Mutation in ZDHHC15 Leads to Hypotonic Cerebral Palsy, Autism, Epilepsy, and Intellectual Disability.
Mutation in ZDHHC15 Leads to Hypotonic Cerebral Palsy, Autism, Epilepsy, and Intellectual Disability.
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DOI：
10.1212/nxg.0000000000000602
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发表时间：
2021-08
期刊：
影响因子：
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通讯作者：
Kruer MC
中科院分区：
文献类型：
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作者：
Lewis SA;Bakhtiari S;Heim J;Cornejo P;Liu J;Huang A;Musmacker A;Jin SC;Bilguvar K;Padilla-Lopez SR;Kruer MC
为了确定ZDHHC 15报告的突变是否会导致混合性神经发育障碍，我们在动物模型中对变体致病性和ZDHHC 15功能进行了功能研究。我们在酵母互补试验中检测了ZDHHC 15中4种已鉴定变体的蛋白质功能，并在果蝇模型中检测了功能缺失基因型的运动缺陷。虽然我们评估了多种患者变体，但只有1种（p.H158R）影响蛋白质功能。我们报告一个诊断为低张性脑性麻痹、自闭症、癫痫和智力残疾的患者，与这种真正的破坏性X连锁变异有关。特征包括高额伴轻度短头畸形、下斜睑裂、大耳、长脸、面部肌肉张力减退、高弓腭伴牙齿拥挤和蜘蛛状指。患者有轻度脑容量减少，左侧T2/FLAIR高信号房周卵圆形病变。我们发现，该基因的直系同源物中的功能缺失突变导致果蝇的飞行和协调运动缺陷。我们的研究结果支持该基因的功能扩展到运动功能障碍中的作用。虽然ZDHHC 15突变代表了神经发育障碍的罕见原因，但在确定致病性之前，需要仔细评估候选变体。
To determine whether mutations reported for ZDHHC15 can cause mixed neurodevelopmental disorders, we performed both functional studies on variant pathogenicity and ZDHHC15 function in animal models. We examined protein function of 4 identified variants in ZDHHC15 in a yeast complementation assay and locomotor defects of loss-of-function genotypes in a Drosophila model. Although we assessed multiple patient variants, only 1 (p.H158R) affected protein function. We report a patient with a diagnosis of hypotonic cerebral palsy, autism, epilepsy, and intellectual disability associated with this bona fide damaging X-linked variant. Features include tall forehead with mild brachycephaly, down-slanting palpebral fissures, large ears, long face, facial muscle hypotonia, high-arched palate with dental crowding, and arachnodactyly. The patient had mild diminished cerebral volume, with left-sided T2/FLAIR hyperintense periatrial ovoid lesion. We found that loss-of-function mutations in orthologs of this gene cause flight and coordinated movement defects in Drosophila. Our findings support a functional expansion of this gene to a role in motor dysfunction. Although ZDHHC15 mutations represent a rare cause of neurodevelopmental disability, candidate variants need to be carefully assessed before pathogenicity can be determined.