Case report: two novel VPS13B mutations in a Chinese family with Cohen syndrome and hyperlinear palms
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Cohen syndrome (CS) is an uncommon developmental disease with evident clinical heterogeneity. VPS13B is the only gene responsible for CS. Only few sporadic cases of CS have been reported in China.
A Chinese family with two offspring–patients affected by developmental delay and intellectual disability was investigated in this study. Exome sequencing was performed, and compound heterozygous mutations in VPS13B were segregated for family members with autosomal recessive disorder. Splicing mutation c.3666 + 1G > T (exon 24) and nonsense mutation c. 9844 A > T:p.K3282X (exon 54) were novel. We revisited the family and learned that both patients are affected by microcephaly, developmental delay, neutropenia, and myopia and have a friendly disposition, all of which are consistent with CS phenotypes. We also found that both patients have hyperlinear palms, which their parents do not have. VPS13B mutations reported among the Chinese population were reviewed accordingly.
This study presents two novel VPS13B mutations in CS. The identification of hyperlinear palms in a family affected by CS expands the phenotype spectrum of CS.
KeywordsCohen syndrome Hyperlinear palm VPS13B gene Mutation Chinese
Copy number variation
Loss of function
Polymerase chain reaction
Cohen syndrome (CS) (MIM# 216550), a rare disorder, was initially described by M. Michael Cohen, Jr., and his colleagues in 1973 . CS is a clinically heterogeneous disorder mainly characterized by developmental delay, intellectual disability, microcephaly, and hypotonia with highly variable clinical findings on myopia, retinal dystrophy, joint hypermobility, neutropenia, overly friendly behavior, truncal obesity, slender fingers, and facial appearance consisting of thick hair, thick eyebrows, long eyelashes, down-slanting eyes, short philtrum, and prominent upper incisors .
The clinical heterogeneity and several phenotypes of CS are unobservable before 10 years old; thus, this rare disease is difficult to diagnose in clinical practice. Nevertheless, CS can now be diagnosed through VPS13B mutation screening with the cloning of the disease-causing gene VPS13B [3, 4, 5]. VPS13B is the only gene that causes CS. Several VPS13B mutations have been recently reported in families with CS in Tunisia and Pakistan [6, 7].
Human VPS13B (NM_017890), which is located on 8q22.2, consists of 62 exons that encode a 4022-amino acid transmembrane protein of the Golgi apparatus functioning in vesicle-mediated transport and sorting of proteins within the cell . Approximately 200 VPS13B mutations (http://www.hgmd.cf.ac.uk/) have been reported in nearly 1000 CS patients worldwide (http://www.cohensyndrome.org/). Founder mutations have been described in several areas . Only a few VPS13B mutations have been reported sporadically in patients with CS (two definitive CS and three probable CS) in the Chinese population [8, 9, 10]. In the present study, exome sequencing identified two novel VPS13B mutations in a Chinese family with two offspring–patients affected by CS and hyperlinear palms. The presence of hyperlinear palms can likely expand the phenotypic spectrum of CS.
The study protocol was approved by the Academic Committee of Hunan Children’s Hospital (Approval No. HCHLL58, Changsha City, Hunan Province, China). The four family members (Han Chinese ethnicity), which included two parents and two children, provided written informed consent to participate in this study. Parental permission for publishing patients’ photos was obtained. The genomic DNAs of all four family members were isolated using standard methods.
The propositus’ younger sister was evaluated when she was 5.8 years old. Her height was 97.5 cm (− 3.72 SD), her weight was normal, and her OFC was 43.5 cm (normal reference: 51.5 cm). She has been walking alone since she was 2.5 years old, but she cannot complete a sentence. Similar to her older brother, she exhibits severe mental retardation, generalized joint hyperextensibility, and hypotonia. Her special facial features include prominent upper central incisors, thick hair, thick eyebrows, long and thick eyelashes, bilateral ptosis, bilateral epicanthus inversus, and bilateral strabismus. Neutropenia and truncal obesity were unobservable. The patient has hyperlinear palms (Fig. 1b).
Discussion and conclusions
A family with two offspring–patients affected by severe mental retardation and speech delay came to our clinic for genetic counselling. The detection of compound heterozygous mutations in VPS13B via exome sequencing directed us to the diagnosis of CS in the family. CS is a clinical heterogeneous disorder whose occurrence is high among patients with different ethnic backgrounds . For example, patients who belong to Finnish and Greek cohorts present much richer skeletal phenotypes featured by slender extremities and/or tapered fingers, joint hypermobility, and sandal gap compared with patients who belong to the same cohort [12, 13].
The two patients with CS in this study have slim or slender fingers. Hyperlinear palms were also observed in the two patients but not in their parents and other family members (Fig. 1). Hyperlinear palms or palms with extra skin creases signify a hand anomaly (“https://www.rightdiagnosis.com/symptom/hyperlinear-palms-extra-skin-creases-in-the-palms.htm”). Hyperlinear palms have been reported among FLG-mutated patients  with atopic dermatitis or ichthyosis vulgaris . We tried contacting VPS13B-mutated Chinese patients [8, 9, 10] to see if they have hyperlinear palms as a means of verifying if hyperlinear palms are a component phenotype of CS. However, we have not received any response from these patients. Therefore, additional supporting data are required to determine if hyperlinear palms are a CS phenotype.
This study identified two novel VPS13B mutations in a Chinese family with two members affected by CS. This work is the first to report a complete set of CS data involving a Chinese family. The presence of hyperlinear palms (identified in this study) is likely a novel phenotype of CS and may provide new clues for CS diagnosis.
Gratitude is extended to the subject family for their cooperation and participation.
YJY, RZ, LPL and YZ designed the study, monitored the family investigation, collected clinic data, conducted experiments, and revised the manuscript. YJY, ZQL, ZHX, LPL and SZ contributed to exome sequencing, PCR experiments, Sanger sequencing, and drafting the paper. SZ and YJY analyzed the clinical data. YJY, LLP, and SZ contributed to sample collection and genetic counselling. All authors read and approved the final manuscript.
This work was supported by the National Natural Science Foundation of China (31501017, to Yongjia Yang), Hunan Health Commission Research Fund (B2019019, to Yongjia Yang), and Key Laboratory Fund of Hunan Province (2018tP1028, to Zhenghui Xiao). The funding body had no influence in the in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
Ethics approval and consent to participate
The study protocol was approved by the Academic Committee of Hunan Children’s Hospital (Approval number: HCHLL58, Changsha City, Hunan Province, China). The four family members provided their written informed consent to participate in this study.
Consent for publication
Written informed consent for publication was obtained from the participants or their guardians.
The authors declare that they have no competing interests.
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