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Clinical Genetics Aug 2014Whole-exome sequencing (WES) has proven its utility in finding novel genes associated with rare conditions and its usefulness is being further demonstrated in expanding...
Whole-exome sequencing (WES) has proven its utility in finding novel genes associated with rare conditions and its usefulness is being further demonstrated in expanding the phenotypes of well known diseases. We present here a family with a previously undiagnosed X-linked condition characterized by progressive restriction of joint range of motion, prominence of the supraorbital ridge, audiology issues and hernias. They had an average stature, normal occipitofrontal circumference and intelligence, absence of dysostosis multiplex and otherwise good health. A diagnosis of Hunter syndrome was determined using WES and further supported by biochemical investigations. The phenotype of this family does not correspond to either the severe or attenuated clinical subtypes of Hunter syndrome. As further atypical families are reported, this classification will need to be modified. Our findings highlight the utility of WES in expanding the recognized phenotypic spectrum of known syndromes.
Topics: Adult; Child; Child, Preschool; Exome; Family; Female; Humans; Infant; Male; Mucopolysaccharidosis II; Mutation; Pedigree; Phenotype; Radiography; Reproducibility of Results; Sequence Analysis, DNA; Skull
PubMed: 23844659
DOI: 10.1111/cge.12236 -
European Journal of Human Genetics :... May 2024Orofaciodigital syndrome is a distinctive subtype of skeletal ciliopathies. Disease-causing variants in the genes encoding the CPLANE complex result in a wide variety of...
Orofaciodigital syndrome is a distinctive subtype of skeletal ciliopathies. Disease-causing variants in the genes encoding the CPLANE complex result in a wide variety of skeletal dysplasia with disturbed ciliary functions. The phenotypic spectrum includes orofaciodigital syndrome and short rib polydactyly syndrome. FUZ, as a part of the CPLANE complex, is involved in intraflagellar vesicular trafficking within primary cilia. Previously, the variants, c.98_111+9del and c.851G>T in FUZ were identified in two individuals with a skeletal ciliopathy, manifesting digital anomalies (polydactyly, syndactyly), orofacial cleft, short ribs and cardiac defects. Here, we present two novel variants, c.601G>A and c.625_636del in biallelic state, in two additional subjects exhibiting phenotypic overlap with the previously reported cases. Our findings underscore the association between biallelic loss of function variants in FUZ and skeletal ciliopathy akin to orofaciodigital syndrome.
PubMed: 38702430
DOI: 10.1038/s41431-024-01619-6 -
Nature Jan 2017XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the...
XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease.
Topics: Adenosine Diphosphate Ribose; Alleles; Animals; Apraxias; Ataxia; Axons; Cerebellar Ataxia; Cerebellum; Chromatin; Cogan Syndrome; DNA Breaks, Single-Stranded; DNA Repair; DNA Repair Enzymes; DNA-Binding Proteins; Female; Humans; Interneurons; Male; Mice; Mutation; Pedigree; Phenotype; Phosphotransferases (Alcohol Group Acceptor); Poly (ADP-Ribose) Polymerase-1; X-ray Repair Cross Complementing Protein 1
PubMed: 28002403
DOI: 10.1038/nature20790 -
European Journal of Medical Genetics Dec 2017Exome sequencing is becoming widely popular and affordable, making it one of the most desirable methods for the identification of rare genetic variants for clinical... (Review)
Review
Exome sequencing is becoming widely popular and affordable, making it one of the most desirable methods for the identification of rare genetic variants for clinical diagnosis. Here, we report the clinical application of whole exome sequencing for the ultimate diagnosis of a ciliary chondrodysplasia case presented with an initial clinical diagnosis of Asphyxiating Thoracic Dystrophy (ATD, Jeune Syndrome). We have identified a novel homozygous missense mutation in WDR35 (c.206G > A), a gene previously associated with Sensenbrenner Syndrome, Ellis-van Creveld syndrome and Short-rib polydactyly syndrome type V. The genetic findings in this family led to the re-evaluation of the initial diagnosis and a differential diagnosis of Sensenbrenner Syndrome was made after cautious re-examination of the patient. Cell culture studies revealed normal subcellular localization of the mutant WDR35 protein in comparison to wildtype protein, pointing towards impaired protein-protein interaction and/or altered cell signaling pathways as a consequence of the mutated allele. This research study highlights the importance of including pathogenic variant identification in the diagnosis pipeline of ciliary chondrodysplasias, especially for clinically not fully defined phenotypes.
Topics: Adult; Bone and Bones; Cells, Cultured; Child; Ciliopathies; Craniosynostoses; Cytoskeletal Proteins; Diagnosis, Differential; Ectodermal Dysplasia; Ellis-Van Creveld Syndrome; Female; Hedgehog Proteins; Humans; Intracellular Signaling Peptides and Proteins; Male; Mutation, Missense; Pedigree; Protein Binding; Protein Transport; Proteins; Exome Sequencing
PubMed: 28870638
DOI: 10.1016/j.ejmg.2017.08.019 -
Pediatric and Developmental Pathology :... 2015The short rib-polydactyly syndromes are a heterogeneous group of lethal autosomal recessive disorders (SRP I-IV), which result from cellular ciliary dysfunction during...
The short rib-polydactyly syndromes are a heterogeneous group of lethal autosomal recessive disorders (SRP I-IV), which result from cellular ciliary dysfunction during embryogenesis. Diagnosis is conventionally based on radiographic imaging. Since 1976, postmortem investigations of 5 affected fetuses or stillbirths have been undertaken and the visceral abnormalities have been documented. These anomalies are discussed in the context of prenatal differential diagnosis and prognostication following imaging in pregnancy and at autopsy following miscarriage or stillbirth.
Topics: Autopsy; Bone and Bones; Diagnosis, Differential; Female; Fetal Death; Humans; Kidney; Liver; Pancreas; Polydactyly; Pregnancy; Radiography; Short Rib-Polydactyly Syndrome; Stillbirth; Whole Body Imaging
PubMed: 25437139
DOI: 10.2350/14-05-1496-OA.1 -
Journal of Applied Research in... Jul 2021People with Down syndrome (DS) have a unique medical profile which may impact views of health. We aimed to explore the use of global health measures in DS.
PURPOSE
People with Down syndrome (DS) have a unique medical profile which may impact views of health. We aimed to explore the use of global health measures in DS.
METHODS
Prospective survey in the Mass General Hospital Down Syndrome Program (MGH DSP) from December 2018 to July 2019 with Patient Reported Outcomes Measurement Information System (PROMIS)® instruments of global health. Analyses included use of scoring manuals, descriptive statistics and dependent samples t test.
RESULTS
Seventeen adolescents, 48 adults with DS and 88 caregivers returned surveys; 137 were complete. Incomplete responses and notes showed limitations of the instruments in this population. Global health T-scores did not differ from the available comparative standardized scores to these measures from PROMIS® reference population (p > 0.05).
CONCLUSIONS
In the MGH DSP, pilot global health instruments were completed by some adults with DS and caregivers, with some limitations and scores similar to the PROMIS® reference population.
Topics: Adolescent; Adult; Down Syndrome; Global Health; Humans; Intellectual Disability; Prospective Studies; Quality of Life; Surveys and Questionnaires
PubMed: 33759305
DOI: 10.1111/jar.12866 -
Cell Reports Mar 2015Sotos syndrome, characterized by intellectual disability and characteristic facial features, is caused by haploinsufficiency in the NSD1 gene. We conducted an...
Sotos syndrome, characterized by intellectual disability and characteristic facial features, is caused by haploinsufficiency in the NSD1 gene. We conducted an etiological study on two siblings with Sotos features without mutations in NSD1 and detected a homozygous frameshift mutation in the APC2 gene by whole-exome sequencing, which resulted in the loss of function of cytoskeletal regulation in neurons. Apc2-deficient (Apc2) mice exhibited impaired learning and memory abilities along with an abnormal head shape. Endogenous Apc2 expression was downregulated by the knockdown of Nsd1, indicating that APC2 is a downstream effector of NSD1 in neurons. Nsd1 knockdown in embryonic mouse brains impaired the migration and laminar positioning of cortical neurons, as observed in Apc2 mice, and this defect was rescued by the forced expression of Apc2. Thus, APC2 is a crucial target of NSD1, which provides an explanation for the intellectual disability associated with Sotos syndrome.
PubMed: 25753423
DOI: 10.1016/j.celrep.2015.02.011 -
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 -
Health Physics Jul 2018In 2015, the Bundeswehr Institute of Radiobiology organized a North Atlantic Treaty Organization exercise to examine the significance of clinical signs and symptoms for...
Successful Teaching of Radiobiology Students in the Medical Management of Acute Radiation Effects From Real Case Histories Using Clinical Signs and Symptoms and Taking Advantage of Recently Developed Software Tools.
In 2015, the Bundeswehr Institute of Radiobiology organized a North Atlantic Treaty Organization exercise to examine the significance of clinical signs and symptoms for the prediction of late-occurring acute radiation syndrome. Cases were generated using either the Medical Treatment Protocols for Radiation Accident Victims (METREPOL, n = 167) system or using real-case descriptions extracted from a database system for evaluation and archiving of radiation accidents based on case histories (SEARCH, n = 24). The cases ranged from unexposed [response category 0 (RC 0, n = 89)] to mild (RC 1, n = 45), moderate (RC 2, n = 19), severe (RC 3, n = 20), and lethal (RC 4, n = 18) acute radiation syndrome. During the previous exercise, expert teams successfully predicted hematological acute radiation syndrome severity, determined whether hospitalization was required, and gave treatment recommendations, taking advantage of different software tools developed by the North Atlantic Treaty Organization teams. The authors provided the same data set to radiobiology students who were introduced to the medical management of acute effects after radiation exposure and the software tools during a class lasting 15 h. Corresponding to the previous results, difficulties in the discrimination between RC 0/RC 1 and RC 3/RC 4, as well as a systematic underestimation of RC 1 and RC 2, were observed. Nevertheless, after merging reported response categories into clinically relevant groups (RC 0-1, RC 2-3, and RC 3-4), it was found that the majority of cases (95.2% ± 2.2 standard deviations) were correctly identified and that 94.7% (±2.6 standard deviations) developing acute radiation syndrome and z96.4% (±1.6 standard deviations) requiring hospitalization were identified correctly. Two out of three student teams also provided a dose estimate. These results are comparable to the best-performing team of the 2015 North Atlantic Treaty Organization exercise (response category: 92.5%; acute radiation syndrome: 95.8%; hospitalization: 96.3%).
Topics: Acute Radiation Syndrome; Databases, Factual; Disease Management; Hospitalization; Humans; Radiation Dosage; Radiation Exposure; Radioactive Hazard Release; Radiobiology; Software; Students
PubMed: 29787430
DOI: 10.1097/HP.0000000000000826 -
BMC Medical Genetics Dec 2014DAVID syndrome is a rare condition combining anterior pituitary hormone deficiency with common variable immunodeficiency. NFKB2 mutations have recently been identified...
BACKGROUND
DAVID syndrome is a rare condition combining anterior pituitary hormone deficiency with common variable immunodeficiency. NFKB2 mutations have recently been identified in patients with ACTH and variable immunodeficiency. A similar mutation was previously found in Nfkb2 in the immunodeficient Lym1 mouse strain, but the effect of the mutation on endocrine function was not evaluated.
METHODS
We ascertained six unrelated DAVID syndrome families. We performed whole exome and traditional Sanger sequencing to search for causal genes. Lym1 mice were examined for endocrine developmental anomalies.
RESULTS
Mutations in the NFKB2 gene were identified in three of our families through whole exome sequencing, and in a fourth by direct Sanger sequencing. De novo origin of the mutations could be demonstrated in three of the families. All mutations lie near the C-terminus of the protein-coding region, near signals required for processing of NFΚB2 protein by the alternative pathway. Two of the probands had anatomical pituitary anomalies, and one had growth and thyroid hormone as well as ACTH deficiency; these findings have not been previously reported. Two children of one of the probands carried the mutation and have to date exhibited only an immune phenotype. No mutations were found near the C-terminus of NFKB2 in the remaining two probands; whole exome sequencing has been performed for one of these. Lym1 mice, carrying a similar Nfkb2 C-terminal mutation, showed normal pituitary anatomy and expression of proopiomelanocortin (POMC).
CONCLUSIONS
We confirm previous findings that mutations near the C-terminus of NFKB2 cause combined endocrine and immunodeficiencies. De novo status of the mutations was confirmed in all cases for which both parents were available. The mutations are consistent with a dominant gain-of-function effect, generating an unprocessed NFKB2 super-repressor protein. We expand the potential phenotype of such NFKB2 mutations to include additional pituitary hormone deficiencies as well as anatomical pituitary anomalies. The lack of an observable endocrine phenotype in Lym1 mice suggests that the endocrine component of DAVID syndrome is either not due to a direct role of NFKB pathways on pituitary development, or else that human and mouse pituitary development differ in its requirements for NFKB pathway function.
Topics: Animals; Disease Models, Animal; Female; Genetic Heterogeneity; Humans; Immunologic Deficiency Syndromes; Male; Mice; Mutation; NF-kappa B p52 Subunit; Pedigree; Pituitary Hormones, Anterior; Pro-Opiomelanocortin
PubMed: 25524009
DOI: 10.1186/s12881-014-0139-9