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Zhonghua Fu Chan Ke Za Zhi Mar 2023To explore the diagnostic value of chromosome karyotype analysis, chromosomal microarray analysis (CMA) and whole exome sequencing (WES) in microcephaly. A total of 9...
To explore the diagnostic value of chromosome karyotype analysis, chromosomal microarray analysis (CMA) and whole exome sequencing (WES) in microcephaly. A total of 9 cases of microcephaly fetuses diagnosed by prenatal ultrasound or children with microcephaly diagnosed after birth were selected from the Sixth Affiliated Hospital of Guangzhou Medical University from January 2014 to August 2022.Karyotype analysis and/or CMA were used to detect. The cases with negative karyotype analysis and CMA results were further sequenced by trio-based WES (Trio-WES). Then the coding genes contained in the pathogenic copy number variation (CNV) fragments were analyzed by gene ontology (GO) enrichment. The genes related to the development of the central nervous system contained in the pathogenic CNV and the pathogenic genes found by Trio-WES were combined for gene interaction network analysis. In this study, 9 cases of microcephaly were recruited, with the time of diagnosis ranged from 23 weeks of gestation to 7 years after birth, and the head circumference of fetus or children ranged from 18.3 to 42.5 cm (-7SD to -2SD). Karyotype analysis was detected in all 9 cases and no abnormality result was found. Eight cases were detected by CMA, and one abnormal was found. Five cases were detected by Trio-WES, and two cases were detected with likely pathogenic genes. The GO enrichment analysis of the coding gene in the 4p16.3 microdeletion (pathogenic CNV) region showed that: in biological process, it was mainly concentrated in phototransduction, visible light; in terms of molecular function, it was mainly concentrated in fibroblast growth factor binding; in terms of cell components, it was mainly concentrated in rough endoplasmic reticulum. Gene interaction network analysis suggested that CDC42 gene could interact with CTBP1, HTT and ASPM gene. CMA could be used as a first-line detection technique for microcephaly. When the results of chromosome karyotype analysis and/or CMA are negative, Trio-WES could improve the detection rate of pathogenicity of microcephaly.
Topics: Female; Humans; Pregnancy; DNA Copy Number Variations; Fetus; Karyotype; Karyotyping; Microarray Analysis; Microcephaly; Prenatal Diagnosis; Infant, Newborn
PubMed: 36935194
DOI: 10.3760/cma.j.cn112141-20221102-00675 -
Cells Jul 2023Primary microcephalies (PMs) are defects in brain growth that are detectable at or before birth and are responsible for neurodevelopmental disorders. Most are caused by... (Review)
Review
Primary microcephalies (PMs) are defects in brain growth that are detectable at or before birth and are responsible for neurodevelopmental disorders. Most are caused by biallelic or, more rarely, dominant mutations in one of the likely hundreds of genes encoding PM proteins, i.e., ubiquitous centrosome or microtubule-associated proteins required for the division of neural progenitor cells in the embryonic brain. Here, we provide an overview of the different types of PMs, i.e., isolated PMs with or without malformations of cortical development and PMs associated with short stature (microcephalic dwarfism) or sensorineural disorders. We present an overview of the genetic, developmental, neurological, and cognitive aspects characterizing the most representative PMs. The analysis of phenotypic similarities and differences among patients has led scientists to elucidate the roles of these PM proteins in humans. Phenotypic similarities indicate possible redundant functions of a few of these proteins, such as ASPM and WDR62, which play roles only in determining brain size and structure. However, the protein pericentrin (PCNT) is equally required for determining brain and body size. Other PM proteins perform both functions, albeit to different degrees. Finally, by comparing phenotypes, we considered the interrelationships among these proteins.
Topics: Humans; Microcephaly; Centrosome; Brain; Brain Diseases; Body Size; Nerve Tissue Proteins; Cell Cycle Proteins
PubMed: 37443841
DOI: 10.3390/cells12131807 -
Biomedicine & Pharmacotherapy =... Sep 2023Zika virus (ZIKV) poses a serious threat to the entire world. The rapid spread of ZIKV and recent outbreaks since 2007 have caused worldwide concern about the virus.... (Review)
Review
Zika virus (ZIKV) poses a serious threat to the entire world. The rapid spread of ZIKV and recent outbreaks since 2007 have caused worldwide concern about the virus. Diagnosis is complicated because of the cross-reactivity of the virus with other viral antibodies. Currently, the virus is diagnosed by molecular techniques such as RT-PCR and IgM-linked enzyme immunoassays (MAC-ELISA). Recently, outbreaks and epidemics have been caused by ZIKV, and severe clinical symptoms and congenital malformations have also been associated with the virus. Although most ZIKV infections present with a subclinical or moderate flu-like course of illness, severe symptoms such as Guillain-Barre syndrome in adults and microcephaly in children of infected mothers have also been reported. Because there is no reliable cure for ZIKV and no vaccine is available, the public health response has focused primarily on preventing infection, particularly in pregnant women. A comprehensive approach is urgently needed to combat this infection and stop its spread and imminent threat. In view of this, this review aims to present the current structural and functional viewpoints, structure, etiology, clinical prognosis, and measures to prevent this transmission based on the literature and current knowledge. Moreover, we provide thorough description of the current understanding about ZIKV interaction with receptors, and a comparative examination of its similarities and differences with other viruses.
Topics: Adult; Child; Female; Humans; Pregnancy; Zika Virus; Zika Virus Infection; Microcephaly; Disease Outbreaks; Epidemics
PubMed: 37473686
DOI: 10.1016/j.biopha.2023.115175 -
Ophthalmology. Retina Sep 2022
Topics: Humans; Kinesins; Microcephaly; Mutation; Retina
PubMed: 36084995
DOI: 10.1016/j.oret.2022.06.002 -
Congenital Anomalies Jan 2021We report population prevalence rates of neural tube defects (NDT) and microcephaly (MIC) as well as levels of incorporated Cs137 by pregnant women in two areas of the...
We report population prevalence rates of neural tube defects (NDT) and microcephaly (MIC) as well as levels of incorporated Cs137 by pregnant women in two areas of the Rivne Province of Ukraine, a northern half (Polissia) polluted by Chornobyl radiation and not-Polissia areas. Monitoring of congenital malformations was conducted with adherence to methods adopted by a European surveillance network (EUROCAT). Incorporated Cs137 (Bq/kg) by pregnant women residing in the Polissia and not-Polissia areas were obtained concurrently with prenatal ultrasound examinations. In Polissia, the incorporated Cs137 levels by pregnant women as well as the prevalence rates of NDTs and MIC are significantly higher than in not-Polissia. In Polissia, the prevalence rates of NDTs and MIC are among the highest in Europe. The debate concerning the teratogenic impact of chronic exposures to low levels of ionizing radiation was re-ignited by our 2010 report. Health agencies uphold the notion that exposure to Chornobyl radiation levels are too low to be teratogenic, which is inconsistent with our observations. Further investigations in Rivne by international teams can, we believe, contribute facts to the ongoing debate. Our monitoring system, experience and data can facilitate concurrent investigations of teratogenic risks from exposures to other sources of ionizing radiation, alcohol, folate, and zinc deficiencies, among other risk factors. Study of genomic impacts can likewise be undertaken.
Topics: Blood Cell Count; Cesium Radioisotopes; Chernobyl Nuclear Accident; Congenital Abnormalities; Female; Geography, Medical; Humans; Microcephaly; Neural Tube Defects; Pregnancy; Prevalence; Public Health Surveillance; Ukraine
PubMed: 33405251
DOI: 10.1111/cga.12388 -
Journal of Infection and Public Health Jan 2020Zika virus (ZIKV), a mosquito transmitted virus in the family Flaviviridae, genus Flavivirus, recently emerged to cause infections in more than 70 countries and... (Review)
Review
Zika virus (ZIKV), a mosquito transmitted virus in the family Flaviviridae, genus Flavivirus, recently emerged to cause infections in more than 70 countries and territories around the world. While human infection is normally asymptomatic, it can also result in a mild febrile disease similar to dengue fever. However, when a pregnant woman is infected, ZIKV can cause fetal abnormalities including microcephaly. Evidence has suggested that ZIKV has circulated in Southeast Asia for more than a decade and yet cases of ZIKV associated microcephaly remain sparsely documented. This review seeks to collate the information currently existing on ZIKV associated microcephaly in Southeast Asia, and assess the potential future risk posed by this virus.
Topics: Asia, Southeastern; Disease Outbreaks; Female; Global Health; Humans; Infectious Disease Transmission, Vertical; Microcephaly; Pregnancy; Pregnant Women; Zika Virus; Zika Virus Infection
PubMed: 31669035
DOI: 10.1016/j.jiph.2019.09.012 -
Developmental Medicine and Child... Apr 2022To characterize the cortical structure, developmental, and cognitive profiles of patients with WD repeat domain 62 (WDR62)-related primary microcephaly. (Observational Study)
Observational Study
AIM
To characterize the cortical structure, developmental, and cognitive profiles of patients with WD repeat domain 62 (WDR62)-related primary microcephaly.
METHOD
In this observational study, we describe the developmental, neurological, cognitive, and brain imaging characteristics of 17 patients (six males, 11 females; mean age 12y 3mo standard deviation [SD] 5y 8mo, range 5y-24y 6mo) and identify 14 new variants of WDR62. We similarly analyse the phenotypes and genotypes of the 59 previously reported families.
RESULTS
Brain malformations, including pachygyria, neuronal heterotopia, schizencephaly, and microlissencephaly, were present in 11 out of 15 patients. The mean full-scale IQ of the 11 assessed patients was 51.8 (standard deviation [SD] 12.6, range 40-70). Intellectual disability was severe in four patients, moderate in four, and mild in three. Scores on the Vineland Adaptive Behavior Scales obtained from 10 patients were low for communication and motor skills (mean 38.29, SD 7.74, and 37.71, SD 5.74 respectively). The socialization score was higher (mean 47.14, SD 12.39). We found a significant difference between scores for communication and daily living skills (mean 54.43, SD 11.6; p=0.001, one-way analysis of variance). One patient displayed progressive ataxia.
INTERPRETATION
WDR62-related cognitive consequences may be less severe than expected because 3 out of 11 of the assessed patients had only mild intellectual disability and relatively preserved abilities of autonomy in daily life. We identified progressive ataxia in the second decade of life in one patient, which should encourage clinicians to follow up patients in the long term.
Topics: Adolescent; Ataxia; Cell Cycle Proteins; Child; Child, Preschool; Female; Humans; Intellectual Disability; Male; Microcephaly; Nerve Tissue Proteins; Young Adult
PubMed: 35726608
DOI: 10.1111/dmcn.15060 -
Clinical Genetics Jan 2024Pathogenic variants in PNPLA8 have been described either with congenital onset displaying congenital microcephaly, early onset epileptic encephalopathy and early...
Pathogenic variants in PNPLA8 have been described either with congenital onset displaying congenital microcephaly, early onset epileptic encephalopathy and early lethality or childhood neurodegeneration with progressive microcephaly. Moreover, a phenotype comprising adulthood onset cerebellar ataxia and peripheral neuropathy was also reported. To our knowledge, only six patients with biallelic variants in PNPLA8 have been reported so far. Here, we report the clinical and molecular characterizations of three additional patients in whom exome sequencing identified a loss of function variant (c.1231C>T, p.Arg411Ter) in Family I and a missense variant (c.1559T>A, p.Val520Asp) in Family II in PNPLA8. Patient 1 presented with the congenital form of the disease while Patients 2 and 3 showed progressive microcephaly, infantile onset seizures, progressive cortical atrophy, white matter loss, bilateral degeneration of basal ganglia, and cystic encephalomalacia. Therefore, our results add the infantile onset as a new distinct phenotype of the disease and suggest that the site of the variant rather than its type is strongly correlated with the disease onset. In addition, these conditions demonstrate some overlapping features representing a spectrum with clinical features always aligning with different age of onset.
Topics: Humans; Adult; Child; Microcephaly; Phenotype; Cerebellar Ataxia; Mutation, Missense; Basal Ganglia
PubMed: 37671596
DOI: 10.1111/cge.14421 -
American Journal of Medical Genetics.... Mar 2023We report a boy with typical clinical features of SHORT syndrome alongside a significant microcephaly and severe developmental delay associated with a de novo single... (Review)
Review
We report a boy with typical clinical features of SHORT syndrome alongside a significant microcephaly and severe developmental delay associated with a de novo single nucleotide missense DNA variant resulting in a single amino acid change in codon 486 of the PIK3R1 gene (PIK3R1 c.1456G>A (p.Ala486Thr)). Our report strikingly coincides with another recently published case from Brazil, describing a 23-year-old woman with the same de novo PIK3R1 DNA variant, who also exhibits SHORT syndrome with severe secondary microcephaly and intellectual disability. On review of the literature, we have identified further cases of PIK3R1-related SHORT Syndrome with a similar phenotype. We note all these cases (including ours) have variants located in the -inter SH2 domain (iSH2); we speculate that pathogenic iSH2 located PIK3R1 variants are associated with a different and otherwise unreported clinical picture of SHORT syndrome that presents with microcephaly and/or significant developmental delay/intellectual disability. The pathogenic mechanism of why these variants apparently lead to a different clinical picture of SHORT syndrome remains unknown.
Topics: Humans; Child; Intellectual Disability; Microcephaly; Hypercalcemia; Nephrocalcinosis; Phenotype; Transcription Factors; Developmental Disabilities
PubMed: 36515361
DOI: 10.1002/ajmg.a.63078 -
American Journal of Medical Genetics.... Oct 2022Hemizygous missense variants in the RPL10 gene encoding a ribosomal unit are responsible for an X-linked syndrome presenting with intellectual disability (ID), autism...
Hemizygous missense variants in the RPL10 gene encoding a ribosomal unit are responsible for an X-linked syndrome presenting with intellectual disability (ID), autism spectrum disorder, epilepsy, dysmorphic features, and multiple congenital anomalies. Among 15 individuals with RPL10-related disorder reported so far, only one patient had retinitis pigmentosa and microcephaly was observed in approximately half of the cases. By exome sequencing, three Italian and one Spanish male children, from three independent families, were found to carry the same hemizygous novel missense variant p.(Arg32Leu) in RPL10, inherited by their unaffected mother in all cases. The variant, not reported in gnomAD, is located in the 28S rRNA binding region, affecting an evolutionary conserved residue and predicted to disrupt the salt-bridge between Arg32 and Asp28. In addition to features consistent with RPL10-related disorder, all four boys had retinal degeneration and postnatal microcephaly. Pathogenic variants in genes responsible for inherited retinal degenerations were ruled out in all the probands. A novel missense RPL10 variant was detected in four probands with a recurrent phenotype including ID, dysmorphic features, progressive postnatal microcephaly, and retinal anomalies. The presented individuals suggest that retinopathy and postnatal microcephaly are clinical clues of RPL10-related disorder, and at least the retinal defect might be more specific for the p.(Arg32Leu) RPL10 variant, suggesting a specific genotype/phenotype correlation.
Topics: Autism Spectrum Disorder; Humans; Intellectual Disability; Male; Microcephaly; Nervous System Malformations; Phenotype
PubMed: 35876338
DOI: 10.1002/ajmg.a.62911