Tatton‐Brown–Rahman syndrome (TBRS) or DNMT3A‐overgrowth syndrome is characterized by overgrowth and intellectual disability associated with minor dysmorphic features, obesity, and behavioral ...problems. It is caused by variants of the DNMT3A gene. We report four patients with this syndrome due to de novo DNMT3A pathogenic variants, contributing to a deeper understanding of the genetic basis and pathophysiology of this autosomal dominant syndrome. Clinical and magnetic resonance imaging assessments were also performed. All patients showed corpus callosum anomalies, small posterior fossa, and a deep left Sylvian fissure; as well as asymmetry of the uncinate and arcuate fascicles and marked increased cortical thickness. These results suggest that structural neuroimaging anomalies have been previously overlooked, where corpus callosum and brain tract alterations might be unrecognized neuroimaging traits of TBRS syndrome caused by DNMT3A variants.
The Fizzy‐related protein 1 (Fzr1) gene encodes Cdh1 protein, a coactivator of the E3 ubiquitin ligase anaphase‐promoting complex/cyclosome (APC/C). Previously, we found that genetic ablation of Fzr1 ...promotes the death of neural progenitor cells leading to neurogenesis impairment and microcephaly in mouse. To ascertain the possible translation of these findings in humans, we searched for mutations in the Fzr1 gene in 390 whole exomes sequenced in trio in individuals showing neurodevelopmental disorders compatible with a genetic origin. We found a novel missense (p.Asp187Gly) Fzr1 gene mutation (c.560A>G) in a heterozygous state in a 4‐year‐old boy, born from non‐consanguineous Spanish parents, who presents with severe antenatal microcephaly, psychomotor retardation, and refractory epilepsy. Cdh1 protein levels in leucocytes isolated from the patient were significantly lower than those found in his parents. Expression of the Asp187Gly mutant form of Cdh1 in human embryonic kidney 293T cells produced less Cdh1 protein and APC/C activity, resulting in altered cell cycle distribution when compared with cells expressing wild‐type Cdh1. Furthermore, ectopic expression of the Asp187Gly mutant form of Cdh1 in cortical progenitor cells in primary culture failed to abolish the enlargement of the replicative phase caused by knockout of endogenous Cdh1. These results indicate that the loss of function of APC/C‐Cdh1 caused by Cdh1 Asp187Gly mutation is a new cause of prenatal microcephaly, psychomotor retardation, and severe epilepsy.
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Cover Image for this issue: doi: 10.1111/jnc.14524.
We previously found that the anaphase promoting complex/cyclosome (APC/C) inactivation, by deletion of its activator Cdh1, promotes microcephaly in mouse. Here, we describe a de novo Cdh1 mutation (p.Asp187Gly) in a 4‐year‐old boy with prenatal microcephaly, psychomotor retardation, and epilepsy. Functional studies in the patient leukocytes, in a human cell line and in mouse neural precursor cells reveal that the Asp187Gly mutation results in decreased Cdh1 protein abundance, likely due to nuclear degradation, leading to APC/C inactivation. Thus, Cdh1 Asp187Gly mutation is herein identified as a novel cause of APC/C‐Cdh1 inactivation triggering prenatal microcephaly, psychomotor retardation, and severe epilepsy in human.
Read the Editorial Highlight for this article on page 8.
Cover Image for this issue: doi: 10.1111/jnc.14524.
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ANO3 and early-onset dyskinetic encephalopathy Jiménez de Domingo, Ana; Lopez-Martín, Sara; Albert, Jacobo ...
European journal of medical genetics,
December 2020, 2020-Dec, 2020-12-00, 20201201, Volume:
63, Issue:
12
Journal Article
Peer reviewed
Mutations in the ANO3 gene have been associated with autosomal dominant craniocervical dystonia. However, little else is known about the genotype-phenotype characteristics of this disorder. Here we ...describe a 3 years-old girl with distal myoclonic dystonia. Whole exome sequencing in trio revealed a de novo missense ANO3 variant not previously described in international databases. A global psychomotor regression was observed once dystonia was present. Brain MRI changes paralleled these findings: whereas MRI at the age of 18 months was normal, mild brain and cerebellar atrophy was observed 18 months later. These results suggest that missense mutations in ANO3 may underlie complex disorders particularly characterized by early psychomotor regression and dystonia.
Autism spectrum disorder (ASD) is a group of neurological and developmental disabilities characterised by clinical and genetic heterogeneity. The current study aimed to expand ASD genotyping by ...investigating potential associations with
mutations. Specifically, the disease-causing variants of
in 410 trios manifesting neurodevelopmental disorders using whole-exome sequencing were explored. The consequences of the identified variants were studied at the transcript level using quantitative polymerase chain reaction (qPCR). For validation, immunofluorescence and immunoblotting were performed to analyse mutational effects at the protein level. The compound heterozygous variants of
(NM_182914.3:c.2483T>G; p.(Val828Gly) and NM_182914.3:c.2362G>A; p.(Glu788Lys)) were identified in a 4.5-year-old male, clinically diagnosed with autism spectrum disorder, developmental delay and intellectual disability. Both variants reside within the nesprin-2 giant spectrin repeat (SR5) domain and are predicted to be highly damaging using in silico tools. Specifically, a significant reduction of nesprin-2 giant protein levels is revealed in patient cells.
transcription and the nuclear envelope localisation of the mutant proteins was however unaffected as compared to parental control cells. Collectively, these data provide novel insights into the cardinal role of the nesprin-2 giant in neurodevelopment and suggest that the biallelic hypomorphic
mutations may be a new cause of intellectual disability and ASD.
Intellectual disability (ID) is a neurological disorder arising from early neurodevelopmental defects. The underlying genetic and molecular mechanisms are complex, but are thought to involve, among ...others, alterations in genes implicated in axon guidance and/or neural circuit formation as demonstrated by studies on mouse models. Here, by combining exome sequencing with in silico analyses, we identified a patient affected by severe ID and cognitive regression, carrying a novel loss-of-function variant in the semaphorin 3E (
) gene, which encodes for a key secreted cue that controls mouse brain development. By performing ad hoc in vitro and ex vivo experiments, we found that the identified variant impairs protein secretion and hampers the binding to both embryonic mouse neuronal cells and tissues. Further, we revealed SEMA3E expression during human brain development. Overall, our findings demonstrate the pathogenic impact of the identified
variant and provide evidence that clinical neurological features of the patient might be due to a defective SEMA3E signaling in the brain.
Experimental evidence indicates that exercise performed at different times of the day may affect circadian rhythms and circadian disruption has been linked to breast and prostate cancer. We examined ...in a population‐based case‐control study (MCC‐Spain) if the time‐of‐day when physical activity is done affects prostate and breast cancer risk. Lifetime recreational and household physical activity was assessed by in‐person interviews. Information on time‐of‐day of activity (assessed approximately 3 years after the assessment of lifetime physical activity and confounders) was available for 781 breast cancer cases, 865 population female controls, 504 prostate cases and 645 population male controls from 10 Spanish regions, 2008‐2013. We estimated odds ratios (ORs) and 95% confidence intervals (95% CI) for different activity timings compared to inactive subjects using unconditional logistic regression adjusting for confounders. Early morning (8‐10 am) activity was associated with a protective effect compared to no physical activity for both breast (OR = 0.74, 95% CI = 0.48‐1.15) and prostate cancer (OR = 0.73, 95% CI = 0.44‐1.20); meta‐OR for the two cancers combined 0.74 (95%CI = 0.53‐1.02). There was no effect observed for breast or prostate cancer for late morning to afternoon activity while a protective effect was also observed for evening activity only for prostate cancer (OR = 0.75, 95% CI = 0.45‐1.24). Protective effects of early morning activity were more pronounced for intermediate/evening chronotypes for both cancers. This is the first population‐based investigation identifying a differential effect of timing of physical activity on cancer risk with more pronounced effects for morning hour activity. Our results, if confirmed, may improve current physical activity recommendations for cancer prevention.
What's new?
Exercise protects against a variety of cancers, but does time of day matter? Disrupting the body's circadian rhythm can boost cancer risk. Here, the authors compared breast and prostate cancer risk among people who exercised in the early morning, late morning, afternoon, and evening. They conducted a population‐based case‐control study, in which participants filled out a questionnaire about their patterns of sleeping, eating, and exercising. Exercising in the early morning appeared to be more strongly protective against breast and prostate cancer than exercising later in the day. Evening exercise appeared to have a moderate protective effect on prostate cancer.
Abstract We describe a 4-year-old male child born to non-consanguineous Spanish parents with progressive encephalopathy (PE), microcephaly, and hypertonia. Whole exome sequencing revealed compound ...heterozygous BRAT1 mutations c.1564G > A (p.Glu522Lys) and c.638dup (p.Val214Glyfs*189). Homozygous and compound heterozygous BRAT1 mutations have been described in patients with lethal neonatal rigidity and multifocal seizure syndrome (MIM# 614498) . The seven previously described patients suffered from uncontrolled seizures, and all of those patients died in their first months of life. BRAT1 acts as a regulator of cellular proliferation and migration and is required for mitochondrial function. The loss of these functions may explain the cerebral atrophy observed in this case of PE. This case highlights the extraordinary potential of next generation technologies for the diagnosis of rare genetic diseases, including PE. Making a prompt diagnosis of PE is important for genetic counseling and disease management.
Abstract Fetal alcohol syndrome represents the classic and most severe manifestation of epigenetic changes induced by exposure to alcohol during pregnancy. Often these patients develop attention ...deficit hyperactivity disorder. We analyzed cortical thickness in 20 children and adolescents with fetal alcohol syndrome and attention deficit hyperactivity disorder (group 1), in 20 patients without fetal alcohol syndrome (group 2), and in 20 control cases. The first group revealed total cortical thickness significantly superior to those of the other two groups. In per-lobe analyses of cortical thickness, group 1 demonstrated greater cortical thickness in the frontal, occipital, and right temporal and left frontal lobes compared with the second group, and in both temporal lobes and the right frontal lobe compared with the control group. This study demonstrated greater cortical thickness in patients with attention deficit hyperactivity disorder and heavy prenatal exposure to alcohol, probably as an expression of immature or abnormal brain development.
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