Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy.
Division of Medical and Laboratory Genetics, Azienda Ospedaliera di Rilievo Nazionale "Antonio Cardarelli", Naples, Italy.
Ital J Pediatr. 2020 May 27;46(1):74. doi: 10.1186/s13052-020-00839-y.
Schinzel-Giedion syndrome (SGS) is a multiple malformation syndrome mainly characterized by severe intellectual disability, distinctive facial features, and multiple congenital anomalies, including skeletal abnormalities, genitourinary and renal malformations, cardiac defects, as well as an increased pediatric cancer risk. Recently, SGS has been associated with de novo heterozygous deleterious variants in the SETBP1 gene; to date, nine different variants, clustering in exon 4 of SETBP1, have been identified in 25 patients.
In this study, by using Whole Exome Sequencing (WES), we identified a patient with a recurrent missense mutation in SETBP1, the c.2608G > A, p.(Gly870Ser) variant, previously reported as likely pathogenic. This finding allowed us to confirm the suspected clinical diagnosis of SGS. Clinical features of patients carrying the same variant, including our patient, were evaluated by a review of medical records.
Our study confirms SGS as a severe disorder potentially presenting at birth as a critically ill neonate and demonstrates the causal role of the c.2608G > A, p.(Gly870Ser) variant in the etiology of the syndrome. Moreover, although the cohort of SETBP1-patients reported in the literature is still small, our study reports for the first time the prevalence of the variant (about 27%, 7/26). Finally, given the heterogeneity of clinical presentations of affected patients hospitalized in Neonatal Intensive Care Units (NICU) and/or Pediatric Intensive Care Units (PICU), in agreement with emerging data from the literature, we suggest that WES should be used in the diagnosis of unexplained syndromic conditions, and even as part of a standard first-line diagnostic approach, as it would allow a better diagnosis, counseling and management of affected patients and their families.
Schinzel-Giedion 综合征（SGS）是一种多系统畸形综合征，主要表现为严重智力障碍、特征性面部特征以及多种先天性异常，包括骨骼异常、泌尿生殖和肾脏畸形、心脏缺陷以及儿科癌症风险增加。最近，SGS 与 SETBP1 基因中的新生杂合有害变异有关；迄今为止，在 25 名患者中已经鉴定出 9 种不同的变异，这些变异集中在 SETBP1 的外显子 4 中。
在这项研究中，我们通过全外显子组测序（WES）发现了一名患者携带 SETBP1 中反复出现的错义突变，即 c.2608G>A，p.(Gly870Ser) 变异，该变异先前被认为是可能致病的。这一发现使我们能够确认疑似 SGS 的临床诊断。通过回顾病历，评估了携带相同变异的患者的临床特征，包括我们的患者。
我们的研究证实 SGS 是一种严重疾病，可能在出生时表现为危重新生儿，并证明了 c.2608G>A，p.(Gly870Ser) 变异在该综合征发病机制中的因果作用。此外，尽管文献中报道的 SETBP1 患者队列仍然很小，但我们的研究首次报告了该变异的流行率（约 27%，7/26）。最后，鉴于在新生儿重症监护病房（NICU）和/或儿科重症监护病房（PICU）住院的受影响患者的临床表现存在异质性，并且与文献中的新数据一致，我们建议在不明原因的综合征情况下使用 WES 进行诊断，甚至作为标准一线诊断方法的一部分，因为它可以更好地诊断、咨询和管理受影响的患者及其家属。
