Illness stress-induced transient hyperglycemia in a patient with a novel YIPF5 homozygous missense variant: expanding the phenotype.

A recently described type of neonatal diabetes mellitus is caused by mutations in the YIPF5 gene and is combined with manifestations from the central nervous system, including developmental delay, epilepsy, and microcephaly. The molecular pathophysiology behind this phenotype involves the breakdown of the endoplasmic reticulum stress response due to the loss of protein folding capacity. This results in overt diabetes present from very early in life. Herein, we describe a patient with a newly reported variant in the YIPF5 gene, who presented with short events of severe hyperglycemia, induced by the stress of common illnesses, which completely resolved after recovery. We discuss the nature of transient hyperglycemia in the context of the YIPF5 gene variant and compare this phenotype with the previously described cases.

Revisiting Exome Data Identified Missed Splice Site Variant of the Asparagine Synthetase ( ASNS ) Gene.

Next-generation sequencing, such as whole-exome sequencing (WES), is increasingly used in the study of Mendelian disorders, yet many are reported as "negative." Inappropriate variant annotation and filtering steps are reasons for missing the molecular diagnosis. Noncoding variants, including splicing mutations, are examples of variants that can be overlooked. Herein, we report a family of four affected newborns, and all presented with severe congenital microcephaly. Initial research WES analysis identified a damaging homozygous variant in NME1 gene as a possible cause of primary microcephaly phenotype in these patients. However, reanalysis of the exome data uncovered a biallelic splice site variant in asparagine synthetase gene which seems to be the possible cause of the phenotype in these patients. This study highlights the importance of revisiting the exome data and the issue of "negative" exome and the afterward approaches to identify and prove new candidate genes.

Novel compound heterozygous variants in the CSPP1 gene causes Joubert syndrome: case report and literature review of the CSPP1 gene's pathogenic mechanism.

Joubert syndrome (JS) is a rare autosomal recessive neurodevelopmental condition characterized by congenital mid-hindbrain abnormalities and a variety of clinical manifestations. This article describes a case of Joubert syndrome type 21 with microcephaly, seizures, developmental delay and language regression, caused by a CSPP1 gene variant and examines the contributing variables. This paper advances the understanding of JS by summarizing the literature and offering detection patterns for practitioners with clinical suspicions of JS.

Congenital anomalies during Covid-19: artifact of surveillance or a real TORCH?

Infections in the first trimester of pregnancy can be teratogenic, but the possibility that Covid-19 could lead to birth defects is unclear. We examined whether SARS-CoV-2 infection during pregnancy or exposure to pandemic conditions were associated with the risk of congenital anomalies. We carried out a retrospective study of 420,222 neonates born in Quebec, Canada in two time periods: prepandemic (January 1, 2017 to March 12, 2020) vs. pandemic (March 13, 2020 to March 31, 2022). We classified pandemic births as early (first trimester completed before the pandemic) or late (first trimester during the pandemic), and identified patients with SARS-CoV-2 infections during pregnancy. We applied (1) adjusted log-binomial regression models to assess the association between SARS-CoV-2 infection and congenital anomalies, and (2) autoregressive interrupted time series regression to analyze temporal trends in the monthly number of defects in all patients regardless of infection. In total, 29,263 newborns (7.0%) had a congenital anomaly. First trimester SARS-CoV-2 infections were not associated with a greater risk of birth defects compared with no infection (RR 1.07, 95% CI 0.59-1.95). However, births during the late pandemic period were more likely to be diagnosed with congenital microcephaly compared with prepandemic births (RR 1.44, 95% CI 1.21-1.71). Interrupted time series analysis confirmed that the frequency of microcephaly increased during the late pandemic period, whereas other anomalies did not. We conclude that Covid-19 is likely not teratogenic, but enhanced surveillance of anomalies among late pandemic births may have heightened the detection of infants with microcephaly.

Autosomal recessive primary microcephaly type 2 associated with a novel WDR62 splicing variant that disrupts the expression of the functional transcript.

Background: Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized primarily by congenital microcephaly and intellectual disability but without extra-central nervous system malformations. This investigation aimed to elucidate the genetic underpinnings of microcephaly in a patient from a Chinese consanguineous family. Methods: A comprehensive clinical assessment, including brain magnetic resonance imaging (MRI), electroencephalogram (EEG), and genetic analyses, was conducted to evaluate the patient's condition. Whole-exome sequencing (WES) was employed to identify the causative gene, followed by Sanger sequencing, to confirm the mutation and its segregation within the family. Reverse transcript polymerase chain reaction (RT-PCR) was utilized to detect changes in splicing. Western blot was employed to reveal the difference of protein expression level between the wild-type and mutant WDR62 in vitro. Results: The patient exhibited classic MCPH symptoms, including microcephaly, recurrent epilepsy, delayed psychomotor development, and intellectual disability. Additionally, asymmetrical limb length was noted as a prominent feature. MRI findings indicated reduced brain volume with cortical malformations, while EEG demonstrated heightened sharp wave activity. A molecular analysis uncovered a novel homozygous variant c.4154-6 C > G in the WDR62 intron, and a functional analysis confirmed the pathogenicity of this mutation, resulting in the formation of an abnormal transcript with premature termination codons. Conclusion: This study enhances our understanding of the genetic heterogeneity associated with MCPH and highlights the pivotal role of genetic testing in the diagnosing and managing of rare neurodevelopmental disorders. Furthermore, it highlights the potential of emerging genetic therapies in treating conditions such as MCPH2.

Novel biallelic SASS6 variants associated with primary microcephaly and fetal growth restriction.

Primary microcephaly is characterized by a head circumference prenatally or at birth that falls below three standard deviations from age-, ethnic-, and sex-specific norms. Genetic defects are one of the underlying causes of primary microcephaly. Since 2014, five variants of the SASS6 gene have been identified as the cause of MCPH 14 in three reported families. In this study, we present the genetic findings of members of a nonconsanguineous Chinese couple with a history of microcephaly and fetal growth restriction (FGR) during their first pregnancy. Utilizing trio whole-exome sequencing, we identified compound heterozygous variants involving a frameshift NM_194292.3:c.450_453del p.(Lys150AsnfsTer7) variant and a splice region NM_194292.3:c.1674+3A>G variant within the SASS6 gene in the affected fetus. Moreover, reverse transcriptase-polymerase chain reaction from RNA of the mother's peripheral blood leukocytes revealed that the c.1674+3A>G variant led to the skipping of exon 14 and an inframe deletion. To the best of our knowledge, the association between FGR and SASS6-related microcephaly has not been reported, and our findings confirm the pivotal role of SASS6 in microcephaly pathogenesis and reveal an expanded view of the phenotype and mutation spectrum associated with this gene.

Importance and application of WES in fetal genetic diagnostics: Identification of novel ASPM mutation in a fetus with microcephaly.

Background: Prenatal whole exome sequencing (WES) approaches can provide genetic diagnosis with rapid turnaround time and high diagnostic rate when conventional tests are negative. Here we report a family with multiple pregnancy loss and with repeated occurrence of fetal microcephaly. Methods and results: Because of positive family history and recurrent structural abnormality during the pregnancies that may lead postnatal neurodevelopmental consequences, WES analysis was indicated. Umbilical cord blood sampling was carried out and WES was performed using Twist Human Core Exome Kit and Illumina sequencing technology. The presence of pathogenic variants was confirmed by Sanger sequencing. WES analysis revealed a known pathogenic c.8506_8507delCA (p.Gln2836Glufs*35, rs587783280) and a novel pathogenic c.3134_3135delTC (p.Leu1045Glnfs*17) ASPM mutations in the fetus in compound heterozygous state. The c.3134_3135delTC has never been reported in the literature. Conclusions: Our findings serve additional evidence that WES can be an efficient and relevant tool to diagnose certain genetic disorders with appropriate indication and to assess the recurrence risk of a disease. With the application of WES in combination with pre-implantation genetic tests, we can avoid the transmission of pathogenic mutations and we can achieve a decreased abortion rate in obstetric care.

A novel variant in ASNS gene responsible for syndromic intellectual disability and microcephaly: Case report and literature review.

BACKGROUND: The ASNS (ASNS, MIM 108370) gene variations are responsible for asparagine synthetase deficiency (ASNSD, MIM 615574), a very rare autosomal recessive disease characterized by cerebral anomalies. These patients have congenital microcephaly, progressive encephalopathy, severe intellectual disability, and intractable seizures. METHOD: Clinical characteristics of the patient were collected. Exome sequencing was used for the identification of variants. Sanger sequencing was used to confirm the variant in the target region. The structure of the protein was checked using the DynaMut2 web server. RESULTS: The proband is an 11-year-old Iranian-Azeri girl with primary microcephaly and severe intellectual disability in a family with a consanguineous marriage. Symptoms emerged around the 10-20th days of life, when refractory epileptic gaze and unilateral tonic-clonic seizures initiated without any provoking factor such as fever. A brain MRI revealed no abnormalities except for brain atrophy. The karyotype was normal. Using exome sequencing, we identified a novel homozygous variant of thymine to adenine (NM_001673.5:c.538T>A) in the ASNS gene. Both parents had a heterozygous variant in this location. Subsequently, Sanger sequencing confirmed this variant. We also reviewed the clinical manifestations and MRI findings of the previously reported patients. CONCLUSION: In the present study, a novel homozygous variant was recognized in the ASNS gene in an Iranian-Azeri girl manifesting typical ASNSD symptoms, particularly intellectual disability and microcephaly. This study expands the mutation spectrum of ASNSD and reviews previously reported patients.

New candidate genes potentially involved in Zika virus teratogenesis.

Despite efforts to elucidate Zika virus (ZIKV) teratogenesis, still several issues remain unresolved, particularly on the molecular mechanisms behind the pathogenesis of Congenital Zika Syndrome (CZS). To answer this question, we used bioinformatics tools, animal experiments and human gene expression analysis to investigate genes related to brain development potentially involved in CZS. Searches in databases for genes related to brain development and CZS were performed, and a protein interaction network was created. The expression of these genes was analyzed in a CZS animal model and secondary gene expression analysis (DGE) was performed in human cells exposed to ZIKV. A total of 2610 genes were identified in the databases, of which 1013 were connected. By applying centrality statistics of the global network, 36 candidate genes were identified, which, after selection resulted in nine genes. Gene expression analysis revealed distinctive expression patterns for PRKDC, PCNA, ATM, SMC3 as well as for FGF8 and SHH in the CZS model. Furthermore, DGE analysis altered expression of ATM, PRKDC, PCNA. In conclusion, systems biology are helpful tools to identify candidate genes to be validated in vitro and in vivo. PRKDC, PCNA, ATM, SMC3, FGF8 and SHH have altered expression in ZIKV-induced brain malformations.

Novel biallelic ZNF335 variant causing primary microcephaly: A case report and radiological review.

Biallelic pathogenic variants in ZNF335 are one of the genetic causes of microcephaly, reported only in the past decade. It regulates neural progenitor proliferation and neurogenesis by interacting with a H3K4 methyltransferase complex. Biallelic pathogenic ZNF335 variants predispose to neuronal cell death and aberrant differentiation, thus causing secondary microcephaly. These neurodevelopmental anomalies lead to imaging findings in the cortex, posterior fossa, and basal ganglia. We report an individual of Nepalese ancestry with a novel homozygous ZNF335 variant (c.3591 + 2dup) (p.?) (NM_022095.3) which on further RNA analysis confirmed a splice site variant in intron 23. The patient presented with primary microcephaly with atrophic cerebral hemispheres, oversimplification of gyri, basal ganglia, and corpus callosal atrophy. Literature review on the topic revealed a spectrum of brain abnormalities, which can present either with a primary or secondary microcephaly depending upon the underlying genetic variant.

Phosphoserine aminotransferase deficiency diagnosed by whole-exome sequencing and LC-MS/MS reanalysis: A case report and review of literature.

BACKGROUND: Phosphoserine aminotransferase deficiency (PSATD) is an autosomal recessive disorder associated with hypertonia, psychomotor retardation, and acquired microcephaly. Patients with PSATD have low concentrations of serine in plasma and cerebrospinal fluid. METHODS: We reported a 2-year-old female child with developmental delay, dyskinesia, and microcephaly. LC-MS/MS was used to detect amino acid concentration in the blood and whole-exome sequencing (WES) was used to identify the variants. PolyPhen-2 web server and PyMol were used to predict the pathogenicity and changes in the 3D model molecular structure of protein caused by variants. RESULTS: WES demonstrated compound heterozygous variants in PSAT1, which is associated with PSATD, with a paternal likely pathogenic variant (c.235G>A, Gly79Arg) and a maternal likely pathogenic variant (c.43G>C, Ala15Pro). Reduced serine concentration in LC-MS/MS further confirmed the diagnosis of PSATD in this patient. CONCLUSIONS: Our findings demonstrate the importance of WES combined with LC-MS/MS reanalysis in the diagnosis of genetic diseases and expand the PSAT1 variant spectrum in PSATD. Moreover, we summarize all the cases caused by PSAT1 variants in the literature. This case provides a vital reference for the diagnosis of future cases.

Chromosomal microarray testing yield in 829 cases of microcephaly: a clinical characteristics-based analysis for prenatal and postnatal cases.

INTRODUCTION: Microcephaly, characterized by abnormal head growth, can often serve as an initial indicator of congenital, genetic, or acquired disorders. In this study, we sought to evaluate the effectiveness of chromosomal microarray (CMA) testing in detecting abnormalities in both prenatal and postnatal cases of microcephaly. MATERIALS AND METHODS: CMA Testing: We conducted CMA testing on 87 prenatally-detected microcephaly cases and 742 postnatal cases at a single laboratory. We evaluated the CMA yield in relation to specific clinical characteristics. RESULTS: In prenatal cases, pathogenic and likely pathogenic (LP) results were identified in 4.6% of cases, a significantly higher rate compared to low-risk pregnancies. The male-to-female ratio in this cohort was 3, and the CMA yield was not influenced by gender or other clinical parameters. For postnatal cases, the CMA yield was 15.0%, with a significantly higher detection rate associated with dysmorphism, hypotonia, epilepsy, congenital heart malformations (CHM), learning disabilities (LD), and a history of Fetal growth restriction (FGR). No specific recurrent copy number variations (CNVs) were observed, and the rate of variants of unknown significance was 3.9%. CONCLUSIONS: The yield of CMA testing in prenatal microcephaly is lower than in postnatal cases (4.6% vs. 15%). The presence of microcephaly, combined with dysmorphism, hypotonia, epilepsy, CHD, LD, and FGR, significantly increases the likelihood of an abnormal CMA result.

PRMT5-mediated homologous recombination repair is essential to maintain genomic integrity of neural progenitor cells.

Maintaining genomic stability is a prerequisite for proliferating NPCs to ensure genetic fidelity. Though histone arginine methylation has been shown to play important roles in safeguarding genomic stability, the underlying mechanism during brain development is not fully understood. Protein arginine N-methyltransferase 5 (PRMT5) is a type II protein arginine methyltransferase that plays a role in transcriptional regulation. Here, we identify PRMT5 as a key regulator of DNA repair in response to double-strand breaks (DSBs) during NPC proliferation. Prmt5F/F; Emx1-Cre (cKO-Emx1) mice show a distinctive microcephaly phenotype, with partial loss of the dorsal medial cerebral cortex and complete loss of the corpus callosum and hippocampus. This phenotype is resulted from DSBs accumulation in the medial dorsal cortex followed by cell apoptosis. Both RNA sequencing and in vitro DNA repair analyses reveal that PRMT5 is required for DNA homologous recombination (HR) repair. PRMT5 specifically catalyzes H3R2me2s in proliferating NPCs in the developing mouse brain to enhance HR-related gene expression during DNA repair. Finally, overexpression of BRCA1 significantly rescues DSBs accumulation and cell apoptosis in PRMT5-deficient NSCs. Taken together, our results show that PRMT5 maintains genomic stability by regulating histone arginine methylation in proliferating NPCs.

Small size, big problems: insights and difficulties in prenatal diagnosis of fetal microcephaly.

Microcephaly is a sign, not a diagnosis. Its incidence varies widely due to the differences in the definition and the population being studied. It is strongly related to neurodevelopmental disorders. Differences in definitions and measurement techniques between fetuses and newborns pose a great challenge for the diagnosis and prognostication of fetal microcephaly. A false positive diagnosis can result (in countries where it is legal) in erroneous termination of pregnancy, where a false negative diagnosis might lead to the birth of a microcephalic newborn. Microcephaly in growth restricted fetuses deserves special attention and separate evaluation as it is an important prognostic factor, and not necessarily part of the general growth retardation. Several genetic syndromes incorporating microcephaly and intrauterine growth retardation (IUGR) are discussed. Deceleration of the head circumference (HC) growth rate even when the HC is still within normal limits might be the only clue for developing microcephaly and should be considered during fetal head growth follow up. Combining additional parameters such as a positive family history, associated anomalies, and new measurement parameters can improve prediction in about 50% of cases, and thus should be part of the prenatal workup. Advances in imaging modalities and in prenatal genetic investigation along with the emergence of new growth charts can also improve diagnostic accuracy. In this article, we review the different definitions and etiologies of fetal microcephaly, discuss difficulties in diagnosis, investigate the reasons for the low yield of prenatal diagnosis, and provide improvement suggestions. Finally, we suggest an updated algorithm that will aid in the diagnosis and management of fetal microcephaly.

Prediction of underweight, short stature, and microcephaly based on brain diffusion-weighted imaging sequence in neonates with stage.2 of hypoxic-ischemic encephalopathy: A follow-up study.

Background: Hypoxic-ischemic encephalopathy (HIE), caused due to reduced oxygenation and brain blood flow, occurs in 1-8 per 1000 live full-term births in developed countries and up to 26 per 1000 live in the developing world. The growth status of survivors of birth HIE has not been evaluated sufficiently. Objective: This study evaluated, the growth parameters (weight, height, and head circumference) of neonates with Sarnat stage.2 of HIE at 6, 10, and 12 months and its relationship with findings of neonatal brain diffusion-weighted imaging (DWI) sequence. Materials and Methods: Medical records and growth parameters of 35 neonates with gestational age > 34 wk who were admitted with stage.2 of HIE in Neonatal Intensive Care Unit of Shahid Sadoughi hospital, Yazd, Iran from March 2021-March 2022, and its relationship with neonatal brain DWI sequence finding was evaluated. Results: 15 girls and 20 boys with a mean birth weight of 2880.3 ± 221.8 gr were evaluated. Conventional magnetic resonance imaging and DWI were found to be abnormal in 6 (17.1%) and 18 neonates (51.4%). The most abnormal finding of DWI was high signal in basal ganglia/thalamus in 9 neonates (25.7%). Abnormal DWI is more frequent in neonates with seizures and low birth weight. Hospital stay days were more prolonged in neonates with abnormal DWI. Microcephaly at 12 months was more frequent in children with abnormal DWI. Conclusion: In survivors of moderate neonatal HIE, abnormal brain DWI sequence might predict inappropriate head growth, and need close medical and nutritional interventions for growth improvement.

ATP-P2X7 signaling mediates brain pathology while contributing to viral control in perinatal Zika virus infection.

Zika virus (ZIKV), the causative agent of Zika fever, is a flavivirus transmitted by mosquitoes of the Aedes genus. Zika virus infection has become an international concern due to its association with severe neurological complications such as fetal microcephaly. Viral infection can induce the release of ATP in the extracellular environment, activating receptors sensitized by extracellular nucleotides, such as the P2X7 receptor. This receptor is the primary purinergic receptor involved in neuroinflammation, neurodegeneration, and immunity. In this work, we investigated the role of ATP-P2X7 receptor signaling in Zika-related brain abnormalities. Wild-type mice (WT) and P2X7 receptor-deficient (P2X7-/-) C57BL/6 newborn mice were subcutaneously inoculated with 5 × 106plaque-forming units of ZIKV or mock solution. P2X7 receptor expression increased in the brain of Zika virus-infected mice compared to the mock group. Comparative analyses of the hippocampi from WT and P2X7-/-mice revealed that the P2X7 receptor increased hippocampal damage in CA1/CA2 and CA3 regions. Doublecortin expression decreased significantly in the brains of ZIKV-infected mice. WT ZIKV-infected mice showed impaired motor performance compared to P2X7-/- infected mice. WT ZIKV-infected animals showed increased expression of glial markers GFAP (astrocytes) and IBA-1 (microglia) compared to P2X7-/- infected mice. Although the P2X7 receptor contributes to neuronal loss and neuroinflammation, WT mice were more efficient in controlling the viral load in the brain than P2X7 receptor-deficient mice. This result was associated with higher induction of TNF-α, IFN-ß, and increased interferon-stimulated gene expression in WT mice than P2X7-/-ZIKV-infected. Finally, we found that the P2X7 receptor contributes to inhibiting the neuroprotective signaling pathway AKT/mTOR while stimulating the caspase-3 activation, possibly two distinct pathways contributing to neurodegeneration. These findings suggest that ATP-P2X7 receptor signaling contributes to the antiviral response in the brain of ZIKV-infected mice while increasing neuronal loss, neuroinflammation, and related brain abnormalities.

Microcephaly with a disproportionate hippocampal reduction, stem cell loss and neuronal lipid droplet symptoms in Trappc9 KO mice.

Mutations of the human TRAFFICKING PROTEIN PARTICLE COMPLEX SUBUNIT 9 (TRAPPC9) cause a neurodevelopmental disorder characterised by microcephaly and intellectual disability. Trappc9 constitutes a subunit specific to the intracellular membrane-associated TrappII complex. The TrappII complex interacts with Rab11 and Rab18, the latter being specifically associated with lipid droplets (LDs). Here we used non-invasive imaging to characterise Trappc9 knock-out (KO) mice as a model of the human hereditary disorder. KOs developed postnatal microcephaly with many grey and white matter regions being affected. In vivo magnetic resonance imaging (MRI) identified a disproportionately stronger volume reduction in the hippocampus, which was associated with a significant loss of Sox2-positive neural stem and progenitor cells. Diffusion tensor imaging indicated a reduced organisation or integrity of white matter areas. Trappc9 KOs displayed behavioural abnormalities in several tests related to exploration, learning and memory. Trappc9-deficient primary hippocampal neurons accumulated a larger LD volume per cell following Oleic Acid stimulation, and the coating of LDs by Perilipin-2 was much reduced. Additionally, Trappc9 KOs developed obesity, which was significantly more severe in females than in males. Our findings indicate that, beyond previously reported Rab11-related vesicle transport defects, dysfunctions in LD homeostasis might contribute to the neurobiological symptoms of Trappc9 deficiency.

Expanding the phenotype of UPF3B-related disorder: Case reports and literature review.

UPF3B encodes the Regulator of nonsense transcripts 3B protein, a core-member of the nonsense-mediated mRNA decay pathway, protecting the cells from the potentially deleterious actions of transcripts with premature termination codons. Hemizygous variants in the UPF3B gene cause a spectrum of neuropsychiatric issues including intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, and schizophrenia/childhood-onset schizophrenia (COS). The number of patients reported to date is very limited, often lacking an extensive phenotypical and neuroradiological description of this ultra-rare syndrome. Here we report three subjects harboring UPF3B variants, presenting with variable clinical pictures, including cognitive impairment, central hypotonia, and syndromic features. Patients 1 and 2 harbored novel UPF3B variants-the p.(Lys207*) and p.(Asp429Serfs*27) ones, respectively-while the p.(Arg225Lysfs*229) variant, identified in Patient 3, was already reported in the literature. Novel features in our patients are represented by microcephaly, midface hypoplasia, and brain malformations. Then, we reviewed pertinent literature and compared previously reported subjects to our cases, providing possible insights into genotype-phenotype correlations in this emerging condition. Overall, the detailed phenotypic description of three patients carrying UPF3B variants is useful not only to expand the genotypic and phenotypic spectrum of UPF3B-related disorders, but also to ameliorate the clinical management of affected individuals.

A Rare Cause of Intellectual Disability.

A seven-year-old female was followed in a developmental clinic from the age of nine months due to delayed psychomotor development. The first physical examination showed a newborn with irritability and a large anterior fontanelle. A transfontanellar ultrasound was performed, revealing mild enlargement of the lateral and third ventricles. Head circumference remained below the third percentile until the age of five months, then rose to the third percentile. Developmental milestones were globally delayed, with expressive language being more severely affected and axial hypotonia with appendicular hypertonia on neurological examination. Subsequent medical observation revealed deep-set eyes, mildly up-slanted palpebral fissures, a high nasal bridge with a broad nasal tip, a thin upper lip, widely spaced teeth, retrognathia, and a slight pectus excavatum. Genetic investigation revealed the diagnosis, with whole-exome sequencing consistent with the genetic diagnosis of autosomal dominant mental retardation type 7 (MRD7). All patients diagnosed with MRD7 have a development delay detected at a young age and, typically, a mild to severe intellectual disability later in life. All individuals present language impairment, especially in verbal expression. Motor development is typically affected by gait disturbances and generalized hypertonia, which are noted early in life. Microcephaly is a prominent feature of this syndrome, present in over 90% of the cases. The most common findings in MRD7 (microcephaly and intellectual disability) have a broad differential diagnosis. Some disorders have multiple findings in common with MRD7, such as Angelman syndrome (AS), MECP2 disorders, or Mowat-Wilson syndrome (MWS). MRD7 is a rare genetic syndrome characterized by developmental delay/intellectual disability, microcephaly, autism spectrum disorder, behavior problems, typical facial features, and seizures. Early intervention is more likely to be effective and potentially change a child's developmental path. Small gains early in life could represent a significant difference in the children's future autonomy.

Postnatal Zika virus infection leads to morphological and cellular alterations within the neurogenic niche.

The Zika virus received significant attention in 2016, following a declaration by the World Health Organization of an epidemic in the Americas, in which infections were associated with microcephaly. Indeed, prenatal Zika virus infection is detrimental to fetal neural stem cells and can cause premature cell loss and neurodevelopmental abnormalities in newborn infants, collectively described as congenital Zika syndrome. Contrastingly, much less is known about how neonatal infection affects the development of the newborn nervous system. Here, we investigated the development of the dentate gyrus of wild-type mice following intracranial injection of the virus at birth (postnatal day 0). Through this approach, we found that Zika virus infection affected the development of neurogenic regions within the dentate gyrus and caused reactive gliosis, cell death and a decrease in cell proliferation. Such infection also altered volumetric features of the postnatal dentate gyrus. Thus, we found that Zika virus exposure to newborn mice is detrimental to the subgranular zone of the dentate gyrus. These observations offer insight into the cellular mechanisms that underlie the neurological features of congenital Zika syndrome in children.