Abstract：
Pettigrew syndrome (PGS), an X-linked intellectual disability (XLID), is caused by mutations in the AP1S2 gene. Herein, we described a Thai family with six patients who had severe-to-profound intellectual impairment, limited verbal communication, and varying degrees of limb spasticity. One patient had a unilateral cataract. We demonstrated facial evolution over time, namely coarse facies, long faces, and thick lip vermilions. We identified a novel AP1S2 variant, c.1-2A>G. The mRNA analysis revealed that the variant resulted in splicing defects with leaky splicing, yielding two distinct aberrant transcripts, one of which likely resulting in the mutant protein lacking the first 44 amino acids whereas the other possibly leading to no production of the protein. By performing a literature review, we found 51 patients and 11 AP1S2 pathogenic alleles described and that all the variants were loss-of-function alleles. The severity of ID in Pettigrew syndrome is mostly severe-to-profound (54.8%), followed by moderate (26.2%) and mild. Progressive spasticity was noted in multiple patients. In summary, leaky splicing found in the present family was likely related to the intrafamilial clinical variability. Our data also support the previous notion of variable expression and neuroprogressive nature of the disorder.
摘要：
Pettigrew综合征（PGS），与X相关的智力残疾(XLID)，是由AP1S2基因突变引起的.在这里，我们描述了一个泰国家庭，有六名患者患有严重到严重的智力障碍，有限的口头交流，不同程度的肢体痉挛.一名患者患有单侧白内障。我们展示了随着时间的推移面部进化，即粗糙相，长脸,和厚厚的嘴唇朱红色。我们鉴定了一个新的AP1S2变体，c.1-2A>G.mRNA分析表明，该变体导致剪接缺陷与泄漏剪接，产生两个不同的异常转录本，其中一个可能导致缺乏前44个氨基酸的突变蛋白，而另一个可能导致不产生蛋白。通过文献综述，我们发现51例患者和11个描述的AP1S2致病等位基因,并且所有变异均为功能缺失等位基因.Pettigrew综合征中ID的严重程度大多为严重至严重（54.8%），其次是中度（26.2%）和轻度。在多个患者中发现进行性痉挛。总之,在本家族中发现的泄漏剪接可能与家族内临床变异性有关。我们的数据也支持以前关于该疾病的可变表达和神经进行性的概念。
