Abstract：
BACKGROUND: Piebaldism is a rare autosomal dominant disorder characterized by congenital white forelock and depigmented patches, which is most commonly caused by deleterious variants in the KIT gene.
METHODS: Four KIT variants were identified in a piebaldism case series by whole-exome sequencing. Functional experiments, including in vitro minigene reporter assay and enzyme-linked immunosorbent assay, were carried out to elucidate the pathogenicity of the variants. The genotype-phenotype correlation was summarized through extensive literature reviewing.
RESULTS: All the four cases had severe piebaldism presented with typical white forelock and diffuse depigmentation on the ventral trunk and limbs. Four germline variants at the tyrosine kinase (TK) domains of the KIT gene were identified: two novel variants c.1990+1G>A (p.Pro627_Gly664delinsArg) and c.2716T>C (p.Cys906Arg), and two known variants c.1879+1G>A (p.Gly592_Pro627delinsAla) and c.1747G>A (p.Glu583Lys). Both splicing variants caused exon skipping and inframe deletions in the TK1 domain. The missense variants resided at the TK1 and TK2 domains respectively impairing PI3K/AKT and MAPK/ERK signaling pathways, the downstream of KIT. All severe cases were associated with variants in the TK domains, eliciting a major dominant-negative mechanism of the disease.
CONCLUSIONS: Our data expand the mutation spectrum of KIT, emphasized by a dominant-negative effect of variants in the critical TK domains in severe cases. We also share the experience of prenatal diagnosis and informed reproductive choices for the affected families.
METHODS: Four KIT variants were identified in a piebaldism case series by whole-exome sequencing. Functional experiments, including in vitro minigene reporter assay and enzyme-linked immunosorbent assay, were carried out to elucidate the pathogenicity of the variants. The genotype-phenotype correlation was summarized through extensive literature reviewing.
RESULTS: All the four cases had severe piebaldism presented with typical white forelock and diffuse depigmentation on the ventral trunk and limbs. Four germline variants at the tyrosine kinase (TK) domains of the KIT gene were identified: two novel variants c.1990+1G>A (p.Pro627_Gly664delinsArg) and c.2716T>C (p.Cys906Arg), and two known variants c.1879+1G>A (p.Gly592_Pro627delinsAla) and c.1747G>A (p.Glu583Lys). Both splicing variants caused exon skipping and inframe deletions in the TK1 domain. The missense variants resided at the TK1 and TK2 domains respectively impairing PI3K/AKT and MAPK/ERK signaling pathways, the downstream of KIT. All severe cases were associated with variants in the TK domains, eliciting a major dominant-negative mechanism of the disease.
CONCLUSIONS: Our data expand the mutation spectrum of KIT, emphasized by a dominant-negative effect of variants in the critical TK domains in severe cases. We also share the experience of prenatal diagnosis and informed reproductive choices for the affected families.
摘要：
背景：Piebaldism是一种罕见的常染色体显性疾病，其特征是先天性白前锁和色素沉着斑块，这通常是由KIT基因的有害变异引起的。
方法：通过全外显子组测序在piebaldism病例系列中鉴定出4种KIT变异体。功能实验,包括体外小基因报告试验和酶联免疫吸附试验，进行以阐明变体的致病性。通过广泛的文献综述，总结了基因型与表型的相关性。
结果：所有4例患者均有严重的piebalism，表现为典型的白色前锁和腹侧躯干和四肢的弥漫性色素脱失。鉴定了KIT基因酪氨酸激酶（TK）结构域的四种种系变体：两种新变体c.19901G>A（p。Pro627_Gly664delinsArg）和c.2716T>C（p。Cys906Arg)，和两个已知的变体c.1879+1G>A（p。Gly592_Pro627delinsAla）和c.1747G>A（p。Glu583Lys）。两种剪接变体都导致TK1结构域中的外显子跳跃和帧内缺失。错义变体位于TK1和TK2结构域，分别损害PI3K/AKT和MAPK/ERK信号通路，KIT的下游。所有严重病例都与TK域的变异相关，引发疾病的主要显性负机制。
结论：我们的数据扩展了KIT的突变谱，在严重的情况下，关键TK域中变体的显性负效应强调。我们还分享了受影响家庭的产前诊断和知情生殖选择的经验。
方法：通过全外显子组测序在piebaldism病例系列中鉴定出4种KIT变异体。功能实验,包括体外小基因报告试验和酶联免疫吸附试验，进行以阐明变体的致病性。通过广泛的文献综述，总结了基因型与表型的相关性。
结果：所有4例患者均有严重的piebalism，表现为典型的白色前锁和腹侧躯干和四肢的弥漫性色素脱失。鉴定了KIT基因酪氨酸激酶（TK）结构域的四种种系变体：两种新变体c.19901G>A（p。Pro627_Gly664delinsArg）和c.2716T>C（p。Cys906Arg)，和两个已知的变体c.1879+1G>A（p。Gly592_Pro627delinsAla）和c.1747G>A（p。Glu583Lys）。两种剪接变体都导致TK1结构域中的外显子跳跃和帧内缺失。错义变体位于TK1和TK2结构域，分别损害PI3K/AKT和MAPK/ERK信号通路，KIT的下游。所有严重病例都与TK域的变异相关，引发疾病的主要显性负机制。
结论：我们的数据扩展了KIT的突变谱，在严重的情况下，关键TK域中变体的显性负效应强调。我们还分享了受影响家庭的产前诊断和知情生殖选择的经验。
