KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.,European Journal of Human Genetics

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KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.
European Journal of Human Genetics ( IF 3.7 ) Pub Date : 2019-09-05 , DOI: 10.1038/s41431-019-0497-z
Maartje Pennings ₁ , Meyke I Schouten ₁ , Judith van Gaalen ₂ , Rowdy P P Meijer ₁ , Susanne T de Bot ₃ , Marjolein Kriek ₄ , Christiaan G J Saris ₂ , Leonard H van den Berg ₅ , Michael A van Es ₅ , Dick M H Zuidgeest ₆ , Mariet W Elting ₇ , Jiddeke M van de Kamp ₇ , Karin Y van Spaendonck-Zwarts ₈ , Christine de Die-Smulders ₉ , Eva H Brilstra ₁₀ , Corien C Verschuuren ₁₁ , Bert B A de Vries ₁ , Jacques Bruijn ₁₂ , Kalliopi Sofou ₁₃ , Floor A Duijkers ₈ , B Jaeger ₁₄ , Jolanda H Schieving ₁₅ , Bart P van de Warrenburg ₂ , Erik-Jan Kamsteeg ₁

Affiliation

Department of Human Genetics, Radboud university medical centre, Nijmegen, The Netherlands.
Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud university medical centre, Nijmegen, The Netherlands.
Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Neurology, Ikazia hospital, Rotterdam, The Netherlands.
Department of Clinical Genetics, Amsterdam UMC, Vrije Universtiteit Amsterdam, Amsterdam, The Netherlands.
Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Department of Human Genetics and research Institute GROW, Maastricht University Medical Center, Maastricht, The Netherlands.
Department of Genetics, Utrecht University Medical Center, Utrecht, The Netherlands.
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Department of Pediatrics, Skaraborg Hospital, Skövde, Sweden.
Department of Pediatrics, The Queen Silvia Children's Hospital, University of Gothenburg Sweden, Gothenburg, Sweden.
Department of Pediatric Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Department of Pediatric Neurology, Radboud University Medical Center, Amalia Children's Hospital and Donders Institute for Brain, Cognition and Behavior, Nijmegen, The Netherlands.

Variants in the KIF1A gene can cause autosomal recessive spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or autosomal (de novo) dominant mental retardation type 9. More recently, variants in KIF1A have also been described in a few cases with autosomal dominant spastic paraplegia. Here, we describe 20 KIF1A variants in 24 patients from a clinical exome sequencing cohort of 347 individuals with a mostly 'pure' spastic paraplegia. In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0-57 years). Segregation analyses showed a de novo occurrence in seven cases, and a dominant inheritance pattern in 11 families. The motor domain of KIF1A is a hotspot for disease causing variants in autosomal dominant spastic paraplegia, similar to mental retardation type 9 and recessive spastic paraplegia type 30. However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families. Finally, three missense variants were outside the motor domain and need further characterization. In conclusion, KIF1A variants are a frequent cause of autosomal dominant spastic paraplegia in our cohort (6-7%). The identification of KIF1A loss-of-function variants suggests haploinsufficiency as a possible mechanism in autosomal dominant spastic paraplegia.

中文翻译：

KIF1A 变异是常染色体显性遗传性痉挛性截瘫的常见原因。

KIF1A 基因的变异可导致常染色体隐性痉挛性截瘫 30、常染色体隐性遗传性感觉神经病或常染色体（新发）显性智力低下 9 型。最近，在少数常染色体显性痉挛性截瘫病例中也描述了 KIF1A 变异. 在这里，我们描述了来自临床外显子组测序队列的 24 名患者的 20 个 KIF1A 变异，该队列由 347 名大部分为“纯”痉挛性截瘫患者组成。在这些患者中，痉挛性截瘫是缓慢进展的，大部分是单纯性的，但疾病的发生（0-57 岁）变化很大。分离分析显示在 7 个病例中为从头发生，在 11 个家庭中为显性遗传模式。KIF1A 的运动域是常染色体显性遗传性痉挛性截瘫中致病变异的热点，类似于 9 型智力低下和 30 型隐性痉挛性截瘫。然而，与这些等位基因疾病不同，显性痉挛性截瘫也是由 6 个家族中该领域之外的功能丧失变异引起的。最后，三个错义变体在运动领域之外，需要进一步表征。总之，KIF1A 变异是我们队列中常染色体显性遗传性痉挛性截瘫的常见原因（6-7%）。KIF1A 功能丧失变异体的鉴定表明单倍剂量不足是常染色体显性遗传性痉挛性截瘫的一种可能机制。三个错义变体在运动领域之外，需要进一步表征。总之，KIF1A 变异是我们队列中常染色体显性遗传性痉挛性截瘫的常见原因（6-7%）。KIF1A 功能丧失变异体的鉴定表明单倍体不足是常染色体显性遗传性痉挛性截瘫的一种可能机制。三个错义变体在运动领域之外，需要进一步表征。总之，KIF1A 变异是我们队列中常染色体显性遗传性痉挛性截瘫的常见原因（6-7%）。KIF1A 功能丧失变异体的鉴定表明单倍体不足是常染色体显性遗传性痉挛性截瘫的一种可能机制。

更新日期：2019-09-06

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