BACKGROUND Phelan-McDermid syndrome (PMS) is a rare genetic disorder characterized by global developmental delay, intellectual disability (ID), autism spectrum disorder (ASD), and mild dysmorphisms associated with several comorbidities caused by SHANK3 loss-of-function mutations. Although SHANK3 haploinsufficiency has been associated with the major neurological symptoms of PMS, it cannot explain the clinical variability seen among individuals. Our goals were to characterize a Brazilian cohort of PMS individuals, explore the genotype-phenotype correlation underlying this syndrome, and describe an atypical individual with mild phenotype. METHODOLOGY A total of 34 PMS individuals were clinically and genetically evaluated. Data were obtained by a questionnaire answered by parents, and dysmorphic features were assessed via photographic evaluation. We analyzed 22q13.3 deletions and other potentially pathogenic copy number variants (CNVs) and also performed genotype-phenotype correlation analysis to determine whether comorbidities, speech status, and ASD correlate to deletion size. Finally, a Brazilian cohort of 829 ASD individuals and another independent cohort of 2297 ID individuals was used to determine the frequency of PMS in these disorders. RESULTS Our data showed that 21% (6/29) of the PMS individuals presented an additional rare CNV, which may contribute to clinical variability in PMS. Increased pain tolerance (80%), hypotonia (85%), and sparse eyebrows (80%) were prominent clinical features. An atypical case diagnosed with PMS at 18 years old and IQ within the normal range is here described. Among Brazilian ASD or ID individuals referred to CNV analyses, the frequency of 22q13.3 deletion was 0.6% (5/829) and 0.61% (15/2297), respectively. Finally, renal abnormalities, lymphedema, and language impairment were found to be positively associated with deletion sizes, and the minimum deletion to cause these abnormalities is here suggested. CONCLUSIONS This is the first work describing a cohort of Brazilian individuals with PMS. Our results confirm the impact of 22q13 deletions on ASD and several comorbidities, such as hypotonia. The estimation of a minimal deletion size for developing lymphedema and renal problem can assist prediction of prognosis in PMS individuals, particularly those diagnosed in early infancy. We also identified one atypical individual carrying SHANK3 deletion, suggesting that resilience to such mutations occurs. This case expands the clinical spectrum of variability in PMS and opens perspectives to identify protective mechanisms that can minimize the severity of this condition.

中文翻译：

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巴西人群Phelan-McDermid综合征的个体：基因型与表型的相关性以及非典型病例的鉴定。

背景技术Phelan-McDermid综合征（PMS）是一种罕见的遗传病，其特征是整体发育延迟，智力残疾（ID），自闭症谱系障碍（ASD）和与SHANK3功能丧失突变引起的多种合并症相关的轻度畸形。尽管SHANK3单倍功能不全与PMS的主要神经系统症状有关，但它不能解释个体之间的临床变异性。我们的目标是鉴定巴西PMS人群的特征，探索该综合征的基因型与表型的相关性，并描述具有轻度表型的非典型个体。方法论共对34名PMS患者进行了临床和遗传学评估。通过父母回答的问卷获得数据，并通过摄影评估来评估畸形特征。我们分析了22q13.3缺失和其他潜在的致病性拷贝数变异（CNV），还进行了基因型与表型的相关性分析，以确定合并症，言语状态和ASD是否与缺失大小相关。最后，巴西队列的829名ASD个体和另一个独立队列的2297名ID个体被用于确定这些疾病中PMS的发生频率。结果我们的数据显示，有21％（6/29）的PMS患者出现了额外的罕见CNV，这可能与PMS的临床变异性有关。疼痛耐受性增加（80％），肌张力低下（85％）和眉毛稀疏（80％）是突出的临床特征。本文介绍了18岁时诊断为PMS且智商在正常范围内的非典型病例。在涉及CNV分析的巴西ASD或ID个人中，频率为22q13。3缺失分别为0.6％（5/829）和0.61％（15/2297）。最后，发现肾脏异常，淋巴水肿和语言障碍与缺失大小呈正相关，并在此建议了引起这些异常的最小缺失。结论这是描述巴西PMS人群的第一篇著作。我们的结果证实了22q13缺失对ASD和几种合并症（如肌张力低下）的影响。估计发生淋巴水肿和肾脏问题的最小缺失大小可以帮助预测PMS患者的预后，尤其是那些在婴儿早期诊断的患者。我们还确定了一个携带SHANK3缺失的非典型个体，表明发生了对此类突变的适应性。