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European Journal of Human Genetics :... Apr 2023Deleterious variants of DYNC2H1 gene are associated with a wide spectrum of skeletal ciliopathies (SC). We used targeted parallel sequencing to analyze 25 molecularly...
Deleterious variants of DYNC2H1 gene are associated with a wide spectrum of skeletal ciliopathies (SC). We used targeted parallel sequencing to analyze 25 molecularly unsolved families with different SCs. Deleterious DYNC2H1 variants were found in six sporadic patients and two monozygotic (MZ) twins. Clinical diagnoses included short rib-polydactyly type 3 in two cases, and asphyxiating thoracic dystrophy (ATD) in one case. Remarkably, clinical diagnosis fitted with EvC, mixed ATD/EvC and short rib-polydactyly/EvC phenotypes in three sporadic patients and the MZ twins. EvC/EvC-like features always occurred in compound heterozygotes sharing a previously unreported splice site change (c.6140-5A>G) or compound heterozygotes for two missense variants. These results expand the DYNC2H1 mutational repertoire and its clinical spectrum, suggesting that EvC may be occasionally caused by DYNC2H1 variants presumably acting as hypomorphic alleles.
Topics: Humans; Ciliopathies; Cytoplasmic Dyneins; Ellis-Van Creveld Syndrome; Mutation; Polydactyly
PubMed: 36599940
DOI: 10.1038/s41431-022-01276-7 -
Radiation Research Jan 2023Radiation-induced gene expression (GE) changes can be used for early and high-throughput biodosimetry within the first three days postirradiation. However, is the method...
Radiation-induced gene expression (GE) changes can be used for early and high-throughput biodosimetry within the first three days postirradiation. However, is the method applicable in situations such as the Alexander Litvinenko case or the Goiania accident, where diagnosis occurred in a prefinal health stage? We aimed to characterize gene expression changes in a prefinal health stage of lethally irradiated male and female rhesus macaques. Peripheral blood was drawn pre-exposure and at the prefinal stage of male and female animals, which did not survive whole-body exposure with 700 cGy (LD66/60). RNA samples originated from a blinded randomized Good Laboratory Practice study comprising altogether 142 irradiated rhesus macaques of whom 60 animals and blood samples (15 samples for both time points and sexes) were used for this analysis. We evaluated GE on 34 genes widely used in biodosimetry and prediction of the hematological acute radiation syndrome severity (H-ARS) employing quantitative real-time polymerase chain reaction (qRT-PCR). These genes were run in duplicate and triplicate and altogether 96 measurements per time point and sex could be performed. In addition, 18S ribosomal RNA (rRNA) was measured to depict the ribosome/transcriptome status as well as for normalization purposes and 16S rRNA was evaluated as a surrogate for bacteremia. Mean differential gene expression (DGE) was calculated for each gene and sex including all replicate measurements and using pre-exposure samples as the reference. From 34 genes, altogether 27 genes appeared expressed. Pre-exposure samples revealed no signs of bacteremia and 18S rRNA GE was in the normal range in all 30 samples. Regarding prefinal samples, 46.7% and 40% of animals appeared infected in females and males, respectively, and for almost all males this was associated with out of normal range 18S rRNA values. The total number of detectable GE measurements was sixfold (females) and 15-fold (males) reduced in prefinal relative to pre-exposure samples and about tenfold lower in 80% of prefinal compared to pre-exposure samples (P < 0.0001). An overall 11-fold (median) downregulation in prefinal compared to pre-exposure samples was identified for most of the 27 genes and even FDXR appeared 4-14-fold downregulated in contrast to a pronounced up-regulation according to cited work. This pattern of overall downregulation of almost all genes and the rapid reduction of detectable genes at a prefinal stage was found in uninfected animals with normal range 18S rRNA as well. In conclusion, in a prefinal stage after lethal radiation exposure, the ribosome/transcriptome status remains present (based on normal range 18S rRNA values) in 60-67% of animals, but the whole transcriptome activity in general appears silenced and cannot be used for biodosimetry purposes, but probably as an indicator for an emerging prefinal health stage.
Topics: Animals; Male; Female; Macaca mulatta; RNA, Ribosomal, 18S; RNA, Ribosomal, 16S; Transcriptome; Bacteremia; Gene Expression Profiling
PubMed: 36445953
DOI: 10.1667/RADE-22-00083.1 -
Cold Spring Harbor Molecular Case... Dec 2022Biallelic pathogenic variants in are the cause of short-rib thoracic dysplasia type III with or without polydactyly (OMIM #613091), a skeletal ciliopathy characterized...
Biallelic pathogenic variants in are the cause of short-rib thoracic dysplasia type III with or without polydactyly (OMIM #613091), a skeletal ciliopathy characterized by thoracic hypoplasia due to short ribs. In this report, we review the case of a patient who was admitted to the Neonatal Intensive Care Unit (NICU) of Indiana University Health (IUH) for respiratory support after experiencing respiratory distress secondary to a small, narrow chest causing restrictive lung disease. Additional phenotypic features include postaxial polydactyly, short proximal long bones, and ambiguous genitalia were noted. Exome sequencing (ES) revealed a maternally inherited likely pathogenic variant c.10322C > T p.(Leu3448Pro) in the gene. However, there was no variant found on the paternal allele. Microarray analysis to detect deletion or duplication in was normal. Therefore, there was insufficient evidence to establish a molecular diagnosis. To further explore the data and perform additional investigations, the patient was subsequently enrolled in the Undiagnosed Rare Disease Clinic (URDC) at Indiana University School of Medicine (IUSM). The investigators at the URDC performed a reanalysis of the ES raw data, which revealed a paternally inherited deep-intronic variant c.10606-14A > G predicted to create a strong cryptic acceptor splice site. Additionally, the RNA sequencing of fibroblasts demonstrated partial intron retention predicted to cause a premature stop codon and nonsense-mediated mRNA decay (NMD). Droplet digital RT-PCR (RT-ddPCR) showed a drastic reduction by 74% of mRNA levels. As a result, the intronic variant was subsequently reclassified as likely pathogenic resulting in a definitive clinical and genetic diagnosis for this patient. Reanalysis of ES and fibroblast mRNA experiments confirmed the pathogenicity of the splicing variants to supplement critical information not revealed in original ES or CMA reports. The NICU and URDC collaboration ended the diagnostic odyssey for this family; furthermore, its importance is emphasized by the possibility of prenatally diagnosing the mother's current pregnancy.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Cytoplasmic Dyneins; Exome Sequencing; Mutation; Polydactyly; Ribs; RNA, Messenger; Short Rib-Polydactyly Syndrome
PubMed: 36442996
DOI: 10.1101/mcs.a006254 -
Ophthalmic Genetics Oct 2023Axial spondylometaphyseal dysplasia(axial SMD) is associated with early-onset retinal dystrophy and various skeletal dysplasias of varying severity. is the causative...
BACKGROUND
Axial spondylometaphyseal dysplasia(axial SMD) is associated with early-onset retinal dystrophy and various skeletal dysplasias of varying severity. is the causative gene for short rib polydactyly syndrome and axial SMD. Here, we report a case of siblings with juvenile retinitis pigmentosa (RP) and variants not associated with systemic disorders.
MATERIALS AND METHODS
The patients were a 7-year-old-girl and a 9-year-old boy with RP, who were followed for 9 years. Whole exome sequencing (WES) was performed on the siblings and their parents, who were not consanguineous.
RESULTS
The corrected visual acuity of the girl and the boy at first visit was binocular 20/63 and 20/100 OD and 20/63 OS, respectively. The siblings had narrowing of retinal blood vessels and retinal pigment epithelium atrophy in the fundus and showed an extinguished pattern in electroretinogram. On optical coherence tomography, there was a mottled ellipsoid band with progressive loss in the outer macular, the edges of which corresponded to the ring of hyperautofluorescence on fundus autofluorescence imaging. The siblings showed progressive visual field constriction. Radiological examination did not reveal any skeletal abnormalities. We identified two rare heterozygous variants in the patients: c.240 G>A; p.(M80I) and c.634_639dup;p.(V212_L213dup). Heterozygous variants were recognized in the father and mother, respectively. According to the guidelines of the American College of Medical Genetics and Genomics, both variants were classified as likely pathogenic.
CONCLUSION
This is the first report of RP patients with variants not associated with skeletal abnormalities.
Topics: Male; Female; Humans; Child; Siblings; Retinitis Pigmentosa; Osteochondrodysplasias; Retinal Dystrophies; Tomography, Optical Coherence; Mutation; NIMA-Related Kinase 1
PubMed: 36341712
DOI: 10.1080/13816810.2022.2141788 -
Journal of Cell Science Mar 2023The primary cilium is a sensory organelle, receiving signals from the external environment and relaying them into the cell. Mutations in proteins required for transport...
The primary cilium is a sensory organelle, receiving signals from the external environment and relaying them into the cell. Mutations in proteins required for transport in the primary cilium result in ciliopathies, a group of genetic disorders that commonly lead to the malformation of organs such as the kidney, liver and eyes and skeletal dysplasias. The motor proteins dynein-2 and kinesin-2 mediate retrograde and anterograde transport, respectively, in the cilium. WDR34 (also known as DYNC2I2), a dynein-2 intermediate chain, is required for the maintenance of cilia function. Here, we investigated WDR34 mutations identified in Jeune syndrome, short-rib polydactyly syndrome and asphyxiating thoracic dysplasia patients. There is a poor correlation between genotype and phenotype in these cases, making diagnosis and treatment highly complex. We set out to define the biological impacts on cilia formation and function of WDR34 mutations by stably expressing the mutant proteins in WDR34-knockout cells. WDR34 mutations led to different spectrums of phenotypes. Quantitative proteomics demonstrated changes in dynein-2 assembly, whereas initiation and extension of the axoneme, localization of intraflagellar transport complex-B proteins, transition zone integrity and Hedgehog signalling were also affected.
Topics: Humans; Dyneins; Carrier Proteins; Hedgehog Proteins; Ellis-Van Creveld Syndrome; Cilia; Mutation
PubMed: 36268591
DOI: 10.1242/jcs.260073 -
BMJ Case Reports Sep 2022Lethal skeletal dysplasias (SDs) are a heterogeneous group of rare but important genetic disorders characterised by abnormal growth and development of bone and...
Lethal skeletal dysplasias (SDs) are a heterogeneous group of rare but important genetic disorders characterised by abnormal growth and development of bone and cartilage. The phenotypic variation of SD highlights the complex aetiology for this group of disorders. Short rib polydactyly syndrome (SRPS) types I-IV are a group of rare congenital autosomal recessive types of SD.We report a case of a non-consanguineous couple whose two successive pregnancies were diagnosed with multiple congenital anomalies in fetuses suggestive of lethal SD (likely SRPS type IV) at 24 and 19 weeks period of gestation, respectively. Pregnancy was terminated, and the whole exome sequencing of the abortus for genetic analysis in the second pregnancy confirmed an autosomal recessive type of short rib thoracic dysplasia-4 (SRTD-4) also called SRPS in homozygous condition. Our case is unique as it was also associated with cystic hygroma which is a rare association with SRPS/SRTD-4.
Topics: Exome; Female; Humans; Pregnancy; Ribs; Short Rib-Polydactyly Syndrome; Ultrasonography, Prenatal; Exome Sequencing
PubMed: 36123010
DOI: 10.1136/bcr-2022-251118 -
Zhonghua Yi Xue Yi Chuan Xue Za Zhi =... Aug 2022To report on the clinical characteristics of a family of short-rib polydactyly syndrome type III and its pathogenic variants.
OBJECTIVE
To report on the clinical characteristics of a family of short-rib polydactyly syndrome type III and its pathogenic variants.
METHODS
Muscle samples from the the third fetus was collected after the induction of labor, and peripheral blood samples of its parents and grandparents were also collected. Whole exome sequencing (WES) was carried out for the pedigree. Candidate variants were verified by Sanger sequencing of the family.
RESULTS
The proband was found to harbor a c.9819+1G>A variant and a c.4625C>A variant of the DYNC2H1 gene, which were respectively inherited from its mother and father. Sanger sequencing verified that the family has fit the autosomal recessive inheritance.
CONCLUSION
The c.9819+1G>A and c.4625C>A variants of the DYNC2H1 gene probably underlay the short-rib polydactyly syndrome type 3 in the proband.
Topics: Child; Cytoplasmic Dyneins; Humans; Mutation; Pedigree; Ribs; Short Rib-Polydactyly Syndrome
PubMed: 35929941
DOI: 10.3760/cma.j.cn511374-20210628-00549 -
Journal of Medical Genetics Apr 2023Ellis-Van Creveld (EVC) syndrome is one of the entities belonging to the skeletal ciliopathies short rib-polydactyly subgroup. Major signs are ectodermal dysplasia,...
BACKGROUND
Ellis-Van Creveld (EVC) syndrome is one of the entities belonging to the skeletal ciliopathies short rib-polydactyly subgroup. Major signs are ectodermal dysplasia, chondrodysplasia, polydactyly and congenital cardiopathy, with a high degree of variability in phenotypes ranging from lethal to mild clinical presentations. The and genes are the major genes causative of EVC syndrome. However, an increased number of genes involved in the ciliopathy complex have been identified in EVC syndrome, leading to a better understanding of its physiopathology, namely, , , , , and . They all code for proteins located in the primary cilia, playing a key role in signal transduction of the Hedgehog pathways.
METHODS
The aim of this study was the analysis of 50 clinically identified EVC cases from 45 families to further define the phenotype and molecular bases of EVC.
RESULTS
Our detection rate in the cohort of 45 families was of 91.11%, with variants identified in (77.8%), (6.7%), (2.2%), (2.2%) or (2.2%). No distinctive feature was remarkable of a specific genotype-phenotype correlation. Interestingly, we identified a high proportion of heterozygous deletions in of variable sizes (26.92%), mostly inherited from the mother, and probably resulting from recombinations involving Alu sequences.
CONCLUSION
We confirmed that and are the major genes involved in the EVC phenotype and highlighted the high prevalence of previously unreported CNVs (Copy Number Variation).
Topics: Humans; Hedgehog Proteins; Ellis-Van Creveld Syndrome; DNA Copy Number Variations; Phenotype; Polydactyly
PubMed: 35927022
DOI: 10.1136/jmg-2022-108435 -
Frontiers in Genetics 2022Ciliopathies are rare congenital disorders, caused by defects in the cilium, that cover a broad clinical spectrum. A subgroup of ciliopathies showing significant...
Ciliopathies are rare congenital disorders, caused by defects in the cilium, that cover a broad clinical spectrum. A subgroup of ciliopathies showing significant phenotypic overlap are known as skeletal ciliopathies and include Jeune asphyxiating thoracic dysplasia (JATD), Mainzer-Saldino syndrome (MZSDS), cranioectodermal dysplasia (CED), and short-rib polydactyly (SRP). Ciliopathies are heterogeneous disorders with >187 associated genes, of which some genes are described to cause more than one ciliopathy phenotype. Both the clinical and molecular overlap make accurate diagnosing of these disorders challenging. We describe two unrelated Polish patients presenting with a skeletal ciliopathy who share the same compound heterozygous variants in (NM_014,714.4) r.2765_2768del; p.(Tyr923Leufs*28) and exon 27-30 duplication; p.(Tyr1152_Thr1394dup). Apart from overlapping clinical symptoms the patients also show phenotypic differences; patient 1 showed more resemblance to a Mainzer-Saldino syndrome (MZSDS) phenotype, while patient 2 was more similar to the phenotype of cranioectodermal dysplasia (CED). In addition, functional testing in patient-derived fibroblasts revealed a distinct cilium phenotyps for each patient, and strikingly, the cilium phenotype of CED-like patient 2 resembled that of known CED patients. Besides two variants in , in depth exome analysis of ciliopathy associated genes revealed a likely-pathogenic heterozygous variant in for patient 2 that possibly affects the same IFT-A complex to which IFT140 belongs and thereby could add to the phenotype of patient 2. Taken together, by combining genetic data, functional test results, and clinical findings we were able to accurately diagnose patient 1 with "IFT140-related ciliopathy with MZSDS-like features" and patient 2 with "IFT140-related ciliopathy with CED-like features". This study emphasizes that identical variants in one ciliopathy associated gene can lead to a variable ciliopathy phenotype and that an in depth and integrated analysis of clinical, molecular and functional data is necessary to accurately diagnose ciliopathy patients.
PubMed: 35873489
DOI: 10.3389/fgene.2022.931822 -
Military Medicine Oct 2022The submarine environment presents unique challenges in mitigating the spread of respiratory viruses because of the re-circulatory atmosphere and lack of ability to...
BACKGROUND
The submarine environment presents unique challenges in mitigating the spread of respiratory viruses because of the re-circulatory atmosphere and lack of ability to physically distance. The atmosphere of a submarine is periodically ventilated and continuously scrubbed. However, the air is recycled for months until the ship is able to ventilate. An outbreak of coronavirus disease 2019 (COVID-19) occurred on a U.S. Navy fast-attack nuclear submarine (SSN) with a crew of 128 personnel.
METHODS
Demographics, symptom data, and test results for all crew members on board during the outbreak were collected. Testing was completed by real-time reverse-transcriptase polymerase chain reaction, and symptom data were collected via a patient-reported online application. Symptom results were collected from August 4, 2020 to September 1, 2020.
RESULTS
The crew was 100% male, with a mean age of 27.0 years. All crew members met the stringent medical standards for submarine and sea duty. Fifty-five Sailors tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (43.0% of the crew) during the outbreak. Additionally, nine Sailors (7.0% of the crew) met the criteria for infection despite testing negative, resulting in an overall attack rate of 50.0%. Among the 64 crew members with suspected or confirmed COVID-19, 1 (1.6%) was hospitalized. There were no deaths. Out of the 55 positive tests, there were 6 (10.9%) asymptomatic positive cases.
CONCLUSIONS
As expected, SARS-CoV-2 was able to spread rapidly among a submarine crew. In 11 days, the infection spread to 64 total crewmembers out of 128. Outbreaks such as these have played a role in future COVID-19 testing and mitigation protocols that have affected day-to-day operations.
Topics: Male; Humans; Adult; Female; COVID-19; SARS-CoV-2; Ships; COVID-19 Testing; Retrospective Studies; Disease Outbreaks
PubMed: 35762151
DOI: 10.1093/milmed/usac155