Wadman Renske I, Jansen Marc D, Curial Chantall A D, Groen Ewout J N, Stam Marloes, Wijngaarde Camiel A, Medic Jelena, Sodaar Peter, van Eijk Kristel R, Huibers Manon M H, van Kuik Joyce, Lemmink Henny H, van Rheenen Wouter, Veldink Jan Herman, van den Berg Leonard H, van der Pol W Ludo
Department of Neurology (R.I.W., M.D.J., C.A.D.C., E.J.N.G., M.S., C.A.W., J.M., P.S., K.R.E., W.R., J.H.V., L.H.B., W.L.P.), Brain Center Rudolf Magnus, University Medical Center Utrecht; Department of Pathology (M.M.H.H., J.K.), University Medical Center Utrecht; Department of Genetics (M.M.H.H.), University Medical Center Utrecht; and Department of Genetics (H.H.L.), University Medical Center Groningen, The Netherlands.
Neurol Genet. 2019 Jan 3;6(1):e386. doi: 10.1212/NXG.0000000000000386. eCollection 2020 Feb.
To investigate mutations in genes that are potential modifiers of spinal muscular atrophy (SMA) severity.
We performed a hypothesis-based search into the presence of variants in fused in sarcoma () transactive response DNA-binding protein 43 (), plastin 3 (), and profilin 2 () in a cohort of 153 patients with SMA types 1-4, including 19 families. Variants were detected with targeted next-generation sequencing and confirmed with Sanger sequencing. Functional effects of the identified variants were analyzed in silico and for PLS3, by analyzing expression levels in peripheral blood.
We identified 2 exonic variants in exons 5 and 6 (p.R216C and p.S135N) in 2 unrelated patients, but clinical effects were not evident. We identified 8 intronic variants in in 33 patients. Five variants (c.1511+82T>C; c.748+130 G>A; c.367+182C>T; c.891-25T>C (rs145269469); c.1355+17A>G (rs150802596)) potentially alter exonic splice silencer or exonic splice enhancer sites. The variant c.367+182C>T, but not RNA expression levels, corresponded with a more severe phenotype in 1 family. However, this variant or level of PLS3 expression did not consistently correspond with a milder or more severe phenotype in other families or the overall cohort. We found 3 heterozygous, intronic variants in and with no correlation with clinical phenotype or effects on splicing.
and sequence variants do not modify SMA severity at the population level. Specific variants in individual patients or families do not consistently correlate with disease severity.
研究可能影响脊髓性肌萎缩症（SMA）严重程度的基因变异。
我们对153例1 - 4型SMA患者（包括19个家系）组成的队列进行了基于假设的研究，检测肉瘤融合基因（）、反式作用应答DNA结合蛋白43（）、丝束蛋白3（）和丝切蛋白2（）中的变异。采用靶向二代测序检测变异，并通过桑格测序进行确认。对鉴定出的变异进行计算机模拟功能分析，并对PLS3进行外周血表达水平分析。
我们在2例无亲缘关系的患者中鉴定出位于外显子5和6的2个外显子变异（p.R216C和p.S135N），但临床效应不明显。我们在33例患者中鉴定出8个位于内含子的变异。5个变异（c.1511 + 82T>C；c.748 + 130G>A；c.367 + 182C>T；c.891 - 25T>C（rs145269469）；c.1355 + 17A>G（rs150802596））可能改变外显子剪接沉默子或外显子剪接增强子位点。变异c.367 + 182C>T（而非RNA表达水平）与1个家系中更严重的表型相关。然而，该变异或PLS3表达水平在其他家系或整个队列中并不总是与较轻或较重的表型相对应。我们在和中发现3个杂合的内含子变异，它们与临床表型或剪接效应均无相关性。
和的序列变异在人群水平上不影响SMA严重程度。个别患者或家系中的特定变异与疾病严重程度并不总是相关。
