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.

为了确定报告的ZDHHC15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异致病性和 ZDHHC15 功能进行了功能研究。

我们在酵母互补测定中检查了 ZDHHC15 中 4 个已识别变体的蛋白质功能，并在果蝇模型中检查了功能丧失基因型的运动缺陷。

尽管我们评估了多个患者变体，但只有 1 个 (p.H158R) 影响了蛋白质功能。我们报告了一名诊断为低渗性脑瘫、自闭症、癫痫和智力障碍的患者，这些患者与这种真正的破坏性 X 连锁变异相关。特征包括高额头伴轻度短头畸形、下斜睑裂、大耳朵、长脸、面部肌肉张力减退、高拱形上颚伴牙齿拥挤和蜘蛛指。患者脑容量轻度减少，左侧 T2/FLAIR 高信号围房卵圆形病变。我们发现该基因直系同源物的功能丧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在运动功能障碍中发挥作用的功能扩展。尽管ZDHHC15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异。