Supplementary Material for: A Novel <b><i>LMX1B</i></b> Variant Identified in a Patient Presenting with Severe Renal Involvement and Thin Glomerular Basement Membrane

We report a case of nail-patella syndrome (NPS) with unusual thinning of the glomerular basement membrane (GBM) associated with a novel heterozygous variant in the LMX1B gene. A 43-year-old female patient with a previous diagnosis of NPS, referred to our hospital for persistent proteinuria, underwent a renal biopsy, which revealed minor glomerular abnormalities. She underwent a second renal biopsy at the age of 56 owing to the presence of persistent proteinuria and decline in serum albumin, meeting the diagnostic criteria for nephrotic syndrome. Light microscopy demonstrated glomerulosclerosis and cystic dilatation of the renal tubules. Notably, electron microscopy revealed unusual thinning of the GBM, which is quite different from typical biopsy findings observed in patients with NPS, characterized by thick GBM with fibrillary material and electron-lucent structures. Comprehensive genetic screening for 168 known genes responsible for inherited kidney diseases using a next-generation sequencing panel identified a novel heterozygous in-frame deletion-insertion (c.723_729delinsCAAC: p.[Ser242_Lys243delinsAsn]) in exon 4 of the LMX1B gene, which may account for the disrupted GBM structure. Further studies are warranted to elucidate the complex genotype-phenotype relationship between LMX1B and proper GBM morphogenesis.本研究报道1例合并罕见肾小球基底膜（glomerular basement membrane, GBM）变薄的指甲-髌骨综合征（nail-patella syndrome, NPS）病例，该病例与LMX1B基因上的新型杂合变异相关。患者为43岁女性，既往已确诊NPS，因持续性蛋白尿转诊至我院，行肾活检后提示轻度肾小球病变。患者56岁时因持续性蛋白尿持续存在、血清白蛋白水平下降，符合肾病综合征诊断标准，再次接受肾活检。光学显微镜下可见肾小球硬化及肾小管囊性扩张。值得注意的是，电子显微镜下可见GBM出现罕见变薄，这与NPS患者典型的肾活检表现截然不同——典型表现为GBM增厚并伴纤维样物质及电子透亮结构。采用下一代测序靶向检测168种已知遗传性肾病致病基因，结果在LMX1B基因第4外显子上发现1种新型杂合框内缺失插入变异（c.723_729delinsCAAC: p.[Ser242_Lys243delinsAsn]），该变异可能是GBM结构受损的致病原因。后续仍需开展进一步研究，以阐明LMX1B与正常GBM形态发生之间复杂的基因型-表型关联。