were described in detail. The mutation (p.S242 N) in ALDH18A1 decreased enzyme activity of P5CS and mutations (p.T55 M, p.S308 T) in AP5Z1 induced lysosomal dysfunction. Conclusion Our results expanded the genetic spectrum and clinical profiles of AR-HSP patients and further demonstrated the efficiency and reliability of targeted NGS diagnosing suspected HSP patients. Electronic supplementary material The online version of this article (10.1186/s40035-019-0157-9) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia

Wei

Dong

Pan

et al. 2019

Transl Neurodegener

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“…The existence of hitherto undetected IDUA CNVs can therefore be expected. The availability of MLPA assays has greatly facilitated the detection of deletions as well as duplications in many other inherited disorders (Günther et al., ). Our corresponding tool will be made available to researchers interested in more accurately defining the prevalence of IDUA CNVs.…”

Section: Discussionmentioning

confidence: 99%

“Missing mutations” in MPS I: Identification of two novel copy number variations by an IDUA‐specific in house MLPA assay

Jahić

Günther

Muschol

et al. 2019

Molec Gen & Gen Med

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Background Mucopolysaccharidosis type I (MPS I) is a rare, recessively inherited lysosomal storage disorder, characterized by progressive multi‐systemic disease. It is caused by a reduced or absent alpha‐l iduronidase (IDUA) enzyme activity secondary to biallelic loss‐of‐function variants in the IDUA. Over 200 causative variants in IDUA have been identified. Nevertheless, there is a fraction of MPS I patients with only a single mutated IDUA allele detectable. Methods As genetic testing of MPS I is usually based on sequencing methods, copy number variations (CNVs) in IDUA can be missed and therefore presumably remain underdiagnosed. The aim of this study was the detection of CNVs using an IDUA‐specific in house multiplex ligation‐dependent probe amplification (MLPA) assay. Results A total of five unrelated MPS I patient samples were re‐analyzed after only a single heterozygous IDUA mutation c.979G>C (p.A327P), c.1469T>C (p.L490P), c.1598C>G (p.P533R), c.1205G>A (p.W402X), c.973‐7C>G (p.?) could be identified. We detected a novel splice site variant c.973‐7C>G (p.?), as well as two novel CNVs, a large deletion of IDUA exon 14 and 3’UTR c.(1828 + 1_1829‐1)_(*1963_?)del, and a large duplication extending from IDUA exon 2 to intron 12 c.(157 + 1_158‐1)_(1727 + 1_1728‐1)dup. Conclusion Together with the CNVs we previously identified, a total of four pathogenic IDUA CNVs have now been reported.

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“…We here report the first exon rearrangement described at the NT5C2 locus. Given the high frequency of exon rearrangements in other complex AR-HSP genes, such as SPG11 , 6 it is not surprising to identify these types of mutations in this recently identified HSP gene. However, copy number variations (CNVs) are more likely to be captured through WGS, rather than whole exome sequencing, as WGS captures both coding and non-coding genetic variation, allowing us to map the CNV breakpoints, and leads to improved detection of CNV and de novo variations due to its read coverage uniformity and allele reduced bias.…”

Section: Discussionmentioning

confidence: 99%

Whole genome sequencing identifies a novel homozygous exon deletion in the NT5C2 gene in a family with intellectual disability and spastic paraplegia

et al. 2017

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Hereditary spastic paraplegias are a rare group of clinically and genetically heterogeneous neurodegenerative diseases, with upper motor neuron degeneration and progressive lower limb spasticity as their main phenotypic features. Despite that 76 distinct loci have been reported and some casual genes identified, most of the underlying causes still remain unidentified. Moreover, a wide range of clinical manifestations is present in most hereditary spastic paraplegias subtypes, adding further complexity to their differential clinical diagnoses. Here, we describe the first exon rearrangement reported in the SPG45/SPG65 (NT5C2) loci in a family featuring a complex hereditary spastic paraplegias phenotype. This study expands both the phenotypic and mutational spectra of the NT5C2-associated disease.

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High Frequency of Pathogenic Rearrangements in SPG11 and Extensive Contribution of Mutational Hotspots and Founder Alleles

Cited by 12 publications

References 41 publications

Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia

Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia

“Missing mutations” in MPS I: Identification of two novel copy number variations by an IDUA‐specific in house MLPA assay

Whole genome sequencing identifies a novel homozygous exon deletion in the NT5C2 gene in a family with intellectual disability and spastic paraplegia

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