Phenome-wide profiling identifies genotype-phenotype associations in Phelan-McDermid syndrome using family-sourced data from an international registry.

IF 6.3 1区 医学 Q1 GENETICS & HEREDITY
Rui Yin, Maxime Wack, Claire Hassen-Khodja, Michael T McDuffie, Geraldine Bliss, Elizabeth J Horn, Cartik Kothari, Brittany McLarney, Rebecca Davis, Kristen Hanson, Megan O'Boyle, Catalina Betancur, Paul Avillach
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引用次数: 0

Abstract

Background: 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.

Methods: 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.

Results: 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.

Limitations: 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.

Conclusions: 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.

利用来自国际登记处的家族数据,全表型分析确定了佩兰-麦克德米综合征的基因型与表型之间的关联。
背景:Phelan-McDermid综合征(PMS)是一种罕见的神经发育障碍性疾病,由包括SHANK3基因的22q13缺失或SHANK3的致病序列变异引起。其特征为全身发育迟缓、智力障碍、语言障碍、自闭症谱系障碍和肌张力低下;其他可变特征包括癫痫、脑和肾畸形以及轻度畸形特征。在此,我们利用 PMS 国际登记处进行了基因型与表型的相关性分析。PMS 国际登记处是一个由家庭驱动的登记处,以家庭报告结果和家庭提供的基因检测结果的形式汇编临床数据:方法:对登记处的数据进行了统一,并将其整合到 i2b2/tranSMART 临床和基因组学数据仓库中。我们收集了 401 例 22q13 缺失个体的信息,其中包括 SHANK3(n = 350,大小从 10 kb 到 9.1 Mb 不等)或致病性或可能致病的 SHANK3 序列变异(n = 51),并使用回归模型将缺失大小作为 328 种表型临床结果的潜在预测因子:我们的研究结果表明,基因缺失大小的增加与粗大运动和精细运动发育迟缓、一系列与肌肉张力差、肾脏畸形、轻度畸形特征(如大肉手、骶骨凹陷、趾甲发育不良、超常牙齿)、淋巴水肿、先天性心脏缺陷以及更常见的神经影像异常和感染有显著相关性。这些研究结果表明,SHANK3 上游的基因也会导致有较大缺失的个体出现经前期综合征的某些表现。我们还发现,在较小缺失和SHANK3变异的个体中,自助技能、语言能力和一系列精神疾病(如自闭症、多动症、焦虑症)的诊断更为常见:局限性:一些参与者使用靶向 22q 芯片而非全基因组芯片进行检测,许多病例无法获得核型,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:这是目前所报道的最大的 PMS 患者病例系列。总之,我们证明了利用来自家庭的登记数据对罕见遗传疾病进行基因型-表型分析的可行性。我们复制并加强了之前的研究结果,并揭示了较大的 22q13 缺失与先天性心脏缺陷、神经影像异常和反复感染之间的新关联。
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来源期刊
Molecular Autism
Molecular Autism GENETICS & HEREDITY-NEUROSCIENCES
CiteScore
12.10
自引率
1.60%
发文量
44
审稿时长
17 weeks
期刊介绍: Molecular Autism is a peer-reviewed, open access journal that publishes high-quality basic, translational and clinical research that has relevance to the etiology, pathobiology, or treatment of autism and related neurodevelopmental conditions. Research that includes integration across levels is encouraged. Molecular Autism publishes empirical studies, reviews, and brief communications.
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