Hashmi Jamil A, Fadhli Fatima, Almatrafi Ahmed, Afzal Sibtain, Ramzan Khushnooda, Thiele Holger, Nürnberg Peter, Basit Sulman
Center for Genetics and Inherited Diseases, Taibah University Almadinah Almunawwarah, Saudi Arabia.
Department of Genetic Diseases, King Abdulla Medical City-Madinah Maternity and Children Hospital, Almadinah Almunawwarah, Saudi Arabia.
Brain Dev. 2020 Sep;42(8):587-593. doi: 10.1016/j.braindev.2020.04.010. Epub 2020 May 10.
Cohen syndrome (CS) is a rare multi-system autosomal recessive disorder with a high prevalence in the Finnish population. Clinical features of Finnish-type CS are homogeneous, however, in non-Finnish populations, CS diagnosis is challenging due to broad phenotypic variability.
We studied a consanguineous family having three affected individuals with clinical features of severe intellectual disability and global developmental delay. Clinical diagnosis of the phenotype could not be established based on the features. Therefore, whole genome SNP genotyping and whole exome sequencing (WES) were performed on DNA samples from affected and unaffected family members.
Homozygosity mapping identified a shared loss of heterozygosity region on chromosome 8q22.1-q22.3 and WES data analysis revealed an insertion-deletion (indel) mutation (c.11519_11521delCAAinsT) in the VPS13B gene. The indel is predicted to cause a frameshift resulting in a premature termination of the VPS13B protein (NP_060360.3:p.Pro3840Leufs*2).
VPS13B encodes a giant transmembrane protein called vacuolar protein sorting 13 homolog B. VPS13B is known to play a role in the glycosylation of Golgi proteins and in endosomal-lysosomal trafficking. Moreover, it is thought to function in vesicle mediated transport and sorting of proteins within the cell. The mechanism by which abnormalities of the VPS13B protein lead to the phenotype of CS is currently unknown. Here, in this study, we successfully established a clinical diagnosis of CS cases from a family using genomic analyses. Clinical re-examination of the patients revealed characteristic ocular abnormalities.
科恩综合征（CS）是一种罕见的多系统常染色体隐性疾病，在芬兰人群中患病率较高。芬兰型CS的临床特征具有同质性，然而，在非芬兰人群中，由于表型变异广泛，CS的诊断具有挑战性。
我们研究了一个近亲家庭，该家庭中有三名受影响个体，具有严重智力残疾和全面发育迟缓的临床特征。基于这些特征无法建立该表型的临床诊断。因此，对受影响和未受影响家庭成员的DNA样本进行了全基因组SNP基因分型和全外显子组测序（WES）。
纯合性定位确定了8号染色体q22.1-q22.3上一个共享的杂合性缺失区域，WES数据分析揭示了VPS13B基因中的一个插入缺失（indel）突变（c.11519_11521delCAAinsT）。该indel预计会导致移码，从而导致VPS13B蛋白（NP_060360.3:p.Pro3840Leufs*2）提前终止。
VPS13B编码一种名为液泡蛋白分选13同源物B的巨大跨膜蛋白。已知VPS13B在高尔基体蛋白的糖基化和内体-溶酶体运输中起作用。此外，它被认为在细胞内囊泡介导的蛋白质运输和分选过程中发挥作用。VPS13B蛋白异常导致CS表型的机制目前尚不清楚。在本研究中，我们通过基因组分析成功地对一个家庭中的CS病例进行了临床诊断。对患者的临床复查发现了特征性眼部异常。
