Craniofacial microsomia (CFM), also known as the oculo-auriculo-vertebral spectrum, is a congenital disorder characterized by hypoplasia of the mandible and external ear due to tissue malformations originating from the first and second branchial arches. However, distinguishing it from other syndromes of branchial arch abnormalities is difficult, and causal variants remain unidentified in many cases. In this report, we performed an exome sequencing analysis of a Brazilian family with CFM. The proband was a 12-month-old boy with clinical findings consistent with the diagnostic criteria for CFM, including unilateral mandibular hypoplasia, microtia, and external auditory canal abnormalities. A heterozygous de novo nonsense variant (c.713C>G, p.S238*) in PUF60 was identified, which was predicted to be pathogenic in silico. PUF60 has been reported as a causal gene in Verheij syndrome, but not in CFM. Although the boy showed craniofacial abnormalities and developmental delay that overlapped with Verheij syndrome, the facial asymmetry with unilateral hypoplasia of the mandible observed in this case did not match the previously reported phenotypes of PUF60 variants. Our findings expand the phenotypic range of PUF60 variants that cover CFM and Verheij syndrome.

Verheij syndrome (VRJS) is a craniofacial spliceosomopathy with a wide phenotypic spectrum. Haploinsufficiency of the poly-uridine binding splicing factor 60 gene (PUF60) and its loss-of-function (LOF) variants are involved in VRJS. We evaluated a human fetus with congenital heart defects and preaxial polydactyly. Clinical data were obtained from the medical record. Whole-exome sequencing (WES) was used to explore the potential genetic etiology, and the detected variant verified using Sanger sequencing. Functional studies were performed to validate the pathogenic effects of the variant. Using trio-WES, we identified a novel PUF60 variant (NM_078480.2; c.1678 T > A, p.*560Argext*204) in the pedigree. Bioinformatic analyses revealed that the variant is potentially pathogenic, and functional studies indicated that it leads to degradation of the elongated protein and subsequently PUF60 LOF, producing some VRJS phenotypes. These findings confirmed the pathogenicity of the variant. This study implicates PUF60 LOF in the etiopathogenesis of VRJS. It not only expands the PUF60 variant spectrum, and also provides a basis for genetic counseling and the diagnosis of VRJS. Although trio-WES is a well-established approach for identifying the genetic etiology of rare multisystemic conditions, functional studies could aid in verifying the pathogenicity of novel variants.

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BACKGROUND: Verheij syndrome is a rare microdeletion syndrome of chromosome 8q24.3 that harbors PUF60, SCRIB, and NRBP2 genes. Subsequently, loss of function mutations in PUF60 have been found in children with clinical features significantly overlapping with Verheij.
METHODS: Here we present the first Chinese Han patient with a de novo nonsense variant (c.1357C > T, p.Gln453*) in PUF60 by clinical whole exome sequencing. The 5-year-old boy presents with dysmorphic facial features, intellectual disability, and growth retardation but without apparent cardiac, renal, ocular, and spinal anomalies.
CONCLUSIONS: Our finding contributes to the understanding of the genotype and phenotype in PUF60 related disorder.

Objective: To investigate the clinical and genetic characteristics of a Chinese boy with Verheij syndrome and review the literature. Methods: The clinical and genetic data of a Chinese boy with Verheij syndrome, who was admitted to the Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology in May 2017 were analyzed. Original papers on Verheij syndrome published up to January 2018 were retrieved at PubMed, Human Gene Mutation Database (HGMD), Online Mendelian Inheritance in Man(OMIM), CNKI and WanFang databases by using the key words \"Verheij syndrome\" and \"PUF60\" . Results: The male patient (at the age of 14 years and 3 months) visited us because of growth retardation for 13 years. Atrial septal defect was repaired at the age 3. Congenital amblyopia and hyperopia were diagnosed at the age 4. On physical examination, serious growth retardation and delayed psychomotor development was noted. His height was 142.5 cm (-3.26 SDS). He had poor academic performance at school. Facial features included: webbed neck, hypertelorism, down-slanting palpebral fissures, long philtrum, thin upper lip, and high palate. Palmar crease was found in the right hand. His bone age was 10 years. Growth hormone stimulation test indicated partial growth hormone deficiency (growth hormone (GH) peak 6.63 μg/L). The level of insulin like growth factor 1 (IGF1) and insulin like growth factor binding protein 3 (IGFBP3) was lower than normal, 73.20 μg/L and 2 500 μg/L respectively. Abdominal ultrasound showed that the volumes of bilateral kidneys were small. The size of the left and right kidney was 8.5 cm × 3.3 cm and 8.4 cm × 4.3 cm respectively. Karyotype was normal (46, XY). MRI of pituitary showed partial empty sella turcica. Ten genes associated with Noonan syndrome (PTPN11, SOS1, RASA2, KRAS, RAF1, NRAS, SHOC2, BRAF, RIT1, A2ML1) were analyzed and no genetic mutations were found. Whole exome-sequencing analysis identified a de novo heterozygous frame shift mutation of PUF60 gene (c.931_934del, P.P.T 311Qfs*47). According to ACMG guidelines in 2015, the mutation is pathogenic and has not been reported in the above databases. Conclusions: This is the first case report of Verheij syndrome caused by mutation of PUF60 gene in Chinese population. It is difficult to discriminate Verheij syndrome from Noonan syndrome, both have clinical manifestations such as severe growth retardation, psychomotor retardation, and congenital heart disease. In addition to Noonan syndrome, PUF60 genetic analysis was recommended for avoiding missed diagnosis with such clinical manifestations of patients.
目的： 总结Verheij综合征的临床及遗传学分析特点。 方法： 对2017年5月华中科技大学同济医学院附属同济医院儿科收治的1例Verheij综合征患儿的临床资料及基因检测结果进行总结分析，并以\"Verheij syndrome\"\"PUF60\"和\"Verheij综合征\"\"PUF60基因\"为检索词，分别检索2018年1月前的PubMed、人类基因组突变数据库（HGMD）、在线人类孟德尔遗传数据库（OMIM）、中国知网数据库（CNKI）和万方数据库，对Verheij综合征病例进行文献复习。 结果： 患儿男，14岁3月龄，因\"生长落后13年\"就诊。出生体重2.9 kg，3岁时在外院行\"房间隔缺损修补术\"，4岁时发现\"先天性弱视及远视\"。身高142.5 cm，标准差积分－3.26。精神运动发育迟缓，学习成绩不佳。颈蹼，眼距宽、双侧外眼角下斜，人中长，腭弓高，后发际低；右手通贯掌。骨龄落后于实际年龄；垂体内分泌功能检测结果提示部分性生长激素（GH）缺乏（GH峰值6.63 μg/L），血胰岛素样生长因子1（IGF1）（73.20 μg/L）及胰岛素样生长因子结合蛋白3（IGFBP3）（2 500 μg/L）低于正常；肾脏B超左肾8.5 cm×3.3 cm，右肾8.4 cm×4.3 cm；染色体核型46,XY；垂体磁共振成像提示垂体高度约4 mm，存在部分空蝶鞍。内分泌基因Panel（与Noonan综合征相关的10个基因）分析，均未发现基因变异或缺失。全外显子基因检测发现患儿存在PUF60基因杂合变异（c.931_934del，p. p.T311Qfs*47）。患儿父母该位点均无变异。经Sanger测序进行验证及父母来源分析，提示为新发突变。根据2015年美国医学遗传学与基因组学学会指南，该移码突变为致病突变，且在上述数据库中尚未见报道。 结论： 首次报道中国人群PUF60基因变异导致的Verheij综合征。患儿有严重的生长发育落后、精神运动发育迟缓、特殊面部特征、先天性心脏病、肾脏发育不良等，临床与Noonan综合征难以鉴别。对具有上述临床表现的患儿除注意Noonan综合征相关基因检测外，还应注意PUF60基因分析，以免漏诊。.