Abstract：
Verheij syndrome (VRJS) is a rare craniofacial spliceosomopathy presenting with craniofacial dysmorphism, multiple congenital anomalies and variable neurodevelopmental delay. It is caused by single nucleotide variants (SNVs) in PUF60 or interstitial deletions of the 8q24.3 region. PUF60 encodes a splicing factor which forms part of the spliceosome. To date, 36 patients with a sole diagnosis of VRJS due to disease-causing PUF60 SNVs have been reported in peer-reviewed publications. Although the depth of their phenotyping has varied greatly, they exhibit marked phenotypic heterogeneity. We report 10 additional unrelated patients, including the first described patients of Khmer, Indian, and Vietnamese ethnicities, and the eldest patient to date, with 10 heterozygous PUF60 variants identified through exome sequencing, 8 previously unreported. All patients underwent deep phenotyping identifying variable dysmorphism, growth delay, neurodevelopmental delay, and multiple congenital anomalies, including several unique features. The eldest patient is the only reported individual with a germline variant and neither neurodevelopmental delay nor intellectual disability. In combining these detailed phenotypic data with that of previously reported patients (n = 46), we further refine the known frequencies of features associated with VRJS. These include neurodevelopmental delay/intellectual disability (98%), axial skeletal anomalies (74%), appendicular skeletal anomalies (73%), oral anomalies (68%), short stature (66%), cardiac anomalies (63%), brain malformations (48%), hearing loss (46%), microcephaly (41%), colobomata (38%), and other ocular anomalies (65%). This case series, incorporating three patients from previously unreported ethnic backgrounds, further delineates the broad pleiotropy and mutational spectrum of PUF60 pathogenic variants.
摘要：
Verheij综合征（VRJS）是一种罕见的颅面剪接瘤病，表现为颅面畸形，多种先天性异常和可变的神经发育迟缓。它是由PUF60中的单核苷酸变体（SNV）或8q24.3区域的间质缺失引起的。PUF60编码形成剪接体的一部分的剪接因子。迄今为止,同行评审的出版物中报道了36例由于引起疾病的PUF60SNV而唯一诊断为VRJS的患者。尽管它们的表型深度差异很大，它们表现出明显的表型异质性。我们报告了另外10名无关患者，包括最早描述的高棉患者，印度人，和越南种族，也是迄今为止最大的病人，通过外显子组测序鉴定出10个杂合PUF60变体，8以前没有报道。所有患者都接受了深层表型鉴定变量异形，生长延迟，神经发育迟缓,和多种先天性异常，包括几个独特的功能。年龄最大的患者是唯一报告的具有种系变异且既无神经发育迟缓也无智力障碍的个体。将这些详细的表型数据与以前报道的患者(n=46)相结合，我们进一步完善了与VRJS相关的已知特征频率。这些包括神经发育迟缓/智力障碍（98％），轴向骨骼异常（74%），阑尾骨骼异常（73%），口腔异常（68%），身材矮小(66%)，心脏异常（63%），大脑畸形（48%），听力损失（46%），小头畸形（41%），结瘤（38%），和其他眼部异常（65%）。这个案例系列,纳入三名来自以前未报告的种族背景的患者，进一步描述了PUF60致病变种的广泛多效性和突变谱.
