OBJECTIVE: We aimed to examine the correlation between clinical characteristics and the pathogenic gene variants in patients with Primary Ciliary Dyskinesia (PCD).
METHODS: We conducted a retrospective single-center study in patients with PCD followed at the University Hospitals Leuven. We included patients with genetically confirmed PCD and described their genotype, data from ultrastructural ciliary evaluation and clinical characteristics. Genotype/phenotype correlations were studied in patients with the most frequently involved genes.
RESULTS: We enrolled 74 patients with a median age of 25.58 years. The most frequently involved genes were DNAH11 (n = 23) and DNAH5 (n = 19). The most frequent types of pathogenic variants were missense (n = 42) and frameshift variants (n = 36) and most patients had compound heterozygous variants (n = 44). Ciliary ultrastructure (p < 0.001), situs (p = 0.015) and age at diagnosis (median 9.50 vs 4.71 years, p = 0.037) differed between DNAH11 and DNAH5. When correcting for situs this difference in age at diagnosis was no longer significant (p = 0.973). Patients with situs inversus were diagnosed earlier (p = 0.031). Respiratory tract microbiology (p = 0.161), lung function (cross-sectional, p = 0.829 and longitudinal, p = 0.329) and chest CT abnormalities (p = 0.202) were not significantly different between DNAH11 and DNAH5 variants.
CONCLUSIONS: This study suggests a genotype-phenotype correlation for some of the evaluated clinical characteristics of the two most frequently involved genes in this study, namely DNAH11 and DNAH5.

OBJECTIVE: To describe the clinical characteristics of Chinese cystic fibrosis (CF) patients and to investigate the variants of CFTR and their potential pathogenicity.
METHODS: Chinese patients with potential CF diagnosis were studied. Clinical data were reviewed retrospectively from medical records. Whole exome sequencing and genetic evaluation were conducted to explore potential gene variants. The disruption of the variants to protein structure and function was explored and validated using in vitro experiments and in silico analysis.
RESULTS: Four patients were recruited to the study, three of them were diagnosed as CF, and one was diagnosed as CFTR-related disorder. The age at symptom onset for the patients in this study ranged from newborn to 6 years, while the age at diagnosis varied from 3 to 11 years. All four patients exhibited bilateral diffuse bronchiectasis with Pseudomonas aeruginosa infections, and three of them had malnutrition. Finger clubbing was observed in three patients, two of whom displayed mixed ventilatory dysfunction. The CFTR variants spectrum of Chinese children with CF differs from that of Caucasian. A total of six variants were identified, two of which were first reported (c.1219G > T [p.Glu407*] and c.1367delT [p.Ala457Leufs*12]). The nonsense variants c.1219G > T, c.1657C > T and c.2551C > T and the frameshift variant c.1367delT were predicted to introduce premature stop codon and produce shorten CFTR protein, which was also first validated by in vitro truncation assay in this study. The missense variant c.1810A > C was predicted to disrupt the function of the nucleotide-binding domain 1 (NBD1) in the CFTR protein. The splicing variant c.1766 + 5G > T caused skipping of exon 13 and damaged the integrity of CFTR protein.
CONCLUSIONS: Our study expands the spectrum of phenotypes and genotypes for CF of Chinese origin, which differs significantly from that of Caucasian. Genetic analysis and counseling are crucial and deserve extensive popularization for the diagnosis ofCF in patients of Chinese origin.

In this study, we report a novel splice variant in the TRA2B gene identified in a patient presenting with seizures and neurodevelopmental delay. This paper represents the second investigation of pathogenic variants in the TRA2B gene in humans, reaffirming the conclusions of the initial study and underscoring the importance of this research. Comprehensive genetic testing, including whole genome sequencing, Sanger sequencing, and mRNA analysis, was performed on the proband and her parents. The proband harbored a de novo c.170+1G>A variant in the RS1 domain of Tra2β, which was confirmed to be pathogenic through mRNA analysis, resulting in exon 2 deletion and a frameshift (p.Glu13Valfs*2). The clinical presentation of the patient was consistent with phenotypes described in one of the previous studies. These findings contribute to the dissemination and reinforcement of prior discoveries in the context of TRA2B-related syndrome and highlight the need for further investigation into the functional consequences and underlying pathogenic mechanisms associated with TRA2B mutations.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease. While biallelic variants affecting IFT140 are responsible for Mainzer-Saldino syndrome (characterized by severe ciliopathy causing skeletal abnormalities, kidney disease, and cysts), monoallelic loss-of-function (LoF) variants have been recently reported as an important cause of ADPKD beyond PKD1/2 genes. Herein, we report 6 non-family-related cases of monoallelic IFT140 LoF variants, identified from 1,340 exomes sequenced for nephrological indications in our local database. Every patient presented with polycystic kidney disease. Furthermore, the mother of a boy diagnosed with Mainzer-Saldino syndrome with a biallelic variant affecting IFT140 presented with several bilateral cysts, revealed after kidney imaging, and was found to carry a pathologic frameshift IFT140 variation. As well as this particular Mainzer-Saldino case, our 6 additional patients confirm that heterozygous IFT140 frameshift variants are responsible for the cystic phenotype and kidney failure. Interestingly, of the 6 patients, 2 also exhibited dilated cardiomyopathy, which was of unknown origin, as no genetic cause was found after exome sequencing analysis, suggesting a potential connection between IFT140 and heart disease.

Treacher Collins syndrome (TCS) is a rare disorder of craniofacial development following different patterns of inheritance. To date, mutations in four genes ( TCOF1, POLR1D, POLR1C , and POLR1B ) have been found to cause the condition. The molecular defect remains unidentified in a significant proportion of patients. In the current study, whole exome sequencing including analysis of copy number variants was applied for genetic testing of eight Egyptian patients with typical TCS phenotype, representing the first molecular analysis of TCS patients in Egypt as well as in Arab countries. Five heterozygous frameshift mutations were reported, including four variants in the TCOF1 gene (c.3676_3694delinsCTCTGG, c.3984_3985delGA, c.4366_4369delGAAA, and c.3388delC) and one variant in the POLR1D gene (c.60dupA). Four variants were novel extending the disease mutation spectrum. In three affected individuals, no variants of interest were identified in genes associated with TCS or clinically overlapping conditions. Additionally, no relevant variant was detected in genes encoding other subunits of RNA polymerase (pol) I. Molecular analysis is important to provide accurate genetic counseling. It would also contribute to reduced disease incidence. Further studies should be designed to investigate other possible etiologies when no pathogenic variants were revealed in either of the known genes.

This study was conducted to investigate potential candidate pathogenic genes in early-onset high myopia (eoHM) in families with eoHM.
Whole-exome sequencing was performed on probands with eoHM to identify potential pathogenic genes. Sanger sequencing was used to verify the identified gene mutations causing eoHM in first-degree relatives of the proband. The identified mutations were screened out by bioinformatics analysis combined with segregation analysis.
A total of 131 variant loci, involving 97 genes, were detected in the 30 families. A total of 28 genes (37 variants), which were carried by 24 families, were verified and analyzed by Sanger sequencing. We identified five genes and 10 loci associated with eoHM, which have not been reported in previous research. Hemizygous mutations in COL4A5, NYX, and CACNA1F were detected in this study. Inherited retinal disease-associated genes were found in 76.67% (23/30) of families. Genes that can be expressed in the retina in the Online Mendelian Inheritance in Man database were found in 33.33% (10/30) of families. Mutations in the genes associated with eoHM, including CCDC111, SLC39A5, P4HA2, CPSF1, P4HA2, and GRM6, were detected. The mutual correlation between candidate genes and phenotype of fundus photography was revealed in our study. The eoHM candidate gene mutation types contain five categories: missense mutations (78.38%), nonsense (8.11%), frameshift mutation (5.41%), classical splice site mutation (5.41%), and initiation codon mutation (2.70%).
Candidate genes carried by patients with eoHM are closely related to inherited retinal diseases. Genetic screening in children with eoHM facilitates the early identification and intervention of syndromic hereditary ocular disorders and certain hereditary ophthalmopathies.

The purpose of this paper is to present a case study illustrating the importance of electrophysiological investigation in the diagnosis and serial monitoring of isolated congenital nystagmus.
Serial electophysiological monitoring was undertaken in the male proband over a 9-year period commencing with initial assessment at 12 weeks of age: Skin electroretinograms (sERGs) were initially absent but subsequently revealed low-amplitude responses, electronegative morphologies and notched flicker responses suggestive of incomplete congenital stationary night blindness (CSNB2), but with an absent dark-adapted rod-specific response, while flash visual evoked potentials (fVEPs) demonstrated persistent crossed asymmetry, typical of albinoid misrouting of the optic nerves. Molecular investigation confirmed a novel hemizygous frame shift mutation in the CACNA1F gene, considered to be pathogenic and causative of X-linked CSNB2; additionally, a novel heterozygous missense variation in one copy of the RIMS1 gene was identified, pathogenic mutations of which underpin late-onset autosomal dominant cone-rod dystrophy (type 7). Segregation studies confirmed maternal inheritance of both mutations in the clinically asymptomatic mother in whom depressed rod-specific responses were confirmed on sERG. The child\'s visual acuity has remained stable as have the sERGs which have been verified by recordings using scleral electrodes.
The importance of recording ERGs as part of evaluating infants who present with nystagmus, even with a normal fundus appearance, is supported. Further, sERGs were able to distinguish an apparent variant of CSNB2 and could give consistent results over many years. FVEP results add to the evidence that albinoid misrouting of the optic nerves may occur in cases of CSNB2. ERGs and fVEPs can provide valuable information in discriminating the relative diagnostic importance of multiple genetic abnormalities.

OBJECTIVE: To investigate the pathogenic gene of a patient with nonsyndromic oligodontia, and analyze its possible pathogenic mechanism.
METHODS: The variant was detected by whole exome sequencing (WES) and Sanger sequencing in a family with oligodontia. Bioinformatic and structural analyses were used to analyze variant. Functional studies including western blotting and immunofluorescent analyses and luciferase reporter assay were conducted to explore the functional effects.
RESULTS: We identified a novel frameshift variant of PAX9 (c.491-510delGCCCT-ATCACGGCGGCGGCC, p.P165Qfs*145) outside the DNA-binding domain causing an autosomal-dominant nonsyndromic oligodontia in a Chinese family. Bioinformatic and structural analyses revealed that the variant is pathogenic and conserved evolutionarily, and the changes might affect protein stability or folding. Functional studies demonstrate dramatically reduced ability in activating transcription activity of BMP4 promoter and a marked decrease in protein production, as evaluated by western blotting and immunofluorescent analyses.
CONCLUSIONS: We found a novel frameshift variant of PAX9 causing nonsyndromic oligodontia in a Chinese family. Our findings indicate that frameshift variants cause loss of function of PAX9 protein during the patterning of the dentition and the subsequent tooth agenesis, providing new molecular insights into the role of frameshift variant of PAX9 and broaden the pathogenic spectrum of PAX9 variants.

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DNA mismatch repair (MMR) deficiency is a hallmark of Lynch syndrome, the most common inherited cancer syndrome. MMR-deficient cancer cells accumulate numerous insertion/deletion mutations at microsatellites. Mutations of coding microsatellites (cMS) lead to the generation of immunogenic frameshift peptide (FSP) neoantigens. As the evolution of MMR-deficient cancers is triggered by mutations inactivating defined cMS-containing tumor suppressor genes, distinct FSP neoantigens are shared by most MMR-deficient cancers. To evaluate safety and immunogenicity of an FSP-based vaccine, we performed a clinical phase I/IIa trial (Micoryx).
The trial comprised three cycles of four subcutaneous vaccinations (FSP neoantigens derived from mutant AIM2, HT001, TAF1B genes) mixed with Montanide ISA-51 VG over 6 months. Inclusion criteria were history of MMR-deficient colorectal cancer (UICC stage III or IV) and completion of chemotherapy. Phase I evaluated safety and toxicity as primary endpoint (six patients), phase IIa addressed cellular and humoral immune responses (16 patients).
Vaccine-induced humoral and cellular immune responses were observed in all patients vaccinated per protocol. Three patients developed grade 2 local injection site reactions. No vaccination-induced severe adverse events occurred. One heavily pretreated patient with bulky metastases showed stable disease and stable CEA levels over 7 months.
FSP neoantigen vaccination is systemically well tolerated and consistently induces humoral and cellular immune responses, thus representing a promising novel approach for treatment and even prevention of MMR-deficient cancer.