School of Basic Sciences, Universidad del Valle, Cali, Colombia.
School of Medicine, Universidad del Valle, Cali, Colombia.
J Dev Behav Pediatr. 2020 Dec;41(9):724-728. doi: 10.1097/DBP.0000000000000850.
Fragile X syndrome (FXS) is an X-linked genetic disorder caused by the absence of the fragile X mental retardation 1 protein. FXS is the most common inherited cause of intellectual disability and autism spectrum disorder (ASD). Approximately 60% of subjects with FXS present with ASD, and 2% to 4% of individuals diagnosed with ASD have FXS. Most individuals with ASD have a genetic disorder, so detailed molecular testing of individuals with ASD is medically indicated. Deletions of the protein patched homolog 1 antisense (PTCHD1-AS) gene have been associated with ASD. Here, we describe, for the first time, a boy with FXS because of a point mutation in the FMR1 gene and autism, and the latter comorbidity of ASD is likely because of a deletion of PTCHD1-AS. Thus, the observed phenotype of FXS with severe autism symptoms is likely caused by a double hit of genetic mutations.
The case is a 5-year-old boy with phenotypic characteristics of FXS. The psychological assessment based on parent report and the Autism Diagnostic Observation Schedule, Second Edition identified severe difficulties on every item of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnostic criteria for ASD, with language impairment, anxiety, attention, and affective problems. Exome sequencing identified a de novo pathogenic variant in the FMR1 gene c.229delT (p.Cys77Alafs*5) and, coupled with comparative genomic hybridization, also diagnosed a maternally inherited partial deletion of the PTCHD1-AS gene.
Fragile X syndrome presents with clinical features in virtually all affected men, predominantly intellectual disability. However, there are other comorbidities present in a subset of patients, including ASD. We propose that the variable expressivity in FXS could be partially explained by the additive effect of a second genetic mutation that increases the individual susceptibility to the unique phenotypic findings, as is the case of the patient described here.
脆性 X 综合征（FXS）是一种由脆性 X 智力低下蛋白 1 缺失引起的 X 连锁遗传性疾病。FXS 是最常见的遗传性智力障碍和自闭症谱系障碍（ASD）病因。大约 60%的 FXS 患者存在 ASD，而 2%至 4%的 ASD 患者存在 FXS。大多数 ASD 患者存在遗传疾病，因此对 ASD 患者进行详细的分子检测在医学上是有意义的。蛋白 patched 同源物 1 反义（PTCHD1-AS）基因缺失与 ASD 相关。在这里，我们首次描述了一名男孩，他因 FMR1 基因的点突变和自闭症而患有 FXS，后者 ASD 的合并症可能是由于 PTCHD1-AS 的缺失。因此，观察到的 FXS 伴有严重自闭症症状的表型可能是由遗传突变的双重打击引起的。
该病例为一名 5 岁男孩，具有 FXS 的表型特征。基于家长报告和自闭症诊断观察量表第二版的心理评估确定了 ASD 诊断标准第五版诊断标准的每个项目都存在严重困难，伴有语言障碍、焦虑、注意力和情感问题。外显子组测序发现 FMR1 基因 c.229delT（p.Cys77Alafs*5）的新生致病性变异，结合比较基因组杂交技术，还诊断出 PTCHD1-AS 基因的母系遗传部分缺失。
脆性 X 综合征在几乎所有受影响的男性中都表现出临床特征，主要是智力障碍。然而，在一部分患者中存在其他合并症，包括 ASD。我们提出，FXS 的可变表达可能部分解释为第二个遗传突变的附加效应，增加了个体对独特表型发现的易感性，就像这里描述的患者一样。
