Stein Quinn, Vostrizansky Anna, Magay Yelena, Jandeska Sara, Westemeyer Maggie, Hendricks Emily, Pitman Tessa, Hager Meg M, Anand Akash, Curry Kathryn, Bloom Michelle, Al Haj Baddar Nour, Tabriziani Hossein, Harrington Melisa, Punj Sumit
Natera, Inc., Austin, Texas, USA.
Ochsner University Hospital and Clinics, New Orleans, Louisiana, USA.
Kidney Int Rep. 2024 Mar 28;9(6):1810-1816. doi: 10.1016/j.ekir.2024.03.030. eCollection 2024 Jun.
Townes-Brocks syndrome (TBS), a rare autosomal dominant genetic condition associated with (Spalt like Transcription Factor 1), is reported to be present in 1:238,000 individuals in the general population. TBS is characterized by the triad of anorectal malformations, dysplastic ears, with or without hearing impairment, and hand or thumb anomalies. Although kidney involvement is less common in TBS, the disease can progress to kidney failure. Here, we sought to characterize the incidence of variants in individuals undergoing broad-based genetic testing with a kidney gene panel and to quantify the presence of (extra)renal features.
A retrospective analysis of the genetic data from a 385-gene panel identified cases with a pathogenic (P) or likely pathogenic (LP) variant in . Data including age, features, and disease progression were collected.
Of 35,044 samples, P or LP variants in were identified in 22, yielding a prevalence of 1:1592 among patients tested for monogenic kidney disease, and 1:342 among cases identified with a monogenic kidney disease. Among this cohort, the median patient age was 23 years (range: 3 months-62 years) with chronic kidney disease (CKD) reported in 91% (20/22) of cases. Reported kidney features included renal agenesis/hypoplasia (7/22; 32%), focal segmental glomerulosclerosis (4/22; 18%), and kidney cysts (3/22; 14%). Confirmed extrarenal features included hearing loss and/or ear features (7/22; 32%), anorectal malformations (6/22; 27%) and hand or thumb abnormalities (4/22; 18%). Three patients (3/22; 14%) had both TBS diagnoses and the traditional "triad."
Traditionally, a molecular diagnosis was ascertained primarily in individuals presenting with cardinal features of TBS; therefore, individuals with mild or atypical presentations were often overlooked clinically. Our findings reveal that P/LP variants could be a consequential contributor to monogenic kidney disease.
汤姆斯-布罗克斯综合征（TBS）是一种罕见的常染色体显性遗传病，与（类Spalt转录因子1）相关，据报道在普通人群中的发病率为1:238,000。TBS的特征为肛门直肠畸形、发育异常的耳朵（伴或不伴有听力障碍）以及手部或拇指异常三联征。尽管肾脏受累在TBS中不太常见，但该疾病可进展为肾衰竭。在此，我们试图确定接受广泛肾脏基因检测的个体中（相关）变异的发生率，并量化（肾外）特征的存在情况。
对来自385个基因检测板的遗传数据进行回顾性分析，以确定携带致病性（P）或可能致病性（LP）变异的病例。收集包括年龄、特征和疾病进展等数据。
在35,044份样本中，22份样本检测到（相关）P或LP变异，在接受单基因肾病检测的患者中患病率为1:1592，在确诊为单基因肾病的病例中患病率为1:342。在该队列中，患者的中位年龄为23岁（范围：3个月至62岁），91%（20/22）的病例报告患有慢性肾脏病（CKD）。报告的肾脏特征包括肾发育不全/发育不良（7/22；32%）、局灶节段性肾小球硬化（4/22；18%）和肾囊肿（3/22；14%）。确诊的肾外特征包括听力丧失和/或耳部特征（7/22；32%）、肛门直肠畸形（6/22；27%）以及手部或拇指异常（4/22；18%）。三名患者（3/22；14%）同时具有TBS诊断和传统的“三联征”。
传统上，分子诊断主要在具有TBS主要特征的个体中确定；因此，临床表现轻微或不典型的个体在临床上常常被忽视。我们的研究结果表明，（相关）P/LP变异可能是单基因肾病的一个重要原因。
