Ramadesikan Swetha, Showpnil Iftekhar A, Marhabaie Mohammad, Daley Allison, Varga Elizabeth A, Gurusamy Umamaheswaran, Pastore Matthew T, Sites Emily R, Manickam Murugu, Bartholomew Dennis W, Hunter Jesse M, White Peter, Wilson Richard K, Stottmann Rolf W, Koboldt Daniel C
Steve and Cindy Rasmussen Institute for Genomic Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
Steve and Cindy Rasmussen Institute for Genomic Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
HGG Adv. 2025 Jan 9;6(1):100379. doi: 10.1016/j.xhgg.2024.100379. Epub 2024 Nov 4.
De novo variants in CSNK2A1 cause autosomal dominant Okur-Chung neurodevelopmental syndrome (OCNDS). OCNDS has an evolving clinical phenotype predominantly characterized by intellectual disability, global delays, dysmorphic features, and immunological manifestations. Microcephaly, defined as a small head circumference, is not widely recognized as a classical clinical presentation. Here, we describe four individuals from three unrelated families who shared several clinical features characteristic of an underlying syndromic neurodevelopmental condition. Trio clinical exome and research genome sequencing revealed that all affected individuals had heterozygous pathogenic missense variants in CSNK2A1. Two variants (c.468T>A p.Asp156Glu and c.149A>G p.Tyr50Cys) were de novo and previously reported, but the third variant (c.137G>T p.Gly46Val) is novel and segregated in two affected individuals in a family. This adds to growing evidence of inherited disease-causing variants in CSNK2A1, an observation reported only twice previously. A detailed phenotypic analysis of our cohort together with those individuals reported in the literature revealed that OCNDS individuals, on average, have a smaller head circumference with one-third presenting with microcephaly. We also show that the incidence of microcephaly is significantly correlated with the location of the variant in the encoded protein. Our findings suggest that small head circumference is a common but under-recognized feature of OCNDS, which may not be apparent at birth.
CSNK2A1基因的新生变异导致常染色体显性遗传的奥库尔-钟神经发育综合征（OCNDS）。OCNDS具有不断演变的临床表型，主要特征为智力残疾、全面发育迟缓、畸形特征和免疫表现。小头畸形（定义为头围小）并未被广泛认可为典型的临床表现。在此，我们描述了来自三个无关家庭的四名个体，他们具有一些潜在综合征性神经发育疾病的共同临床特征。三联体临床外显子组和研究基因组测序显示，所有受影响个体在CSNK2A1基因中均有杂合致病性错义变异。两个变异（c.468T>A p.Asp156Glu和c.149A>G p.Tyr50Cys）是新生的且先前已有报道，但第三个变异（c.137G>T p.Gly46Val）是新发现的，在一个家庭的两名受影响个体中呈分离状态。这进一步证明了CSNK2A1基因中存在导致疾病的遗传性变异，此前仅有两次相关报道。对我们队列以及文献中报道的个体进行的详细表型分析显示，OCNDS个体平均头围较小，三分之一的个体表现为小头畸形。我们还表明，小头畸形的发生率与编码蛋白中变异的位置显著相关。我们的研究结果表明，小头围是OCNDS常见但未被充分认识的特征，可能在出生时并不明显。
