SUFU haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum.
SUFU haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum.
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DOI：
10.1136/jmedgenet-2021-108114
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发表时间：
2022-09
影响因子：
4
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中科院分区：
文献类型：
--
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Joubert综合征（JS）是一种隐性遗传性纤毛病，其特征为先天性眼运动失用症（COMA）、发育迟缓（DD）、智力残疾、共济失调、多器官受累以及一种独特的小脑和脑干畸形。已知超过40个js相关基因，诊断率为60%-75%。2018年，我们在两个轻度JS家族中报道了SUFU基因的纯合次型错义变异。最近，在显性遗传性昏迷的家族中发现了杂合截断SUFU变异，偶尔与轻度DD和轻微小脑异常相关。我们重新分析了两个队列的下一代测序（NGS）数据，其中包括1097个先证者，用于JS基因的基因检测。来自17个家庭（1.5%）的22例患者检测到杂合截断和剪接位点SUFU变异，其中男性患病率较高（86%），8例无症状父母。患者表现为昏迷、张力低下、共济失调和轻度DD，只有三分之一表现为不同程度的智力残疾。脑部MRI表现一致，表现为蚓部发育不全，小脑上部发育不良，小脑上部脚有轻微到轻度异常。同样的情况也出现在三分之二的无症状父母身上。杂合子截断或剪接位点SUFU变异引起一种新的神经发育综合征，包括昏迷和轻度JS，这可能代表重叠实体。变异可以从头产生，也可以从健康的父母那里遗传，这是JS的第一原因，具有显性遗传和外显率降低。对这种情况的认识将提高JS基因检测的诊断率，并允许对预后、医疗监测和复发风险进行适当的咨询。
Joubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%–75%. In 2018, we reported homozygous hypomorphic missense variants of the SUFU gene in two families with mild JS. Recently, heterozygous truncating SUFU variants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies. We reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes. Heterozygous truncating and splice-site SUFU variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents. Heterozygous truncating or splice-site SUFU variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk.
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影响因子：
1.9
作者：
Maria, BL;Hoang, KBN;Frerking, B
通讯作者：
Frerking, B
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