BACKGROUND Joubert syndrome is a genetically heterogeneous autosomal recessive ciliopathy characterized by the combination of hypoplasia/aplasia of the cerebellar vermis, thickened and elongated superior cerebellar peduncles and a deep interpeduncular fossa, known as "molar tooth sign" associated with hypotonia, respiratory control disturbances and abnormal eye movements. To date, pathogenic variants in over 35 genes are known to cause autosomal recessive Joubert Syndrome, while one gene is associated with X-linked recessive inheritance. CASE PRESENTATION We describe here a non-consanguineous Vietnamese family with Joubert syndrome, a fetus and 10-year-old developmentally delayed boy. Ultrasonography showed ventriculomegaly at 26 + 6 weeks of gestation in the fetus. The 10-year-old-boy was diagnosed with cerebral palsy of unknown origin. Clinical physical examination at the age of 10, he showed clinical features of Joubert syndrome including typical facial dysmorphism, ataxia, severe psychomotor delay, oculomotor apraxia and molar tooth sign on brain MRI. Whole exome sequencing analysis identified a novel compound heterozygous c.725A > G p.Asn242Ser and c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant in the proband and the affected fetus. These two variants were inherited from each parent and confirmed by Sanger sequencing. The variant c.725A > G p.Asn242Ser was previously documented in patients with JS, the novel splice-site c.313-3 T > G p.Lys105Valfs*16 TMEM67 variant produced an aberrant transcript with the loss of four nucleotides of exon 03. CONCLUSION This study confirms the diagnosis of Joubert syndrome in a Vietnamese family and expands the mutational spectrum of TMEM67 sequence variations. We also highlight the importance of molecular approaches to unravel underlying mechanisms of human genetic disorders. Early precise diagnosis could help provide further accurate genetic counseling for recurrence-risk assessment, future diagnostic option, management as well as treatment guidance for rare disorders.

中文翻译：

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越南乔氏综合征家庭中的新型复合杂合TMEM67变异：病例报告。

背景技术Joubert综合征是遗传上异质的常染色体隐性睫状体病，其特征是小脑ver部发育不全/小,、小脑上superior的增厚和伸长以及小椎间窝深部结合，称为“摩尔齿征”，伴有肌张力减退，呼吸控制障碍和异常眼动。迄今为止，已知超过35个基因的致病变异会导致常染色体隐性遗传乔伯特综合症，而一个基因与X连锁隐性遗传有关。病例介绍我们在这里描述一个患有约伯综合征的越南近亲家庭，一个胎儿和一个10岁的发育迟缓男孩。超声检查显示胎儿在妊娠26 + 6周时出现脑室扩大。该10岁男孩被诊断​​出患有未知来源的脑瘫。在10岁时进行的临床体格检查中，他在大脑MRI上显示了Joubert综合征的临床特征，包括典型的面部畸形，共济失调，严重的精神运动性延迟，动眼性运动失用和磨牙迹象。整个外显子组测序分析在先证者和患病胎儿中发现了一个新的杂合子c.725A> G p.Asn242Ser和c.313-3 T> G p.Lys105Valfs * 16 TMEM67变体。这两个变体均从每个亲本继承，并通过Sanger测序证实。先前在JS患者中记录了变体c.725A> G p.Asn242Ser，新的剪接位点c.313-3 T> G p.Lys105Valfs * 16 TMEM67变体产生异常转录本，外显子的四个核苷酸缺失03。结论这项研究证实了越南家庭Joubert综合征的诊断，并扩大了TMEM67序列变异的突变谱。我们还强调了揭示人类遗传疾病潜在机制的分子方法的重要性。早期的精确诊断可能有助于为复发风险评估，将来的诊断选择，治疗以及罕见疾病的治疗指导提供进一步的精确遗传咨询。