Proximal variants in CCND2 associated with microcephaly, short stature, and developmental delay: A case series and review of inverse brain growth phenotypes.
Proximal variants in CCND2 associated with microcephaly, short stature, and developmental delay: A case series and review of inverse brain growth phenotypes.
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与小头畸形、身材矮小和发育迟缓相关的CCND2近端变异：一个病例系列和反向脑生长表型的回顾
DOI：
10.1002/ajmg.a.62362
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Mirzaa GM
中科院分区：
文献类型：
--
作者：
Pirozzi F;Lee B;Horsley N;Burkardt DD;Dobyns WB;Graham JM Jr;Dentici ML;Cesario C;Schallner J;Porrmann J;Di Donato N;Sanchez-Lara PA;Mirzaa GM
细胞周期蛋白D2（CCND 2）是一种重要的细胞周期调节因子，是细胞周期蛋白D2-CDK 4（DC）复合物的关键成员。聚集在蛋白质远端部分的CCND 2的新生变体已被鉴定为儿童脑过度生长（巨脑畸形，MEG）和严重皮质畸形（包括巨脑-多小脑回-多指-脑积水（MPPH）综合征）的致病原因。巨脑相关的CCND 2变异体定位于末端外显子，并导致耐降解蛋白的积累。我们从三个不相关的家族中发现了五个个体，这些个体在CCND 2近端区域具有新的变异，这些变异与小头畸形、轻度简化的皮质脑回模式、对称性身材矮小和轻度发育迟缓相关。鉴定的变体包括从头移码变体和与表型分离的显性遗传停止增益变体。据我们所知，这是第一次报道近端CCND 2变异与小头畸形之间的关联。该系列扩展了CCND 2相关疾病的表型谱，并表明不同类别的CCND 2变体与人类大脑生长的相互作用（分别由于蛋白质功能的可能丧失或获得而导致的小头畸形和巨脑畸形）相关，增加了由于关键脑生长基因失调而导致的反向表型的增长范式。
Cyclin D2 (CCND2) is a critical cell cycle regulator and key member of the cyclin D2-CDK4 (DC) complex. De novo variants of CCND2 clustering in the distal part of the protein have been identified as pathogenic causes of brain overgrowth (megalencephaly, MEG) and severe cortical malformations in children including the megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome. Megalencephaly-associated CCND2 variants are localized to the terminal exon and result in accumulation of degradation-resistant protein. We identified five individuals from three unrelated families with novel variants in the proximal region of CCND2 associated with microcephaly, mildly simplified cortical gyral pattern, symmetric short stature, and mild developmental delay. Identified variants include de novo frameshift variants and a dominantly inherited stop-gain variant segregating with the phenotype. This is the first reported association between proximal CCND2 variants and microcephaly, to our knowledge. This series expands the phenotypic spectrum of CCND2-related disorders and suggests that distinct classes of CCND2 variants are associated with reciprocal effects on human brain growth (microcephaly and megalencephaly due to possible loss or gain of protein function, respectively), adding to the growing paradigm of inverse phenotypes due to dysregulation of key brain growth genes.
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