Novel case of neurodegeneration with brain iron accumulation 4 (NBIA4) caused by a pathogenic variant affecting splicing

Sparber, Peter; Marakhonov, Andrey V.; Filatova, Alexandra; Шаркова, И. В.; Skoblov, Mikhail

doi:10.1007/s10048-018-0558-4

Cited by 8 publications

(5 citation statements)

References 11 publications

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“…Reads were aligned to the human reference genome (hg19) with BWA and filtered based on frequency and annotation. The two variants in the COL9A3 gene identified in the proband and the parents were confirmed by Sanger sequencing on an ABI3130xl sequencer (Life Technologies, Carlsbad, CA) using the BigDye Terminator v1.1 Cycle Sequencing Kit (Life Technologies) as previously described (Sparber et al, 2018).…”

Section: Methodsmentioning

confidence: 99%

Clinical and genetic characterization of autosomal recessive stickler syndrome caused by novel compound heterozygous mutations in the COL9A3 gene

Маркова

Sparber

Borovikov

et al. 2021

Molec Gen & Gen Med

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Background Stickler syndrome (STL) is a clinically variable and genetically heterogeneous collagenopathy characterized by ophthalmic, auditory, skeletal, and orofacial abnormalities. STL is mainly inherited in an autosomal dominant pattern with mutations in the COL2A1, COL11A1, and COL11A2 genes. Autosomal recessive forms are rare. However, 19 patients have been reported to date, with STL caused by homozygous or compound heterozygous mutations in genes that encode for the three chains of type IX collagen: COL9A1, COL9A2, and COL9A3. Methods Genetic analysis was performed using the next‐generation sequencing of 166 genes associated with skeletal disorders and sequenced on an Ion Torrent S5 system with a minimum coverage of 100X. The two variants in the COL9A3 gene identified in the proband and the parents were confirmed by Sanger sequencing on an ABI3130xl sequencer. Results We describe a novel case of autosomal recessive Stickler syndrome caused by two undescribed mutations in the COL9A3 gene: c.268C>T (p.Arg90Ter) and c.1729C>T (p.Arg577Ter). The clinical features included severe sensorineural hearing loss, high myopia, vitreoretinal degeneration, and early‐onset arthropathy of the lower limbs. Radiography revealed mild spondyloepiphyseal dysplasia. Conclusion This case further expands the mutational and phenotypic spectrum of COL9A‐associated STL with a more severe presentation.

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Section: Methodsmentioning

confidence: 99%

Clinical and genetic characterization of autosomal recessive stickler syndrome caused by novel compound heterozygous mutations in the COL9A3 gene

Маркова

Sparber

Borovikov

et al. 2021

Molec Gen & Gen Med

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“…Finally, the proband #1 had a mild peripheral sensory neuropathy that was not previously described in SPG43 or C19orf12-related ALS-like syndrome and only rarely in NBIA4 [9].…”

Section: Discussionmentioning

confidence: 64%

“…The c.32C>T mutation was previously described [3,4,7,[12][13][14][15][16] and the c.204_214delCGGGGGGCTGT mutation as well [4,9,14,[17][18][19][20][21].…”

Section: Molecular Datamentioning

confidence: 99%

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SPG43 and ALS-like syndrome in the same family due to compound heterozygous mutations of the C19orf12 gene: a case description and brief review

et al. 2021

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C19orf12 gene biallelic mutations lead mainly to neurodegeneration with brain iron accumulation-4. A 15-year-old male and his 17-year-old sister complained of cramps and exercise intolerance. Clinical examination of the boy mainly showed distal amyotrophy and mild weakness, while the sister predominantly had a tetrapyramidal syndrome. Widespread chronic neurogenic signs and hypointense signals on the striatum were present in both patients. Clinical exome sequencing identified, on both patients, the compound heterozygous pathogenic mutations c.204_214del p.(Gly69ArgfsTer10) and c.32C>T p.(Thr11Met). The description of these rare SPG43 and ALS-like phenotypes in the same family contributes to improve genotype-phenotype correlation in C19orf12-related diseases.

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“…In order to investigate the potential impact of the c.4852G>A variant on splicing, we performed a midigene splicing assay. The genomic region containing exon 28 with 146 nucleotides of intron 27, intron 28, and exon 29 of the SCN1A gene was amplified from the genomic DNA of the proband and cloned into a pSpl3-Flu splicing vector ( Figure 2A ) ( 17 ). Wild-type (WT) and mutant (MUT) plasmids were transfected separately to HEK293T, and 48 h post transfection RT-PCR was performed.…”

Section: Functional Analysismentioning

confidence: 99%

Case Report: Functional Investigation of an Undescribed Missense Variant Affecting Splicing in a Patient With Dravet Syndrome

et al. 2021

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Pathogenic variants in the SCN1A gene are associated with a spectrum of epileptic disorders ranging in severity from familial febrile seizures to Dravet syndrome. Large proportions of reported pathogenic variants in SCN1A are annotated as missense variants and are often classified as variants of uncertain significance when no functional data are available. Although loss-of-function variants are associated with a more severe phenotype in SCN1A, the molecular mechanism of single nucleotide variants is often not clear, and genotype-phenotype correlations in SCN1A-related epilepsy remain uncertain. Coding variants can affect splicing by creating novel cryptic splicing sites in exons or by disrupting exonic cis-regulation elements crucial for proper pre-mRNA splicing. Here, we report a novel case of Dravet syndrome caused by an undescribed missense variant, c.4852G>A (p.(Gly1618Ser)). By midigene splicing assay, we demonstrated that the identified variant is in fact splice-affecting. To our knowledge, this is the first report on the functional investigation of a missense variant affecting splicing in Dravet syndrome.

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Novel case of neurodegeneration with brain iron accumulation 4 (NBIA4) caused by a pathogenic variant affecting splicing

Cited by 8 publications

References 11 publications

Clinical and genetic characterization of autosomal recessive stickler syndrome caused by novel compound heterozygous mutations in the COL9A3 gene

Clinical and genetic characterization of autosomal recessive stickler syndrome caused by novel compound heterozygous mutations in the COL9A3 gene

SPG43 and ALS-like syndrome in the same family due to compound heterozygous mutations of the C19orf12 gene: a case description and brief review

Case Report: Functional Investigation of an Undescribed Missense Variant Affecting Splicing in a Patient With Dravet Syndrome

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