Intragenic and structural variation in the SMN locus and clinical variability in spinal muscular atrophy
| Autor: | Jelena Medic, Camiel A. Wijngaarde, Henny H. Lemmink, Marc D. Jansen, Raymon Vijzelaar, Peter Sodaar, Leonard H. van den Berg, W. Ludo van der Pol, Renske I. Wadman, Chantall A.D. Curial, Marloes Stam, Ewout J N Groen, Jan S. A. G. Schouten |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Population Locus (genetics) SMN1 Biology PHENOTYPE Gene dosage CODON Structural variation 03 medical and health sciences symbols.namesake 0302 clinical medicine medicine III SMA Copy-number variation SMA education spinal muscular atrophy Sanger sequencing Genetics education.field_of_study IDENTIFICATION AcademicSubjects/SCI01870 General Engineering Spinal muscular atrophy SURVIVAL MOTOR-NEURON NATURAL-HISTORY medicine.disease GENE nervous system diseases DELETIONS 030104 developmental biology COPY NUMBER DISEASE SEVERITY symbols Original Article AcademicSubjects/MED00310 030217 neurology & neurosurgery SMN2 |
| Zdroj: | Brain Communications Brain Communications, 2(2):fcaa075. Oxford University Press |
| ISSN: | 2632-1297 |
| Popis: | Clinical severity and treatment response vary significantly between patients with spinal muscular atrophy. The approval of therapies and the emergence of neonatal screening programmes urgently require a more detailed understanding of the genetic variants that underlie this clinical heterogeneity. We systematically investigated genetic variation other than SMN2 copy number in the SMN locus. Data were collected through our single-centre, population-based study on spinal muscular atrophy in the Netherlands, including 286 children and adults with spinal muscular atrophy Types 1–4, including 56 patients from 25 families with multiple siblings with spinal muscular atrophy. We combined multiplex ligation-dependent probe amplification, Sanger sequencing, multiplexed targeted resequencing and digital droplet polymerase chain reaction to determine sequence and expression variation in the SMN locus. SMN1, SMN2 and NAIP gene copy number were determined by multiplex ligation-dependent probe amplification. SMN2 gene variant analysis was performed using Sanger sequencing and RNA expression analysis of SMN by droplet digital polymerase chain reaction. We identified SMN1–SMN2 hybrid genes in 10% of spinal muscular atrophy patients, including partial gene deletions, duplications or conversions within SMN1 and SMN2 genes. This indicates that SMN2 copies can vary structurally between patients, implicating an important novel level of genetic variability in spinal muscular atrophy. Sequence analysis revealed six exonic and four intronic SMN2 variants, which were associated with disease severity in individual cases. There are no indications that NAIP1 gene copy number or sequence variants add value in addition to SMN2 copies in predicting the clinical phenotype in individual patients with spinal muscular atrophy. Importantly, 95% of spinal muscular atrophy siblings in our study had equal SMN2 copy numbers and structural changes (e.g. hybrid genes), but 60% presented with a different spinal muscular atrophy type, indicating the likely presence of further inter- and intragenic variabilities inside as well as outside the SMN locus. SMN2 gene copies can be structurally different, resulting in inter- and intra-individual differences in the composition of SMN1 and SMN2 gene copies. This adds another layer of complexity to the genetics that underlie spinal muscular atrophy and should be considered in current genetic diagnosis and counselling practices. Clinical variability, variation in treatment response and the introduction of neonatal screening programmes urgently require a better understanding of the genetic background of spinal muscular atrophy. Here, we report that SMN2 copies are structurally different between and within patients and show that (partial) deletions, conversions and single-nucleotide variants correlate with clinical severity. Graphical Abstract Graphical Abstract |
| Databáze: | OpenAIRE |
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