To identify further Mendelian causes of intellectual disability (ID), we screened a cohort of 996 individuals with ID for variants in 565 known or candidate genes by using a targeted next-generation ...sequencing approach. Seven loss-of-function (LoF) mutations—four nonsense (c.1195A>T p.Lys399∗, c.1333C>T p.Arg445∗, c.1866C>G p.Tyr622∗, and c.3001C>T p.Arg1001∗) and three frameshift (c.2177_2178del p.Thr726Asnfs∗39, c.3771dup p.Ser1258Glufs∗65, and c.3856del p.Ser1286Leufs∗84)—were identified in SETD5, a gene predicted to encode a methyltransferase. All mutations were compatible with de novo dominant inheritance. The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears. Skeletal anomalies, including significant leg-length discrepancy, were a frequent finding in two individuals. Congenital heart defects, inguinal hernia, or hypospadias were also reported. Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features. SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition. Our findings add to the growing evidence that mutations in genes encoding methyltransferases regulating histone modification are important causes of ID. This analysis provides sufficient evidence that rare de novo LoF mutations in SETD5 are a relatively frequent (0.7%) cause of ID.
The discovery of mutations causing human disease has so far been biased toward protein-coding regions. Having excluded all annotated coding regions, we performed targeted massively parallel ...resequencing of the nonrepetitive genomic linkage interval at Xq28 of family MRX3. We identified in the binding site of transcription factor YY1 a regulatory mutation that leads to overexpression of the chromatin-associated transcriptional regulator HCFC1. When tested on embryonic murine neural stem cells and embryonic hippocampal neurons, HCFC1 overexpression led to a significant increase of the production of astrocytes and a considerable reduction in neurite growth. Two other nonsynonymous, potentially deleterious changes have been identified by X-exome sequencing in individuals with intellectual disability, implicating HCFC1 in normal brain function.
The first family identified as having a nonsyndromic intellectual disability was mapped in 1988. Here we show that a mutation of IQSEC2, encoding a guanine nucleotide exchange factor for the ...ADP-ribosylation factor family of small GTPases, caused this disorder. In addition to MRX1, IQSEC2 mutations were identified in three other families with X-linked intellectual disability. This discovery was made possible by systematic and unbiased X chromosome exome resequencing.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Massively parallel genetic sequencing allows rapid testing of known intellectual disability (ID) genes. However, the discovery of novel syndromic ID genes requires molecular confirmation in at least ...a second or a cluster of individuals with an overlapping phenotype or similar facial gestalt. Using computer face-matching technology we report an automated approach to matching the faces of non-identical individuals with the same genetic syndrome within a database of 3681 images 1600 images of one of 10 genetic syndrome subgroups together with 2081 control images. Using the leave-one-out method, two research questions were specified: 1) Using two-dimensional (2D) photographs of individuals with one of 10 genetic syndromes within a database of images, did the technology correctly identify more than expected by chance: i) a top match? ii) at least one match within the top five matches? or iii) at least one in the top 10 with an individual from the same syndrome subgroup? 2) Was there concordance between correct technology-based matches and whether two out of three clinical geneticists would have considered the diagnosis based on the image alone?
The computer face-matching technology correctly identifies a top match, at least one correct match in the top five and at least one in the top 10 more than expected by chance (P < 0.00001). There was low agreement between the technology and clinicians, with higher accuracy of the technology when results were discordant (P < 0.01) for all syndromes except Kabuki syndrome.
Although the accuracy of the computer face-matching technology was tested on images of individuals with known syndromic forms of intellectual disability, the results of this pilot study illustrate the potential utility of face-matching technology within deep phenotyping platforms to facilitate the interpretation of DNA sequencing data for individuals who remain undiagnosed despite testing the known developmental disorder genes.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations ...affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.
Nonsense-mediated mRNA decay (NMD) is of universal biological significance. It has emerged as an important global RNA, DNA and translation regulatory pathway. By systematically sequencing 737 genes ...(annotated in the Vertebrate Genome Annotation database) on the human X chromosome in 250 families with X-linked mental retardation, we identified mutations in the UPF3 regulator of nonsense transcripts homolog B (yeast) (UPF3B) leading to protein truncations in three families: two with the Lujan-Fryns phenotype and one with the FG phenotype. We also identified a missense mutation in another family with nonsyndromic mental retardation. Three mutations lead to the introduction of a premature termination codon and subsequent NMD of mutant UPF3B mRNA. Protein blot analysis using lymphoblastoid cell lines from affected individuals showed an absence of the UPF3B protein in two families. The UPF3B protein is an important component of the NMD surveillance machinery. Our results directly implicate abnormalities of NMD in human disease and suggest at least partial redundancy of NMD pathways.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The third wave of COVID-19 is unique in that vaccines have been widely available; however, the highly transmissible Delta variant has been the predominant strain. Temporal changes of hospitalized ...patient characteristics should continue to be analyzed as COVID-19 progresses.
Compare the demographics and outcomes of hospitalized patients during New York City's third wave of COVID-19 to the first two waves.
Retrospective cohort study across five hospitals within Mount Sinai Health System, a quaternary academic medical system in New York City. Participants were adult inpatients admitted with COVID-19 identified by positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction at admission or clinical documentation of infection during the three waves of COVID-19.
Patient demographics, comorbidities, vaccination status, and outcomes of COVID-19 patients hospitalized at Mount Sinai Health System were examined. Patients admitted during the third wave were notably younger than the first two, were mostly unvaccinated against COVID-19, and there was a higher rate of patients who self-report as Black or African American as compared with the first two waves. The rate of patients requiring ICU level of care remained consistent throughout all three periods; however, the rate of patients requiring invasive mechanical ventilation decreased and inhospital mortality has trended down. Unvaccinated patients in the third wave are significantly younger with lower comorbidity burden than fully vaccinated patients.
A total of 13,036 patients were included between the 3 waves. In the 3rd wave patients were notably younger, with a lower intubation rate and lower inhospital death rate. In the 3rd wave, 400 (62.9%) were unvaccinated, 236 (37.1%) were fully vaccinated, and 34 (4.8%) were partially vaccinated. Unvaccinated patients had similar rates of intubation and invasive mechanical ventilation compared with vaccinated patients, though inhospital mortality was lower in unvaccinated patients compared with vaccinated patients which may be expected given their lower age and burden of comorbidities.
We continue to see improved outcomes in hospitalized COVID-19 patients. Patients that are unvaccinated against COVID-19 are younger and have less reported comorbidities.
Copy number variants and indels in 251 families with evidence of X-linked intellectual disability (XLID) were investigated by array comparative genomic hybridization on a high-density oligonucleotide ...X chromosome array platform. We identified pathogenic copy number variants in 10% of families, with mutations ranging from 2 kb to 11 Mb in size. The challenge of assessing causality was facilitated by prior knowledge of XLID-associated genes and the ability to test for cosegregation of variants with disease through extended pedigrees. Fine-scale analysis of rare variants in XLID families leads us to propose four additional genes,
PTCHD1,
WDR13,
FAAH2, and
GSPT2, as candidates for XLID causation and the identification of further deletions and duplications affecting X chromosome genes but without apparent disease consequences. Breakpoints of pathogenic variants were characterized to provide insight into the underlying mutational mechanisms and indicated a predominance of mitotic rather than meiotic events. By effectively bridging the gap between karyotype-level investigations and X chromosome exon resequencing, this study informs discussion of alternative mutational mechanisms, such as noncoding variants and non-X-linked disease, which might explain the shortfall of mutation yield in the well-characterized International Genetics of Learning Disability (IGOLD) cohort, where currently disease remains unexplained in two-thirds of families.
Background: We aim to describe the demographics and outcomes of patients with severe disease with the Omicron variant. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus continues ...to mutate, and the availability of vaccines and boosters continue to rise, it is important to understand the health care burden of new variants. We analyze patients admitted to intensive care units (ICUs) in a large Academic Health System during New York City’s fourth surge beginning on November 27, 2021.Methods: All patients admitted to an ICU were included in the primary analysis. Key demographics and outcomes were retrospectively compared between patients stratified by vaccination status. Univariate and multivariate logistic regression was used to identify risk factors for in-hospital mortality.Results: In-hospital mortality for all admitted patients during the fourth wave was significantly lower than in previous waves. However, among patients requiring intensive care, in-hospital mortality was high across all levels of vaccination status. In a multivariate model older age was associated with increased in-hospital mortality, vaccination status of overdue for booster was associated with decreased in hospital mortality, and vaccination status of up-to-date with vaccination showed a trend to reduced mortality.Conclusions: In-hospital mortality of patients with severe respiratory failure from coronavirus disease 2019 (COVID-19) remains high despite decreasing overall mortality. Vaccination against SARS-CoV-2 was protective against mortality. Vaccination remains the best and safest way to protect against serious illness and death from COVID-19. It remains unclear that any other treatment will have success in changing the natural history of the disease.
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