Hypomyelinating leukodystrophies are genetically heterogeneous disorders with overlapping clinical and neuroimaging features reflecting variable abnormalities in myelin formation. We report on the identification of biallelic inactivating mutations in NKX6-2, a gene encoding a transcription factor regulating multiple developmental processes with a main role in oligodendrocyte differentiation and regulation of myelin-specific gene expression, as the cause underlying a previously unrecognized severe variant of hypomyelinating leukodystrophy. Five affected subjects (three unrelated families) were documented to share biallelic inactivating mutations affecting the NKX6-2 homeobox domain. A trio-based whole exome sequencing analysis in the first family detected a homozygous frameshift change [c.606delinsTA; p.(Lys202Asnfs*?)]. In the second family, homozygosity mapping coupled to whole exome sequencing identified a homozygous nucleotide substitution (c.565G>T) introducing a premature stop codon (p.Glu189*). In the third family, whole exome sequencing established compound heterozygosity for a non-conservative missense change affecting a key residue participating in DNA binding (c.599G>A; p.Arg200Gln) and a nonsense substitution (c.589C>T; p.Gln197*), in both affected siblings. The clinical presentation was homogeneous, with four subjects having severe motor delays, nystagmus and absent head control, and one individual showing gross motor delay at the age of 6 months. All exhibited neuroimaging that was consistent with hypomyelination. These findings define a novel, severe form of leukodystrophy caused by impaired NKX6-2 function.

中文翻译：

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NKX6-2同源域中的双等位基因突变是严重的低髓性白细胞营养不良的基础

降髓鞘性白细胞营养不良是遗传异质性疾病，具有重叠的临床和神经影像学特征，反映了髓鞘形成中的异常异常。我们报告了NKX6-2中双等位基因失活突变的鉴定，是一种编码转录因子的基因，该转录因子调控着多个发育过程，在少突胶质细胞分化和髓鞘特异性基因表达的调控中起主要作用，这是先前无法识别的低髓鞘性白细胞营养不良的严重变体的原因。五个受影响的对象（三个不相关的家庭）被记录为共享影响NKX6-2同源异型域的双等位基因失活突变。第一个家庭中基于三重奏的全外显子组测序分析检测到纯合的移码变化[c.606delinsTA; 第（Lys202Asnfs *？）]。在第二个家族中，纯合性作图与整个外显子组测序相结合，确定了纯合核苷酸取代（c.565G> T），该核苷酸引入了提前终止密码子（p.Glu189 *）。在第三家庭中 整个外显子组测序确定了一个非保守错义改变的复合杂合性，该改变影响参与DNA结合的关键残基（c.599G> A; p.Arg200Gln）和无义取代（c.589C> T; p.Gln197 *），都受影响的兄弟姐妹。临床表现均一，四名受试者有严重的运动延迟，眼球震颤和头部控制缺失，一名个体在6个月大时显示出明显的运动延迟。所有患者均表现出与髓鞘减少有关的神经影像学检查。这些发现确定了由NKX6-2功能受损引起的新的严重形式的白细胞营养不良。其中四名受试者有严重的运动延迟，眼球震颤和缺乏头部控制，一名个体在6个月大时显示出明显的运动延迟。所有患者均表现出与髓鞘减少有关的神经影像学检查。这些发现确定了由NKX6-2功能受损引起的新的严重形式的白细胞营养不良。其中四名受试者有严重的运动延迟，眼球震颤和缺乏头部控制，一名个体在6个月大时显示出明显的运动延迟。所有患者均表现出与髓鞘减少有关的神经影像学检查。这些发现确定了由NKX6-2功能受损引起的新的严重形式的白细胞营养不良。