未经证实:COL4A3和COL4A4(COL4A3/COL4A4)的单等位基因变体已在一系列肾小球基底膜肾病中得到鉴定,包括薄基底膜肾病和常染色体显性遗传Alport综合征。随着下一代测序的使用越来越多,单等位基因COL4A3/COL4A4变体被更频繁地检测到,但是表型异质性阻碍了咨询。我们的目的是调查表型谱,肾活检结果,和通过全外显子组测序鉴定的具有单等位基因COL4A3/COL4A4变异的患者的分离模式。
未经评估:案例系列。
UNASSIGNED:我们评估了17例荷兰指数患者的临床和病理特征,这些患者通过诊断性全外显子组测序检测到COL4A3/COL4A4单等位基因变异,以及25例受影响的家族成员通过Sanger测序证实变异。
未经鉴定:在11个家族的成员中鉴定出8个不同的单等位基因COL4A3/COL4A4变体,包含7个甘氨酸取代的错义变体和1个移码变体。所有指标患者在临床表现时都有显微镜下血尿(中位年龄43岁),14名患者有(微量)白蛋白尿/蛋白尿。所有家庭成员均显示该变体与至少血尿的共分离。在所有42名个体的随访结束时(平均年龄54岁),16/42例患者有肾功能损害,其中6人患有肾衰竭。14例患者的肾活检报告描述了薄基底膜肾病,局灶性节段肾小球硬化,微小病变改变,和Alport综合征.与特发性局灶性节段性肾小球硬化和其他遗传性肾小球疾病患者的图像相比,7例患者的电子显微镜图像显示肾小球基底膜明显变薄。无法建立基因型-表型相关性。
未经评估:回顾性设计,确定对严重肾脏表型的偏见,家族性血尿.
未经证实:这项研究证实了与单等位基因COL4A3/COL4A4变体相关的广泛表型谱,从孤立的显微镜下血尿延伸到肾功能衰竭,具有高度的内部和家族间变异性。
UNASSIGNED: Mono-allelic variants in COL4A3 and COL4A4 (COL4A3/COL4A4) have been identified in a spectrum of glomerular basement membrane nephropathies, including thin basement membrane nephropathy and autosomal dominant Alport syndrome. With the increasing use of next generation sequencing, mono-allelic COL4A3/COL4A4 variants are detected more frequently, but phenotypic heterogeneity impedes counseling. We aimed to investigate the phenotypic spectrum, kidney biopsy results, and segregation patterns of patients with mono-allelic COL4A3/COL4A4 variants identified by whole exome sequencing.
UNASSIGNED: Case series.
UNASSIGNED: We evaluated clinical and pathologic characteristics of 17 Dutch index patients with mono-allelic variants in COL4A3/COL4A4 detected by diagnostic whole exome sequencing and 25 affected family members with variants confirmed by Sanger sequencing.
UNASSIGNED: Eight different mono-allelic COL4A3/COL4A4 variants were identified across members of 11 families, comprising 7 glycine substituted missense variants and 1 frameshift variant. All index patients had microscopic hematuria at clinical presentation (median age 43 years) and 14 had (micro)albuminuria/proteinuria. All family members showed co-segregation of the variant with at least hematuria. At end of follow-up of all 42 individuals (median age 54 years), 16/42 patients had kidney function impairment, of whom 6 had kidney failure.
Reports of kidney biopsies of 14 patients described thin basement membrane nephropathy, focal segmental glomerulosclerosis, minimal change lesions, and Alport syndrome. Electron microscopy images of 7 patients showed a significantly thinner glomerular basement membrane compared with images of patients with idiopathic focal segmental glomerulosclerosis and other hereditary glomerular diseases. No genotype-phenotype correlations could be established.
UNASSIGNED: Retrospective design, ascertainment bias toward severe kidney phenotypes, and familial hematuria.
UNASSIGNED: This study confirms the wide phenotypic spectrum associated with mono-allelic COL4A3/COL4A4 variants, extending from isolated microscopic hematuria to kidney failure with high intra- and interfamilial variability.