A homozygous mutation p.Arg2167Trp in FREM2 causes isolated cryptophthalmos

Qian, Yu; Lin, Bin; Xie, Shuang; Gao, Song; Li, Wei; Liu, Yizhi; Wang, Yan; Huang, Danping

doi:10.1093/hmg/ddy144

Cited by 14 publications

(8 citation statements)

References 35 publications

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“…Other gene mutations hypothesized to play a role in the pathogenesis of Fraser syndrome based on animal studies but not human studies include Hemicentin 1 (HMCN1), Furin and Fibrillin 2 gene. Noteworthy, FREM1 gene mutations are known to cause diseases of phenotypic variants different from Fraser Syndrome such as bifid nose with or without renal anomalies, Manitoba oculotrichonal syndrome [13], Trigonocephaly 2. Manitoba oculotrichonal syndrome differs dysmorphically from Fraser syndrome by the presence of a bifid nose, hypertelorism (spaced eyes) and microphthalmia in the former [13].…”

Section: Discussionmentioning

confidence: 99%

“…Noteworthy, FREM1 gene mutations are known to cause diseases of phenotypic variants different from Fraser Syndrome such as bifid nose with or without renal anomalies, Manitoba oculotrichonal syndrome [13], Trigonocephaly 2. Manitoba oculotrichonal syndrome differs dysmorphically from Fraser syndrome by the presence of a bifid nose, hypertelorism (spaced eyes) and microphthalmia in the former [13]. Like Fraser syndrome, infants with Trigonocephaly 2 also have mental retardation due to FREM1 gene mutation.…”

Section: Discussionmentioning

confidence: 99%

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Diagnosis of Fraser syndrome missed out until the age of six months old in a low-resource setting: a case report

et al. 2019

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Background Fraser syndrome is a rare genetic disorder that often presents with ocular, renal, genital and limb’s congenital anomalies. The prognosis of this genetic disorder depends on the severity of the combination of congenital malformations, some of which may be fatal. The diagnosis of Fraser syndrome is based on established clinical criteria and genetic tests. The criteria enabling clinical diagnosis are visible dysmorphic features present at birth, hence, Fraser syndrome can easily diagnosed at birth, except when health professionals are inexperienced in clinical recognition. Herein, we report a case of Fraser syndrome missed out at birth and fortuitously diagnosed at the age of six months in a bid to raise clinicians’ awareness, particularly in resource-limited settings. Case presentation We report a case of a six-month-old Cameroonian female infant, born at home and taken the following day to a primary healthcare facility for neonatal care. Her mother had no antenatal care until birth. She presented at our health center with respiratory distress and fever. She had a temperature of 38.8 °C and signs of left lung basal consolidation, suggestive of a left lower lober pneumonia, confirmed on chest x-ray. Other incidental clinical findings were several dysmorphic features like bilateral cryptophthalmos, nasal malformation, anal imperforation (with a perianal fistula), an external genital anomaly and syndactyly characteristic of Fraser syndrome associated with pneumonia. The patient responded well to intravenous antibiotics for the treatment of her pneumonia. Thereafter, she was referred to a pediatric surgeaon for surgical corrections of her bilateral cryptophthalmos, anal imperforation, external genital defect and syndactyly. Conclusion Here we presented a case of Fraser syndrome in a Cameroonian infant whose diagnosis was missed out at birth and fortuitously made at six months of age. In view of the serious and potentially fatal complications of this genetic disorder, we draw clinicians’ attention, especially obstetricians, midwives and pediatricians for a high index of clinical suspicion geared at a timely diagnosis and management. Also, for a timely diagnosis, health education on regular antenatal and postnatal follow ups of the mother-infant couple respectively, cannot be overemphasized.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Diagnosis of Fraser syndrome missed out until the age of six months old in a low-resource setting: a case report

et al. 2019

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“…This variant was predicted as pathogenic by the functional prediction programs SIFT, Polyphen-2 and MutationTaster, with a GERP score of 3.79 and a CADD score of 18.07. It was reported that homozygosity for a splice site mutation in the FREM2 gene was associated with Fraser syndrome and that compound heterozygosity for a missense mutation was related to cryptophthalmos [28,29].…”

Section: Variants Identified In Potential Kfs-associated Genesmentioning

confidence: 99%

The mutational burden and oligogenic inheritance in Klippel-Feil syndrome

Zhao

Cai

et al. 2020

BMC Musculoskelet Disord

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Background: Klippel-Feil syndrome (KFS) represents a rare anomaly characterized by congenital fusion of the cervical vertebrae. The underlying molecular etiology remains largely unknown because of the genetic and phenotypic heterogeneity. Methods: We consecutively recruited a Chinese cohort of 37 patients with KFS. The clinical manifestations and radiological assessments were analyzed and whole-exome sequencing (WES) was performed. Additionally, rare variants in KFS cases and controls were compared using genetic burden analysis. Results: We primarily examined rare variants in five reported genes (GDF6, MEOX1, GDF3, MYO18B and RIPPLY2) associated with KFS and detected three variants of uncertain significance in MYO18B. Based on rare variant burden analysis of 96 candidate genes related to vertebral segmentation defects, we identified BAZ1B as having the highest probability of association with KFS, followed by FREM2, SUFU, VANGL1 and KMT2D. In addition, seven patients were proposed to show potential oligogenic inheritance involving more than one variants in candidate genes, the frequency of which was significantly higher than that in the in-house controls. Conclusions: Our study presents an exome-sequenced cohort and identifies five novel genes potentially associated with KFS, extending the spectrum of known mutations contributing to this syndrome. Furthermore, the genetic burden analysis provides further evidence for potential oligogenic inheritance of KFS.

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“…FRAS1 Related Extracellular Matrix 2 (FREM2), located on 13q13.3, encodes an integral membrane protein that contains a large amount of chondroitin sulfate proteoglycan element repeats and Calx-beta domains (Yu et al, 2018), which confer it with sodium-calcium exchanger activity, permitting this protein to export calcium from the cell. Additionally, FREM2 forms part of the FREM2-FRAS1-FREM1 protein complex, which plays an important role in epidermal-dermal interactions (Kiyozumi et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Identification and Comprehensive Analysis of FREM2 Mutation as a Potential Prognostic Biomarker in Colorectal Cancer

Wang

Kong

et al. 2022

Front. Mol. Biosci.

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Gene mutations play an important role in tumor progression. This study aimed to identify genes that were mutated in colorectal cancer (CRC) and to explore their biological effects and prognostic value in CRC patients. We performed somatic mutation analysis using data sets from The Cancer Genome Atlas and International Cancer Genome Consortium, and identified that FREM2 had the highest mutation frequency in patients with colon adenocarcinoma (COAD). COAD patients were divided into FREM2-mutated type (n = 36) and FREM2-wild type (n = 278), and a Kaplan-Meier survival curve was generated to perform prognostic analysis. A FREM2-mutation prognosis model was constructed using random forest method, and the performance of the model was evaluated using receiver operating characteristic curve. Next, the random forest method and Cox regression analysis were used to construct a prognostic model based on the gene expression data of 36 FREM2-mutant COAD patients. The model showed a high prediction accuracy (83.9%), and 13 prognostic model characteristic genes related to overall survival were identified. Then, the results of tumor mutation burden (TMB) and microsatellite instability (MSI) analyses revealed significant differences in TMB and MSI among the risk scores of different prognostic models. Differentially expressed genes were identified and analyzed for functional enrichment and immune infiltration. Finally, 30 samples of CRC patients were collected for immunohistochemical staining to analyze the FREM2 expression levels, which showed that FREM2 was highly expressed in tumor tissues. In conclusion, CRC patients had a high level of FREM2 mutations associated with a worse prognosis, which indicated that FREM2 mutations may be potential prognostic markers in CRC.

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A homozygous mutation p.Arg2167Trp in FREM2 causes isolated cryptophthalmos

Cited by 14 publications

References 35 publications

Diagnosis of Fraser syndrome missed out until the age of six months old in a low-resource setting: a case report

Diagnosis of Fraser syndrome missed out until the age of six months old in a low-resource setting: a case report

The mutational burden and oligogenic inheritance in Klippel-Feil syndrome

Identification and Comprehensive Analysis of FREM2 Mutation as a Potential Prognostic Biomarker in Colorectal Cancer

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