To analyze the pathogenicity and clinical characteristics of patients with Cohen syndrome caused by a compound heterozygous variation of VPS13B gene.

A pedigree investigation was conducted.A Chinese Han family with Cohen syndrome was recruited from Henan Eye Hospital in September 2021.There were three members of two generations in this family, including one patient.The clinical data of the proband and his parents were collected, and the relevant ophthalmic and general examinations were performed to evaluate the clinical phenotype.The peripheral venous blood samples of the family members were collected to extract whole genomic DNA, and the whole exome sequencing was performed.Sanger sequencing and pedigree co-segregation analysis were performed among the family members.According to the ACMG guidelines, the pathogenicity of the selected variants was evaluated and the online tools were used to predict the pathogenicity of the variants.Relevant literature of Cohen syndrome were retrieved in Online Mendelian Inheritance in Man (OMIM) and PubMed, China National Knowledge Infrastructure and Wanfang databases by taking Cohen syndrome and VPS13B gene as the searching keywords.The clinical manifestations and pathogenic variants of patients in the literature were summarized, and the relationship between genotype and clinical phenotype was analyzed.This study protocol adhered to the Declaration of Helsinki and was approved by the Ethics Committee of Henan Eye Hospital (No.HNEECKY-2019[15]). Both the subject and the patient's guardian were aware of the study purpose and method.Written informed consent was obtained.

The family was consistent with autosomal recessive inheritance.The proband, a 5-year-old male, had bilateral night blindness with photophobia, ptosis, lower eyelid entropion, and trichiasis; high myopia in both eyes; osteoblastoid pigmentation in the peripheral retina, atrophy and thinning of the outer layer of the peripheral retina, extinguished flashing electroretinogram; global growth retardation, typical facial features, slender fingers and toes, flatfoot, foot valgus, dystonia, no cardiac abnormalities; excessively cheerful personality.The clinical manifestations of the proband were consistent with Cohen syndrome.No obvious abnormality was found in the clinical phenotype and the auxiliary examination of the proband's parents.Whole exon sequencing revealed that the proband carried two heterozygous variations, a nonsense variation c. 11713C>T(p.Gln3905*) and a splicing variation c. 6940+ 1G>T.Sanger sequencing confirmed that the above variations were co-segregated in this family.c.11713C>T(p.Gln3905*) was a novel variant, which prematurely terminated the protein encoded by it and affected the normal function of the protein.The two variations were pathogenic variants according to the ACMG guidelines.A total of 12 articles on variants and clinical characteristics of Cohen syndrome in China were retrieved.Combined with the results of this study, a total of 24 VPS13B variants were found in Chinese patients, of which the incidence of frameshift variation was 41.7%(10/24), missense variation 20.8%(5/24), splicing variation 20.8%(5/24) and nonsense variation 16.7%(4/24), respectively.The onset age of patients with Cohen syndrome was from 28 days to 12 years old.The symptoms such as nerve system, eye, brain, and bone were sporadic, and the clinical manifestations were highly heterogeneous.

A novel pathogenic variation c. 11713C>T is found in the VPS13B gene of the Cohen syndrome pedigree in this study, and expands the pathogenic variation spectrum of the VPS13B gene.The clinical manifestations of Cohen syndrome are highly heterogeneous.

Cohen syndrome; VPS13B; Genetic variation; Retinitis pigmentosa; Phenotype