Abstract：
BACKGROUND: NOTCH3, a large type I transmembrane receptor expressed on arterial smooth muscle cells and capillary pericytes, features a diverse extracellular domain with 34 epidermal growth factor-like repeats. It exhibits distinct phenotypes due to variant zygosity and type; missense mutations cause CADASIL with cerebral vasculopathy, while null mutations lead to severe congenital manifestations.
METHODS: This report describes two cases with homozygous loss- of- function variants in NOTCH3 along with their clinical manifestations.
RESULTS: These patients presented with a severe congenital phenotype, including eye misalignment, visual impairment, epilepsy, global developmental delay, and subsequent development of pyramidal signs. Biallelic nonsense variants were discovered in both the cases (NM_000435.3:c.2203 C > T (p. [Arg735Ter]). Livedo reticularis was not reported in our cases, although it was present in previously reported patients. Autosomal recessive NOTCH3-related leukodystrophy is usually caused by biallelic null mutations in NOTCH3.
CONCLUSIONS: The phenotype of biallelic null variants is associated with a more severe phenotype than the dominantly inherited form of the disease.
METHODS: This report describes two cases with homozygous loss- of- function variants in NOTCH3 along with their clinical manifestations.
RESULTS: These patients presented with a severe congenital phenotype, including eye misalignment, visual impairment, epilepsy, global developmental delay, and subsequent development of pyramidal signs. Biallelic nonsense variants were discovered in both the cases (NM_000435.3:c.2203 C > T (p. [Arg735Ter]). Livedo reticularis was not reported in our cases, although it was present in previously reported patients. Autosomal recessive NOTCH3-related leukodystrophy is usually caused by biallelic null mutations in NOTCH3.
CONCLUSIONS: The phenotype of biallelic null variants is associated with a more severe phenotype than the dominantly inherited form of the disease.
摘要：
背景：NOTCH3，一种在动脉平滑肌细胞和毛细血管周细胞上表达的大型I型跨膜受体，具有34个表皮生长因子样重复序列的不同胞外域。由于接合性和类型的变异，它表现出不同的表型；错义突变导致CADASIL伴脑血管病变，而无效突变会导致严重的先天性表现。
方法：本报告描述了2例NOTCH3纯合功能缺失变异的病例及其临床表现。
结果：这些患者表现为严重的先天性表型，包括眼睛错位，视力障碍，癫痫,全球发育迟缓，和随后发展的金字塔的迹象。在两种情况下都发现了双等位基因无义变体（NM_000435.3：c.2203C>T（p。[Arg735Ter]).在我们的病例中没有报告网状Livedo，尽管它存在于以前报道的患者中。常染色体隐性遗传NOTCH3相关的脑白质营养不良通常由NOTCH3的双等位基因无效突变引起。
结论：双等位基因无效变异体的表型与比显性遗传形式更严重的表型相关。
方法：本报告描述了2例NOTCH3纯合功能缺失变异的病例及其临床表现。
结果：这些患者表现为严重的先天性表型，包括眼睛错位，视力障碍，癫痫,全球发育迟缓，和随后发展的金字塔的迹象。在两种情况下都发现了双等位基因无义变体（NM_000435.3：c.2203C>T（p。[Arg735Ter]).在我们的病例中没有报告网状Livedo，尽管它存在于以前报道的患者中。常染色体隐性遗传NOTCH3相关的脑白质营养不良通常由NOTCH3的双等位基因无效突变引起。
结论：双等位基因无效变异体的表型与比显性遗传形式更严重的表型相关。
