Cohen syndrome (CS) is a rare, autosomal recessive disorder characterized by intellectual disability, postnatal microcephaly, facial abnormalities, abnormal truncal fat distribution, myopia, and pigmentary retinopathy. It is often considered an underdiagnosed condition, especially in children with developmental delay and intellectual disability. Here we report on four individuals from a large Jordanian family clinically diagnosed with CS. Using Trio Exome Sequencing (Trio-WES) and MLPA analyses we identified a maternally inherited novel intronic nucleotide substitution c.3446-23T>G leading to the activation of a cryptic splice site and a paternally inherited multi-exon deletion in VPS13B (previously termed COH1) in the index patient. Expression analysis showed a strong decrease of VPS13B mRNA levels and direct sequencing of cDNA confirmed splicing at a cryptic upstream splice acceptor site, resulting in the inclusion of 22 intronic bases. This extension results in a frameshift and a premature stop of translation (p.Gly1149Valfs*9). Segregation analysis revealed that three affected maternal cousins were homozygous for the intronic splice site variant. Our data show causality of both alterations and strongly suggest the expansion of the diagnostic strategy to search for intronic splice variants in molecularly unconfirmed patients affected by CS.

科恩综合症（CS）是一种罕见的常染色体隐性遗传疾病，其特征在于智力残疾，出生后的小头畸形，面部异常，不正常的躯干脂肪分布，近视和色素性视网膜病。它通常被认为是诊断不足的疾病，特别是在发育迟缓和智力残疾的儿童中。在这里，我们报告了临床上被确诊为CS的约旦大家庭的四个人。使用三重奏外显子测序（重奏-WES）和MLPA分析我们确定了母系遗传新颖的内含子的核苷酸取代c.3446-23T“G导致隐蔽剪接位点的活化，并在父本遗传的多外显子缺失VPS13B（以前称为索引患者中的COH1）。表达分析显示VPS13B mRNA的水平和cDNA的直接测序证实了在一个隐秘的上游剪接受体位点的剪接，导致包含22个内含子碱基。此扩展会导致移码和翻译的过早停止（p.Gly1149Valfs * 9）。分离分析显示，三个受影响的母亲表亲对于内含子剪接位点变体是纯合的。我们的数据显示了这两种改变的因果关系，并强烈建议扩大诊断策略，以在受CS影响的分子未经证实的患者中寻找内含子剪接变体。