Cuppens Tania, Shatto Julie, Mangnier Loïc, Kumar Ajay A, Ng Andy Cheuk-Him, Kaur Manpreet, Bui Truong An, Leclercq Mickael, Droit Arnaud, Dunham Ian, Bolduc Francois V
Centre de Recherche du CHU de Québec-Université Laval, Département de Médecine Moléculaire de L'Université Laval, Québec, QC, Canada.
Department of Pediatric Neurology, University of Alberta, Edmonton, AB, Canada.
Front Pediatr. 2023 Aug 7;11:1172154. doi: 10.3389/fped.2023.1172154. eCollection 2023.
Gain a better understanding of sex-specific differences in individuals with global developmental delay (GDD), with a focus on phenotypes and genotypes.
Using the Deciphering Developmental Disorders (DDD) dataset, we extracted phenotypic information from 6,588 individuals with GDD and then identified statistically significant variations in phenotypes and genotypes based on sex. We compared genes with pathogenic variants between sex and then performed gene network and molecular function enrichment analysis and gene expression profiling between sex. Finally, we contrasted individuals with autism as an associated condition.
We identified significantly differentially expressed phenotypes in males vs. females individuals with GDD. Autism and macrocephaly were significantly more common in males whereas microcephaly and stereotypies were more common in females. Importantly, 66% of GDD genes with pathogenic variants overlapped between both sexes. In the cohort, males presented with only slightly increased X-linked genes (9% vs. 8%, respectively). Individuals from both sexes harbored a similar number of pathogenic variants overall (3) but females presented with a significantly higher load for GDD genes with high intolerance to loss of function. Sex difference in gene expression correlated with genes identified in a sex specific manner. While we identified sex-specific GDD gene mutations, their pathways overlapped. Interestingly, individuals with GDD but also co-morbid autism phenotypes, we observed distinct mutation load, pathways and phenotypic presentation.
Our study shows for the first time that males and females with GDD present with significantly different phenotypes. Moreover, while most GDD genes overlapped, some genes were found uniquely in each sex. Surprisingly they shared similar molecular functions. Sorting genes by predicted tolerance to loss of function (pLI) led to identifying an increased mutation load in females with GDD, suggesting potentially a tolerance to GDD genes of higher pLI compared to overall GDD genes. Finally, we show that considering associated conditions (for instance autism) may influence the genomic underpinning found in individuals with GDD and highlight the importance of comprehensive phenotyping.
更深入了解全球发育迟缓（GDD）个体的性别差异，重点关注表型和基因型。
利用发育障碍解析（DDD）数据集，我们从6588名GDD个体中提取表型信息，然后基于性别确定表型和基因型的统计学显著差异。我们比较了不同性别中具有致病变异的基因，然后进行基因网络和分子功能富集分析以及不同性别间的基因表达谱分析。最后，我们将患有自闭症作为相关病症的个体进行了对比。
我们在患有GDD的男性和女性个体中发现了显著差异表达的表型。自闭症和巨头畸形在男性中明显更常见，而小头畸形和刻板动作在女性中更常见。重要的是，66%具有致病变异的GDD基因在两性之间重叠。在该队列中，男性仅表现出X连锁基因略有增加（分别为9%和8%）。两性个体总体上携带的致病变异数量相似（3个），但女性对于功能丧失不耐受的GDD基因携带负荷显著更高。基因表达的性别差异与以性别特异性方式鉴定的基因相关。虽然我们鉴定出了性别特异性的GDD基因突变，但其途径重叠。有趣的是，对于患有GDD且伴有自闭症表型的个体，我们观察到了不同的突变负荷、途径和表型表现。
我们的研究首次表明，患有GDD的男性和女性表现出显著不同的表型。此外，虽然大多数GDD基因重叠，但在每个性别中都发现了一些独特的基因。令人惊讶的是，它们具有相似的分子功能。通过预测的功能丧失耐受性（pLI）对基因进行分类，导致在患有GDD的女性中鉴定出增加的突变负荷，这表明与总体GDD基因相比，女性可能对更高pLI的GDD基因具有耐受性。最后，我们表明考虑相关病症（例如自闭症）可能会影响在患有GDD的个体中发现的基因组基础，并突出了全面表型分析的重要性。
