OBJECTIVE: The goal of the study was to search for novel bi-allelic CRB1 mutations, and then to analyze the CRB1 literature at the genotypic and phenotypic levels.
METHODS: We screened various variables such as the CRB1 mutation types, domains, exons, and genotypes and their relation with specific ocular phenotypes. An emphasis was given to the bi-allelic missense and nonsense mutations because of their high prevalence compared to other mutation types. Finally, we quantified the effect of various non-modifiable factors over the best-corrected visual acuity oculus uterque (BCVA OU) using multivariate linear regression models and identified genetic interactions.
RESULTS: A novel bi-allelic missense in the exon 9 of CRB1; c.2936G > A; p.(Gly979Asp) was found to be associated with rod-cone dystrophy (RCD). CRB1 mutation type, exons, domains, and genotype distribution varied significantly according to fundus characteristics, such as peripheral pigmentation and condition, optic disc, vessels, macular condition, and pigmentation (P < 0.05). Of the 154 articles retrieved from PubMed, 96 studies with 439 bi-allelic CRB1 patients were included. Missense mutations were significantly associated with an absence of macular pigments, pale optic disc, and periphery pigmentation, resulting in a higher risk of RCD (P < 0.05). In contrast, homozygous nonsense mutations were associated with macular pigments, periphery pigments, and a high risk of LCA (P < 0.05) and increased BCVA OU levels. We found that age, mutation types, and inherited retinal diseases were critical determinants of BCVA OU as they significantly increased it by 33% 26%, and 38%, respectively (P < 0.05). Loss of function alleles additively increased the risk of LCA, with nonsense having a more profound effect than indels. Finally, our analysis showed that p.(Cys948Tyr) and p.(Lys801Ter) and p.(Lys801Ter); p.(Cys896Ter) might interact to modify BCVA OU levels.
CONCLUSIONS: This meta-analysis updated the literature and identified genotype-phenotype associations in bi-allelic CRB1 patients.

BACKGROUND: Although the p.C759F (c.2276G>T, p.Cys759Phe) variant in the USH2A gene has been identified in association with retinal degeneration by several authors, its pathogenicity has been questioned once by the publication of two unaffected homozygotes from a single family.
OBJECTIVE: The objective of the study was to ascertain the role of p.C759F in hereditary retinal disease.
METHODS: We examined 87 research articles reporting on patients carrying this variant and then used this information as primary data for a series of meta-analytical tests.
RESULTS: Independent statistical analyses showed that p.C759F (i) is highly enriched in patients with respect to healthy individuals, (ii) represents a clear-cut recessive allele causing disease when it is in trans with other mutations, (iii) is pathogenic in homozygotes.
CONCLUSIONS: Our results confirm that p.C759F is a bona fide mutation, leading to retinal blindness according to a recessive pattern of inheritance.

Familial exudative vitreoretinopathy (FEVR) is a severe clinically and genetically heterogeneous disease that is characterized by vascular disorder. FEVR exhibits strikingly variable clinical phenotypes, ranging from asymptomatic to total blindness. In this case, we present a patient who was first treated as having high myopia and retinopathy but was finally diagnosed with FEVR caused by the heterozygous deletion of exon 7 in TSPAN12 with the aid of whole genome sequencing (WGS). Typical vascular changes, including vascular leakage and an avascular zone in the peripheral retina, were observed in the proband using fundus fluorescein angiography (FFA), and the macular dragging was shown to be progressing in the follow-up visit. Furthermore, the proband showed unreported TSPAN12-related phenotypes of FEVR: ERG (full-field electroretinogram) abnormalities and retinoschisis. Only mild vascular changes were exhibited in the FFA for the other three family members who carried the same deletion of exon 7 in TSPAN12. This case expands our understanding of the phenotype resulting from TSPAN12 mutations and signifies the importance of combining both clinical and molecular analysis approaches to establish a complete diagnosis.

OBJECTIVE: Primary double KIT/PDGFRA mutations are very rare in gastrointestinal stromal tumours (GISTs) but have not been comprehensively studied to date. In the present study, we investigated the clinicopathologic and genetic features of eight cases of primary double-mutant GISTs, and we reviewed the literature.
RESULTS: The tumours occurred in six males and two females (age range 57-83 years) and involved the small intestine (n = 4), stomach (n = 2), rectum (n = 1) and retroperitoneum (n = 1). Clinical manifestations were variable, ranging from indolent (no symptoms) to aggressive disease (tumour rupture and haemorrhage). All patients underwent surgical excision, and six of them were treated with imatinib. No one experienced recurrence or other complications during the follow-up time (10 to 61 months). Histologically, all the tumours exhibited mixed cell types, accompanied by variable interstitial changes. KIT mutations were detected in all cases, and the majority of them were present in different exons (n = 5). No PDGFRA exon 12, 14 or 18 mutations were found. All the mutations were validated by next-generation sequencing, and two additional variants with comparatively low allelic fractions were identified in one case. Two of the cases had available allele distribution data, one with an in cis compound mutation and the other with an in trans compound mutation.
CONCLUSIONS: Primary double-mutant GISTs have distinctive clinicopathologic and mutational features. Studies of more cases are necessary for a better understanding of these tumours.

Ongoing trials for retinitis pigmentosa (RP) are genotype-specific, with most trials conducted on European cohorts. Due to genetic differences across diverse ancestries and populations, these therapies may not be efficacious in East Asians.
A literature search was conducted from 1966 to September 2022 for cohort studies on East Asian populations reporting on non-syndromic RP genotypes and variants. Population-weighted prevalence was used to determine the genotypes and individual variants across the entire cohort. The carrier prevalence of common variants was compared against those in Europe.
A total of 12 articles describing 2,932 clinically diagnosed East Asian RP probands were included. We identified 876 variants across 54 genes. The most common genotypes included USH2A, EYS, RPGR, ABCA4, PRPF31, RHO, RP1, RP2, PDE6B and SNRNP200, with USH2A as the most common (17.1%). Overall, 60.5% of probands with clinically relevant variants were found to have one of the genotypes above, with 543/876 (62.0%) of the variants occurring in these genes. The most frequently reported variant was USH2A missense variant c.2802T>G/p.C934W (4.9%). Carrier prevalence of these variants was significantly different (p < 0.0001) than in Europe.
USH2A was the most commonly affected RP gene in this East Asian cohort, although sub-population analysis revealed distinct genotype prevalence patterns. While the genotypes are similar between East Asia and European cohorts, variants are specific to East Asia. The identification of several prevalent variants in USH2A and EYS provides an opportunity for the development of therapeutics that are relevant for East Asia patients.

Marfan syndrome (MFS) is a life-threatening autosomal dominant genetic disorder of connective tissue caused by the pathogenic mutation of FBN1. Whole exome sequencing and Sanger sequencing were performed to identify the pathogenic mutation. The transcriptional consequence of the splice-altering mutation was analyzed via minigene assays and reverse-transcription PCR. We identified a novel pathogenic mutation (c.8051+1G>C) in the splice site of exon 64 of the FBN1 gene in an MFS-pedigree. This mutation was confirmed to cause two different truncated transcripts (entire exon 64 skipping; partial exon 64 exclusion). We also systematically summarized previously reported transcriptional studies of pathogenic splice-altering mutations in the FBN1 gene to investigate the clinical and transcriptional consequences. In conclusion, we reported for the first time that a splice-altering mutation in the FBN1 gene leads to two abnormal transcripts simultaneously.

RPGR mutations are the most common cause of X-linked retinitis pigmentosa (XLRP). High myopia has been described as a very frequent feature among affected female carriers of XLRP. However, the clinical phenotype of female patients presenting with X-linked RPGR-related high myopia has not been well described.
Retrospective case series of four female patients with RPGR mutations and a diagnosis of high myopia, who presented to two academic eye centers. Clinical data, including age, family history, visual acuity, refractive error, dilated fundus exam, fundus photography, optical coherence tomography, electroretinography, and results of genetic testing, were collected.
Three RPGR variants identified in the present study have not been previously associated with myopia in female carriers. One variant (c.2405_2406delAG, p.Glu802Glyfs *32) has been previously associated with a myopic phenotype in a female patient. Patients became symptomatic between the first and sixth decades of life. Myopia-associated tilted optic discs and posterior staphyloma were present in all patients. Two patients presented with intraretinal migration of the retinal pigment epithelium.
RPGR-related high myopia has been associated with mutations in exons 1-14 and ORF15 in heterozygous females. There is a wide range of visual function among carriers. Although the exact mechanism of RPGR-related high myopia is still unclear, continued molecular diagnosis and description of phenotypes remain a crucial step in understanding the impact of RPGR mutations on visual function in female XLRP carriers.

Sinonasal mucosal melanoma is a rare tumor arising within the nasal cavity, paranasal sinuses, or nasopharynx (sinonasal tract). This study evaluated 90 cases diagnosed in 29 males and 61 females with median age 68 years. Most tumors involved the nasal cavity and had an epithelioid morphology. Spectrum of research techniques used in this analysis includes targeted-DNA and -RNA next-generation sequencing, Sanger sequencing, fluorescence in situ hybridization and immunohistochemistry. Sinonasal melanomas were commonly driven by RAS (38/90, 42%), especially NRAS (n = 36) mutations and rarely (4/90, 4%) displayed BRAF pathogenic variants. BRAF/RAS mutants were more frequent among paranasal sinuses (10/14, 71%) than nasal (26/64, 41%) tumors. BRAF/RAS-wild type tumors occasionally harbored alterations of the key components and regulators of Ras-MAPK signaling pathway: NF1 mutations (1/17, 6%) or NF1 locus deletions (1/25, 4%), SPRED1 (3/25, 12%), PIK3CA (3/50, 6%), PTEN (4/50, 8%) and mTOR (1/50, 2%) mutations. These mutations often occurred in a mutually exclusive manner. In several tumors some of which were NRAS mutants, TP53 was deleted (6/48, 13%) and/or mutated (5/90, 6%). Variable nuclear accumulation of TP53, mirrored by elevated nuclear MDM2 expression was seen in >50% of cases. Furthermore, sinonasal melanomas (n = 7) including RAS/BRAF-wild type tumors (n = 5) harbored alterations of the key components and regulators of canonical WNT-pathway: APC (4/90, 4%), CTNNB1 (3/90, 3%) and AMER1 (1/90, 1%). Both, TERT promoter mutations (5/53, 9%) and fusions (2/40, 5%) were identified. The latter occurred in BRAF/RAS-wild type tumors. No oncogenic fusion gene transcripts previously reported in cutaneous melanomas were detected. Eight tumors including 7 BRAF/RAS-wild type cases expressed ADCK4::NUMBL cis-fusion transcripts. In summary, this study documented mutational activation of NRAS and other key components and regulators of Ras-MAPK signaling pathway such as SPRED1 in a majority of sinonasal melanomas.

To systematically review the relationship between genotypes and clinical phenotypes of Familial exudative vitreoretinopathy (FEVR) to support risk estimation and therapeutic decisions.
Systematic review with meta-analysis.
The data of our study were collected from PubMed, Embase, Web of Science, Cochrane, CBM, China National Knowledge Infrastructure (CNKI), WAN FANG and VIP databases since inception to August 2021.
A total of 3257 patients from 32 studies were included according to the inclusion and exclusion criteria. Among all the cases, the mutation frequencies of LRP5, FZD4, NDP, TSPAN12, ZNF408 and KIF11 were 13.6%, 11.5%, 4.6%, 6.7%, 1.6%, and 5.7%, respectively. We found that the patients with NDP and FZD4 suffer more severe symptoms, among which 86.4% patients of NDP and 78.6% patients of FZD4 were in the advanced stage of FEVR. Retinal detachment is the most frequent symptom with patients of LRP5 and NDP mutations, accounting for 51.9% and 64.5%, respectively. For the patients with the mutation of TSPAN12, retinal fold is the most common clinical manifestation, and suffer the mildest clinical phenotypes compared with the other three genes.
The results of the meta-analysis indicate that different types of genetic mutations occur at different frequencies. In addition, the clinical manifestations of FEVR are related to the type of gene mutation. Therefore, targeted treatment strategies and follow-up recommendations should be adopted for different pathogenic genes of FEVR.

Circulating tumor DNA (ctDNA) is a type of cell-free DNA released by tumor cells after necrosis and apoptosis, and it can be actively secreted by tumor cells. Since ctDNA is derived from various tumor sites, it can provide far more comprehensive genomic and epigenomic information than a single-site biopsy. Therefore, ctDNA can overcome tumor heterogeneity, which is the major limitation of a traditional tissue biopsy approach. Noninvasive ctDNA assays allow continuous real-time monitoring of the molecular status of cancers. Recently, ctDNA assays have been widely used in clinical practice, including cancer diagnosis, evaluation of therapeutic efficacy and prognosis, and monitoring of relapse and metastasis. Although ctDNA shows a high diagnostic performance in advanced esophageal cancer, it is far from satisfactory for early diagnosis of esophageal cancer. Monitoring the dynamic changes of ctDNA is beneficial for the evaluation of therapeutic efficacy and prediction of early recurrence in esophageal cancer. It is necessary to establish standards for individualized ctDNA detection in the evaluation of treatment response and surveillance of esophageal cancer and to develop clinical practice guideline for the systemic treatment of patients with \"ctDNA recurrence.\" This review aims to provide an update on the role of ctDNA in the diagnosis and monitoring of esophageal cancer.