Phenotypic spectrum associated with CASK loss-of-function mutations
Phenotypic spectrum associated with CASK loss-of-function mutations
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DOI：
10.1136/jmedgenet-2011-100218
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发表时间：
2011-11-01
影响因子：
4
通讯作者：
Uyanik, Goekhan
中科院分区：
文献类型：
--
作者：
Moog, Ute;Kutsche, Kerstin;Uyanik, Goekhan
背景CASK基因在Xp11.4杂合突变已被证明与一个独特的脑畸形表型的女性，包括不成比例的脑桥和小脑发育不全，方法本研究的特点是在20个新的女性患者的CASK改变分子核型分析，荧光原位杂交，测序，逆转录酶（RT）和/或定量实时PCR。结果共报告11例亚显微拷贝数改变，包括9例11 kb ~ 4.5Mb的缺失，2例重复，均覆盖部分CASK，4例剪接，4例无义，1例1bp缺失。这些杂合CASK突变最可能导致无效等位基因。脑成像始终显示弥漫性脑干和小脑发育不全伴第四脑室扩张，但程度差异显著。对本研究中的20例患者和5例先前报告的患者进行分析，发现核心临床表型包括重度发育迟缓/智力残疾、重度出生后小头畸形（通常与生长迟缓相关）、（轴向）张力减退伴或不伴四肢张力亢进、视神经发育不全和/或其他眼部异常。一个可识别的面部表型出现，包括突出和广泛的鼻梁和鼻尖，小或短鼻子，长人中，小下巴，和/或大ears.Conclusions这些发现定义的表型谱与CASK功能丧失突变。发育和脑成像特征与轻度面部畸形的结合高度提示这种疾病，并应提示随后的CASK基因检测。
Background Heterozygous mutations in the CASK gene in Xp11.4 have been shown to be associated with a distinct brain malformation phenotype in females, including disproportionate pontine and cerebellar hypoplasia.Methods The study characterised the CASK alteration in 20 new female patients by molecular karyotyping, fluorescence in situ hybridisation, sequencing, reverse transcriptase (RT) and/or quantitative real-time PCR. Clinical and brain imaging data of a total of 25 patients were reviewed.Results 11 submicroscopic copy number alterations, including nine deletions of similar to 11 kb to 4.5 Mb and two duplications, all covering (part of) CASK, four splice, four nonsense, and one 1 bp deletion are reported. These heterozygous CASK mutations most likely lead to a null allele. Brain imaging consistently showed diffuse brainstem and cerebellar hypoplasia with a dilated fourth ventricle, but of remarkably varying degrees. Analysis of 20 patients in this study, and five previously reported patients, revealed a core clinical phenotype comprising severe developmental delay/intellectual disability, severe postnatal microcephaly, often associated with growth retardation, (axial) hypotonia with or without hypertonia of extremities, optic nerve hypoplasia, and/or other eye abnormalities. A recognisable facial phenotype emerged, including prominent and broad nasal bridge and tip, small or short nose, long philtrum, small chin, and/or large ears.Conclusions These findings define the phenotypic spectrum associated with CASK loss-of-function mutations. The combination of developmental and brain imaging features together with mild facial dysmorphism is highly suggestive of this disorder and should prompt subsequent testing of the CASK gene.