Department of Biomedical and Biotechnological Sciences, Medical Genetics, University of Catania, Catania, Italy.
Oasi Research Institute-IRCCS, Troina, Italy.
Genes Genomics. 2023 Apr;45(4):491-505. doi: 10.1007/s13258-023-01369-7. Epub 2023 Feb 20.
Individuals with the 2p15p16.1 microdeletion syndrome share a complex phenotype including neurodevelopmental delay, brain malformations, microcephaly, and autistic behavior. The analysis of the shortest region of overlap (SRO) between deletions in ~ 40 patients has led to the identification of two critical regions and four strongly candidate genes (BCL11A, REL, USP34 and XPO1). However, the delineation of their role in the occurrence of specific traits is hampered by their incomplete penetrance.
To better delineate the role of hemizygosity of specific regions in selected traits by leveraging information both from penetrant and non - penetrant deletions.
Deletions in patients that do not present a specific trait cannot contribute to delineate the SROs. We recently developed a probabilistic model that, by considering also the non - penetrant deletions, allows a more reliable assignment of peculiar traits to specific genomic segments. We apply this method adding two new patients to the published cases.
Our results delineate an intricate pattern of genotype - phenotype correlation where BCL11A emerges as the main gene for autistic behavior while USP34 and/or XPO1 haploinsufficiency are mainly associated with microcephaly, hearing loss and IUGR. BCL11A, USP34 and XPO1 genes are broadly related with brain malformations albeit with distinct patterns of brain damage.
The observed penetrance of deletions encompassing different SROs and that predicted when considering each single SRO as acting independently, may reflect a more complex model than the additive one. Our approach may improve the genotype/phenotype correlation and may help to identify specific pathogenic mechanisms in contiguous gene syndromes.
2p15p16.1 微缺失综合征患者具有复杂的表型，包括神经发育迟缓、脑畸形、小头畸形和自闭症行为。对~40 名患者缺失的最短重叠区域（SRO）的分析导致了两个关键区域和四个强候选基因（BCL11A、REL、USP34 和 XPO1）的鉴定。然而，由于其不完全外显率，它们在特定特征发生中的作用的描述受到阻碍。
通过利用外显和非外显缺失的信息，更好地描述特定区域的半合性在选定特征中的作用。
未表现出特定特征的患者的缺失不能有助于描绘 SRO。我们最近开发了一种概率模型，通过考虑非外显缺失，更可靠地将特殊特征分配给特定的基因组片段。我们应用这种方法，将两名新患者加入到已发表的病例中。
我们的结果描绘了一种复杂的基因型-表型相关性模式，其中 BCL11A 是自闭症行为的主要基因，而 USP34 和/或 XPO1 单倍不足主要与小头畸形、听力损失和 IUGR 相关。尽管存在不同的脑损伤模式，但 BCL11A、USP34 和 XPO1 基因与脑畸形广泛相关。
包含不同 SRO 的缺失的观察外显率以及考虑每个单独 SRO 作为独立作用时预测的外显率，可能反映出比加性模型更复杂的模型。我们的方法可以提高基因型/表型相关性，并有助于识别连续基因综合征中的特定致病机制。
