Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
CAPES Foundation, Ministry of Education of Brazil, Brasília, Brazil.
Mol Genet Genomic Med. 2019 Oct;7(10):e00861. doi: 10.1002/mgg3.861. Epub 2019 Aug 15.
Eight different deletions and point variants of the X-chromosomal gene CNKSR2 have been reported in families with males presenting intellectual disability (ID) and epilepsy. Obligate carrier females with a frameshift variant in the N-terminal protein coding part of CNKSR2 or with a deletion of the complete gene are not affected. Only for one C-terminal nonsense variant, two carrier females were mildly affected by seizures without or with mild motor and language delay.
Exome sequencing was performed in one female child of a Dutch family, presenting seizures, mild ID, facial dysmorphisms, and abnormalities of the extremities. Potential causative variants were validated by Sanger sequencing. X-chromosome-inactivation (XCI) analysis was performed by methylation-sensitive PCR and fragment-length analysis of the androgen-receptor CAG repeat polymorphism.
We identified a de novo variant, c.2304G>A (p.(Trp768*)), in the C-terminal protein coding part of the X-chromosomal gene CNKSR2 in a female patient with seizures and mild ID. Sanger sequencing confirmed the presence of this nonsense variant. XCI analysis showed a mild skewing of X inactivation (20:80) in the blood of our patient. Our variant is the second C-terminal-affecting CNKSR2 variant described in neurologically affected females.
Our results indicate that CNKSR2 nonsense variants in the C-terminal coding part can result in ID with seizures in female variant carriers.
已在伴有男性智力障碍（ID）和癫痫的家系中报道了 X 染色体基因 CNKSR2 的 8 种不同缺失和点变异。具有 CNKSR2 N 末端蛋白编码部分移码变异或完整基因缺失的强制性携带者女性不受影响。只有一种 C 末端无义变异，两名携带者女性受癫痫影响轻微，或伴有轻微的运动和语言延迟。
对一名荷兰家族中表现为癫痫、轻度 ID、面型异常和四肢异常的女性儿童进行外显子组测序。通过 Sanger 测序验证潜在的致病变异。通过甲基化敏感 PCR 和雄激素受体 CAG 重复多态性的片段长度分析进行 X 染色体失活（XCI）分析。
我们在一名患有癫痫和轻度 ID 的女性患者的 X 染色体基因 CNKSR2 的 C 末端蛋白编码部分发现了一个新的变异 c.2304G>A（p.(Trp768*)）。Sanger 测序证实了该无义变异的存在。XCI 分析显示我们患者血液中的 X 失活存在轻微偏斜（20:80）。我们的变异是第二个影响 CNKSR2 的 C 末端变异，在神经受累的女性中描述过。
我们的结果表明，CNKSR2 在 C 末端编码区的无义变异可导致女性变异携带者的 ID 伴癫痫。
