Zellers McKenzie, Solanki Kaushal, Kelly Melissa A, Murphy Karyn M, Retterer Kyle, Kirchner H Lester, Bucaloiu Ion Dan, Moore Bryn, Mirshahi Tooraj, Chang Alexander R
Geisinger Commonwealth School of Medicine, Scranton, Pennsylvania.
Department of Population Health Sciences, Geisinger, Danville, Pennsylvania.
J Am Soc Nephrol. 2025 Jun 1;36(6):1138-1151. doi: 10.1681/ASN.0000000580. Epub 2024 Dec 3.
In an unselected health system–based research study, we show that the phenotypic spectrum of X-linked Alport syndrome is wider than previously known. Kidney risks were lower for patients with p.Gly624Asp, a hypomorphic variant that is thought to have originated in Central and Eastern Europe. Many patients in this study had not been diagnosed with Alport syndrome, and consequently, many had not received appropriate testing and treatment.
Our knowledge of X-linked Alport syndrome comes mostly from selected cohorts with more severe disease.
We examined the phenotypic spectrum of X-linked Alport syndrome in men and women with a genotype-based approach using data from the Geisinger MyCode DiscovEHR study, an unselected health system–based cohort with exome sequencing and electronic health records. Patients with variants reported as pathogenic or likely pathogenic in ClinVar, or protein-truncating variants, were each matched with up to five controls without variants by sociodemographics, diabetes diagnosis, and year of first outpatient encounter. Phenotypes examined included dipstick hematuria, bilateral sensorineural hearing loss, proteinuria, lower eGFR, and kidney failure.
Of 170,856 patients, there were 29 hemizygous men (mean age 52 years [SD 20]) and 55 heterozygous women (mean age 59 years [SD 19]) with a pathogenic/likely pathogenic variant, including 48 with the hypomorphic variant p.Gly624Asp. Overall, penetrance (having any Alport syndrome phenotypic feature) was the highest for non-p.Gly624Asp variants (men: 94%, women: 85%) and intermediate for p.Gly624Asp (men: 77%, women: 69%) compared with controls (men: 32%, women: 50%). The proportion with kidney failure was the highest for men with non-p.Gly624Asp variants (44%) and intermediate for men with p.Gly624Asp (15%) and women with non-p.Gly624Asp variants (10%) compared with controls (men: 3%, women: 2%). Only 47% of patients with had completed albuminuria screening, and a minority were taking renin-angiotensin-aldosterone system inhibitors. Only 38% of men and 16% of women had a known diagnosis of Alport syndrome or thin basement membrane disease.
Using a genotype-first approach, we show that men and women with X-linked Alport syndrome are at higher risk of related phenotypic features with a wider spectrum of severity than has been described previously and variability by genotype.
在一项基于卫生系统的非选择性研究中，我们发现X连锁遗传性肾炎综合征的表型谱比之前所知的更广泛。携带p.Gly624Asp（一种被认为起源于中欧和东欧的低表达变异）的患者肾脏疾病风险较低。本研究中的许多患者此前未被诊断为遗传性肾炎综合征，因此，许多患者未接受适当的检测和治疗。
我们对X连锁遗传性肾炎综合征的了解大多来自病情更严重的特定队列。
我们采用基于基因型的方法，利用盖辛格MyCode DiscovEHR研究的数据，研究X连锁遗传性肾炎综合征在男性和女性中的表型谱。该研究是一个基于卫生系统的非选择性队列，包含外显子组测序和电子健康记录。将ClinVar中报告为致病或可能致病的变异患者或蛋白截短变异患者，按照社会人口统计学、糖尿病诊断和首次门诊就诊年份，与至多5名无变异的对照进行匹配。所检查的表型包括试纸法血尿、双侧感音神经性听力损失、蛋白尿、估算肾小球滤过率降低和肾衰竭。
在170856例患者中，有29例半合子男性（平均年龄52岁[标准差20]）和55例杂合子女性（平均年龄59岁[标准差19]）携带致病/可能致病变异，其中48例携带低表达变异p.Gly624Asp。总体而言，与对照（男性：32%，女性：50%）相比，非p.Gly624Asp变异的外显率（具有任何遗传性肾炎综合征表型特征）最高（男性：94%，女性：85%），p.Gly624Asp变异的外显率居中（男性：77%，女性：69%）。非p.Gly624Asp变异男性的肾衰竭比例最高（44%），p.Gly624Asp变异男性和非p.Gly624Asp变异女性的肾衰竭比例居中（分别为15%和10%），对照中男性为3%，女性为2%。只有47%的携带变异患者完成了蛋白尿筛查，少数患者正在服用肾素-血管紧张素-醛固酮系统抑制剂。只有38%的男性和16%的女性已知被诊断为遗传性肾炎综合征或薄基底膜病。
采用先基因型的方法，我们发现X连锁遗传性肾炎综合征的男性和女性出现相关表型特征的风险更高，其严重程度谱比之前描述的更广泛，且存在基因型差异。
