Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities.
Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities.
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MBD5的破坏有助于一系列精神病理学和神经发育异常。
DOI：
10.1038/mp.2013.42
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发表时间：
2014-03
影响因子：
11
通讯作者：
Talkowski ME
中科院分区：
文献类型：
--
作者：
Hodge JC;Mitchell E;Pillalamarri V;Toler TL;Bartel F;Kearney HM;Zou YS;Tan WH;Hanscom C;Kirmani S;Hanson RR;Skinner SA;Rogers RC;Everman DB;Boyd E;Tapp C;Mullegama SV;Keelean-Fuller D;Powell CM;Elsea SH;Morton CC;Gusella JF;DuPont B;Chaubey A;Lin AE;Talkowski ME
破坏 MBD5 的染色体区域 2q23.1 的微缺失会导致一系列神经发育表型，但该基因座对人类精神病理学的影响尚未描述。为了表征 MBD5 破坏的结构变异景观和相关的精神病理学，通过全基因组测序或细胞基因组微阵列在 11 个分子诊断中心鉴定了 22 名患有 MBD5 基因组破坏（易位、点突变和缺失）的个体。基因组影响范围从单个碱基对到 5.4 Mb。 11 个病例的父母都在场，所有这些病例都证实了重组是从头开始的。具有全段 2q23.1 缺失的患者和具有基因内 MBD5 重排（包括完全局限于 5'UTR 的改变）的患者之间的表型在很大程度上无法区分，这证实了该位点非编码序列的关键影响。我们发现了 MBD5 破坏的异质性、多系统致病效应，并表征了相关的精神病理学谱，包括感觉统合障碍、焦虑、自我拥抱、双相情感障碍等。重要的是，接受评估的最年长患者的独特特征是早发性痴呆和行为倒退。分析还揭示了将 MBD5 破坏与七种具有显着诊断重叠的既定综合征区分开来的表型。这项研究表明，MBD5 的单倍体不足会导致不同的表型，深入了解由此产生的神经发育和行为精神病理学的范围，并为解释 MBD5 结构变异提供临床背景。经验证据还表明，非编码 MBD5 调控区域的破坏足以引起临床表现，凸显了以外显子为中心的评估的局限性。这些结果表明，在整个生命周期中，神经功能持续受到干扰，包括神经行为退化和早发性痴呆的风险。
Microdeletions of chromosomal region 2q23.1 that disrupt MBD5 contribute to a spectrum of neurodevelopmental phenotypes, however the impact of this locus in human psychopathology has not been described. To characterize the structural variation landscape of MBD5 disruptions and the associated psychopathology, 22 individuals with genomic disruption of MBD5 (translocation, point mutation, and deletion) were identified through whole-genome sequencing or cytogenomic microarray at 11 molecular diagnostic centers. The genomic impact ranged from a single base pair to 5.4 Mb. Parents were available for 11 cases, all of which confirmed the rearrangement arose de novo. Phenotypes were largely indistinguishable between patients with full-segment 2q23.1 deletions and those with intragenic MBD5 rearrangements, including alterations confined entirely to the 5′UTR, confirming the critical impact of non-coding sequence at this locus. We found heterogeneous, multi-system pathogenic effects of MBD5 disruption and characterized the associated spectrum of psychopathology, which includes sensory integration disorder, anxiety, self-hugging, bipolar disorder and others. Importantly, unique features of the oldest assessed patient were early-onset dementia and behavioral regression. Analyses also revealed phenotypes that distinguish MBD5 disruptions from seven well-established syndromes with significant diagnostic overlap. This study indicates that haploinsufficiency of MBD5 causes diverse phenotypes, yields insight into the spectrum of resulting neurodevelopmental and behavioral psychopathology, and provides clinical context for interpretation of MBD5 structural variations. Empirical evidence also suggests that disruption of non-coding MBD5 regulatory regions is sufficient for clinical manifestation, highlighting the limitations of exon-focused assessments. These results suggest an ongoing perturbation of neurological function throughout the lifespan, including risks for neurobehavioral regression and early-onset dementia.