Somatic Mutations in Cerebral Cortical Malformations Jamuar, Saumya S; Lam, Anh-Thu N; Kircher, Martin ...
New England journal of medicine/The New England journal of medicine,
08/2014, Letnik:
371, Številka:
8
Journal Article
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Somatic mutations can cause brain malformations but may escape detection if their prevalence in blood is low. The authors of this study used deep-coverage targeting sequencing to gauge the extent to ...which somatic mutations cause relatively common forms of brain malformation.
Somatic mutation, a postzygotic event, leads to two or more populations of cells with distinct genotypes in an organism, despite development from a single fertilized egg.
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Although the role of somatic mutation in cancer cells is well established,
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an analogous role for somatic mutations that occur randomly during the normal mitotic cell divisions of embryonic development — and that are therefore present in clones of cells in one or more tissues of the body — has been recognized only recently. Somatic mutations have been described in several noncancerous disorders, including the McCune–Albright syndrome,
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the Sturge–Weber syndrome,
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the Proteus syndrome, . . .
More than 98% of the human genome is made up of non-coding DNA, but techniques to ascertain its contribution to human disease have lagged far behind our understanding of protein coding variations. ...Autism spectrum disorder (ASD) has been mostly associated with coding variations via de novo single nucleotide variants (SNVs), recessive/homozygous SNVs, or de novo copy number variants (CNVs); however, most ASD cases continue to lack a genetic diagnosis. We analyzed 187 consanguineous ASD families for biallelic CNVs. Recessive deletions were significantly enriched in affected individuals relative to their unaffected siblings (17% versus 4%, p < 0.001). Only a small subset of biallelic deletions were predicted to result in coding exon disruption. In contrast, biallelic deletions in individuals with ASD were enriched for overlap with regulatory regions, with 23/28 CNVs disrupting histone peaks in ENCODE (p < 0.009). Overlap with regulatory regions was further demonstrated by comparisons to the 127-epigenome dataset released by the Roadmap Epigenomics project, with enrichment for enhancers found in primary brain tissue and neuronal progenitor cells. Our results suggest a novel noncoding mechanism of ASD, describe a powerful method to identify important noncoding regions in the human genome, and emphasize the potential significance of gene activation and regulation in cognitive and social function.
Progressive microcephaly is a heterogeneous condition with causes including mutations in genes encoding regulators of neuronal survival. Here, we report the identification of mutations in QARS ...(encoding glutaminyl-tRNA synthetase QARS) as the causative variants in two unrelated families affected by progressive microcephaly, severe seizures in infancy, atrophy of the cerebral cortex and cerebellar vermis, and mild atrophy of the cerebellar hemispheres. Whole-exome sequencing of individuals from each family independently identified compound-heterozygous mutations in QARS as the only candidate causative variants. QARS was highly expressed in the developing fetal human cerebral cortex in many cell types. The four QARS mutations altered highly conserved amino acids, and the aminoacylation activity of QARS was significantly impaired in mutant cell lines. Variants p.Gly45Val and p.Tyr57His were located in the N-terminal domain required for QARS interaction with proteins in the multisynthetase complex and potentially with glutamine tRNA, and recombinant QARS proteins bearing either substitution showed an over 10-fold reduction in aminoacylation activity. Conversely, variants p.Arg403Trp and p.Arg515Trp, each occurring in a different family, were located in the catalytic core and completely disrupted QARS aminoacylation activity in vitro. Furthermore, p.Arg403Trp and p.Arg515Trp rendered QARS less soluble, and p.Arg403Trp disrupted QARS-RARS (arginyl-tRNA synthetase 1) interaction. In zebrafish, homozygous qars loss of function caused decreased brain and eye size and extensive cell death in the brain. Our results highlight the importance of QARS during brain development and that epilepsy due to impairment of QARS activity is unusually severe in comparison to other aminoacyl-tRNA synthetase disorders.
Motor, sensory, and integrative activities of the brain are coordinated by a series of midline-bridging neuronal commissures whose development is tightly regulated. Here we report a new human ...syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported. Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis. Combined with data from animal models, these findings show that DCC is a master regulator of midline crossing and development of white-matter projections throughout the human CNS.
Atopic dermatitis (AD) is an inflammatory skin disorder that is common in children and associated with medical and psychosocial comorbidities. Previous studies have shown that there exist significant ...racial disparities in healthcare utilization in children with AD; however, literature on disparities in dermatology access is limited.BACKGROUNDAtopic dermatitis (AD) is an inflammatory skin disorder that is common in children and associated with medical and psychosocial comorbidities. Previous studies have shown that there exist significant racial disparities in healthcare utilization in children with AD; however, literature on disparities in dermatology access is limited.The primary aim of this study was to identify differences in diagnosis of AD and access to dermatologic care by race and ethnicity in infants with AD.OBJECTIVESThe primary aim of this study was to identify differences in diagnosis of AD and access to dermatologic care by race and ethnicity in infants with AD.We conducted a retrospective chart review of infants diagnosed with AD at Boston Children's Hospital from January 1, 2015 - December 31, 2019. Race and ethnicity were categorized as Native American or Alaska Native, Asian, non-Hispanic Black, Hispanic, Native Hawaiian or Other Pacific Islander, non-Hispanic white, and other. Outcomes included time to diagnosis and dermatology visit from rash onset and were analyzed utilizing a Kruskal-Wallis test. Severity of presentation at first dermatology visit, presentation to the emergency department (ED), medications prescribed, and follow up were analyzed using Chi-squared tests.METHODSWe conducted a retrospective chart review of infants diagnosed with AD at Boston Children's Hospital from January 1, 2015 - December 31, 2019. Race and ethnicity were categorized as Native American or Alaska Native, Asian, non-Hispanic Black, Hispanic, Native Hawaiian or Other Pacific Islander, non-Hispanic white, and other. Outcomes included time to diagnosis and dermatology visit from rash onset and were analyzed utilizing a Kruskal-Wallis test. Severity of presentation at first dermatology visit, presentation to the emergency department (ED), medications prescribed, and follow up were analyzed using Chi-squared tests.Significantly more non-Hispanic white infants received a prescription by their pediatrician for AD than Hispanic infants (p = 0.002). Non-Hispanic Black and Asian infants waited longer to see a dermatologist after receiving a prescription for AD by their pediatrician compared to non-Hispanic white patients (p < 0.001; p = 0.007). Significantly more non-Hispanic Black and Hispanic infants presented to the ED for AD within the first year of life than non-Hispanic white patients (p < 0.001; p = 0.003).RESULTSSignificantly more non-Hispanic white infants received a prescription by their pediatrician for AD than Hispanic infants (p = 0.002). Non-Hispanic Black and Asian infants waited longer to see a dermatologist after receiving a prescription for AD by their pediatrician compared to non-Hispanic white patients (p < 0.001; p = 0.007). Significantly more non-Hispanic Black and Hispanic infants presented to the ED for AD within the first year of life than non-Hispanic white patients (p < 0.001; p = 0.003).Our study suggests disparities in diagnosis and access to care for non-Hispanic Black and Hispanic infants with AD, with differences in prescriptions, time to see a dermatologist, and presentation to the ED compared to non-Hispanic white infants.CONCLUSIONSOur study suggests disparities in diagnosis and access to care for non-Hispanic Black and Hispanic infants with AD, with differences in prescriptions, time to see a dermatologist, and presentation to the ED compared to non-Hispanic white infants.
To characterize the socioeconomic and racial and/or ethnic disparities impacting the diagnosis and outcomes of multisystem inflammatory syndrome in children (MIS-C).
This multicenter retrospective ...case-control study was conducted at 3 academic centers from January 1 to September 1, 2020. Children with MIS-C were compared with 5 control groups: children with coronavirus disease 2019, children evaluated for MIS-C who did not meet case patient criteria, children hospitalized with febrile illness, children with Kawasaki disease, and children in Massachusetts based on US census data. Neighborhood socioeconomic status (SES) and social vulnerability index (SVI) were measured via a census-based scoring system. Multivariable logistic regression was used to examine associations between SES, SVI, race and ethnicity, and MIS-C diagnosis and clinical severity as outcomes.
Among 43 patients with MIS-C, 19 (44%) were Hispanic, 11 (26%) were Black, and 12 (28%) were white; 22 (51%) were in the lowest quartile SES, and 23 (53%) were in the highest quartile SVI. SES and SVI were similar between patients with MIS-C and coronavirus disease 2019. In multivariable analysis, lowest SES quartile (odds ratio 2.2 95% confidence interval 1.1-4.4), highest SVI quartile (odds ratio 2.8 95% confidence interval 1.5-5.1), and racial and/or ethnic minority background were associated with MIS-C diagnosis. Neither SES, SVI, race, nor ethnicity were associated with disease severity.
Lower SES or higher SVI, Hispanic ethnicity, and Black race independently increased risk for MIS-C. Additional studies are required to target interventions to improve health equity for children.
Despite recent advances in understanding the genetic bases of microcephaly, a large number of cases of microcephaly remain unexplained, suggesting that many microcephaly syndromes and associated ...genes are yet to be identified. Here we report mutations in PYCR2, which encodes an enzyme in the proline biosynthesis pathway, as the cause of a unique syndrome characterized by postnatal microcephaly, hypomyelination, and reduced cerebral white matter volume. Linkage mapping and whole-exome sequencing identified homozygous mutations in PYCR2 (c.355C>T p.Arg119Cys and c.751C>T p.Arg251Cys) in the affected individuals of two consanguineous families. A lymphoblastoid cell line from one affected individual showed a strong reduction in PYCR2 level. When mutant cDNAs were transfected into HEK293FT cells, the mutant protein retained normal mitochondrial localization but the level was lower than the wild-type protein, suggesting that mutant protein is less stable. A PYCR2-deficient HEK293FT cell line generated by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 genome-editing showed that PYCR2 loss of function led to decreased mitochondrial membrane potential and increased susceptibility to apoptosis under oxidative stress. Morpholino-based knockdown of the zebrafish PYCR2 homolog, pycr1b, recapitulated the human microcephaly phenotype, which was rescued by wild-type human PYCR2 mRNA, but not by mutant mRNAs, further supporting the pathogenicity of the identified variants. Hypomyelination and the absence of lax, wrinkly skin distinguishes this condition from that caused by previously reported mutations in the gene encoding PYCR2’s isozyme, PYCR1, suggesting a unique and indispensable role for PYCR2 in the human central nervous system during development.
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