Department of Biomedical Informatics, Harvard Medical School, Boston, MA, 02115, USA.
Department of Health Outcomes and Biomedical Informatics, University of Florida, Gainesville, FL, USA.
Mol Autism. 2024 Sep 30;15(1):40. doi: 10.1186/s13229-024-00619-z.
Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by 22q13 deletions that include the SHANK3 gene or pathogenic sequence variants in SHANK3. It is characterized by global developmental delay, intellectual disability, speech impairment, autism spectrum disorder, and hypotonia; other variable features include epilepsy, brain and renal malformations, and mild dysmorphic features. Here, we conducted genotype-phenotype correlation analyses using the PMS International Registry, a family-driven registry that compiles clinical data in the form of family-reported outcomes and family-sourced genetic test results.
Data from the registry were harmonized and integrated into the i2b2/tranSMART clinical and genomics data warehouse. We gathered information from 401 individuals with 22q13 deletions including SHANK3 (n = 350, ranging in size from 10 kb to 9.1 Mb) or pathogenic or likely pathogenic SHANK3 sequence variants (n = 51), and used regression models with deletion size as a potential predictor of clinical outcomes for 328 phenotypes.
Our results showed that increased deletion size was significantly associated with delay in gross and fine motor acquisitions, a spectrum of conditions related to poor muscle tone, renal malformations, mild dysmorphic features (e.g., large fleshy hands, sacral dimple, dysplastic toenails, supernumerary teeth), lymphedema, congenital heart defects, and more frequent neuroimaging abnormalities and infections. These findings indicate that genes upstream of SHANK3 also contribute to some of the manifestations of PMS in individuals with larger deletions. We also showed that self-help skills, verbal ability and a range of psychiatric diagnoses (e.g., autism, ADHD, anxiety disorder) were more common among individuals with smaller deletions and SHANK3 variants.
Some participants were tested with targeted 22q microarrays rather than genome-wide arrays, and karyotypes were unavailable in many cases, thus precluding the analysis of the effect of other copy number variants or chromosomal rearrangements on the phenotype.
This is the largest reported case series of individuals with PMS. Overall, we demonstrate the feasibility of using data from a family-sourced registry to conduct genotype-phenotype analyses in rare genetic disorders. We replicate and strengthen previous findings, and reveal novel associations between larger 22q13 deletions and congenital heart defects, neuroimaging abnormalities and recurrent infections.
Phelan-McDermid 综合征（PMS）是一种由 22q13 缺失引起的罕见神经发育障碍，这些缺失包括 SHANK3 基因或 SHANK3 中的致病性序列变异。其特征为全面发育迟缓、智力障碍、言语障碍、自闭症谱系障碍和张力减退；其他可变特征包括癫痫、脑和肾脏畸形以及轻度畸形特征。在这里，我们使用 PMS 国际注册处进行了基因型-表型相关性分析，该注册处是一个由家庭驱动的注册处，以家庭报告的结果和家庭来源的基因检测结果的形式汇编临床数据。
从注册处收集的数据经过协调并整合到 i2b2/tranSMART 临床和基因组学数据仓库中。我们从 401 名 22q13 缺失患者（包括 SHANK3[n=350，缺失大小为 10kb 至 9.1Mb]或致病性或可能致病性 SHANK3 序列变异[n=51]）中收集信息，并使用回归模型，将缺失大小作为 328 种表型的临床结果的潜在预测因子。
我们的结果表明，缺失大小的增加与粗大运动和精细运动发育延迟、一系列与肌肉张力差相关的疾病、肾脏畸形、轻度畸形特征（例如，大而多肉的手、骶骨凹陷、发育不良的脚趾甲、额外的牙齿）、淋巴水肿、先天性心脏缺陷以及更频繁的神经影像学异常和感染有关。这些发现表明，SHANK3 上游的基因也与较大缺失个体的 PMS 一些表现有关。我们还表明，较小缺失和 SHANK3 变异的个体中，自助技能、语言能力和一系列精神科诊断（例如，自闭症、ADHD、焦虑障碍）更为常见。
一些参与者接受了靶向 22q 微阵列检测，而不是全基因组阵列检测，许多情况下没有核型分析，因此无法分析其他拷贝数变异或染色体重排对表型的影响。
这是迄今为止报道的最大的 PMS 病例系列。总的来说，我们证明了使用源自家庭的注册处的数据进行罕见遗传疾病的基因型-表型分析是可行的。我们复制和加强了以前的发现，并揭示了较大的 22q13 缺失与先天性心脏缺陷、神经影像学异常和反复感染之间的新关联。
