The phenotypic spectrum of terminal 6q deletions based on a large cohort derived from social media and literature: a prominent role for DLL1.

BACKGROUND: Terminal 6q deletions are rare, and the number of well-defined published cases is limited. Since parents of children with these aberrations often search the internet and unite via international social media platforms, these dedicated platforms may hold valuable knowledge about additional cases. The Chromosome 6 Project is a collaboration between researchers and clinicians at the University Medical Center Groningen and members of a Chromosome 6 support group on Facebook. The aim of the project is to improve the surveillance of patients with chromosome 6 aberrations and the support for their families by increasing the available information about these rare aberrations. This parent-driven research project makes use of information collected directly from parents via a multilingual online questionnaire. Here, we report our findings on 93 individuals with terminal 6q deletions and 11 individuals with interstitial 6q26q27 deletions, a cohort that includes 38 newly identified individuals. RESULTS: Using this cohort, we can identify a common terminal 6q deletion phenotype that includes microcephaly, dysplastic outer ears, hypertelorism, vision problems, abnormal eye movements, dental abnormalities, feeding problems, recurrent infections, respiratory problems, spinal cord abnormalities, abnormal vertebrae, scoliosis, joint hypermobility, brain abnormalities (ventriculomegaly/hydrocephaly, corpus callosum abnormality and cortical dysplasia), seizures, hypotonia, ataxia, torticollis, balance problems, developmental delay, sleeping problems and hyperactivity. Other frequently reported clinical characteristics are congenital heart defects, kidney problems, abnormalities of the female genitalia, spina bifida, anal abnormalities, positional foot deformities, hypertonia and self-harming behaviour. The phenotypes were comparable up to a deletion size of 7.1 Mb, and most features could be attributed to the terminally located gene DLL1. Larger deletions that include QKI (> 7.1 Mb) lead to a more severe phenotype that includes additional clinical characteristics. CONCLUSIONS: Terminal 6q deletions cause a common but highly variable phenotype. Most clinical characteristics can be linked to the smallest terminal 6q deletions that include the gene DLL1 (> 500 kb). Based on our findings, we provide recommendations for clinical follow-up and surveillance of individuals with terminal 6q deletions.

Adar-associated Aicardi Goutières syndrome in a child with bilateral striatal necrosis and recurrent episodes of transaminitis.

Aicardi-Goutières syndrome (AGS) refers to a group of genetic diseases characterised by severe inflammatory encephalopathy that usually present within the first year of life, resulting in progressive loss of cognition, spasticity, dystonia and motor disability. Pathogenic variants in the adenosine deaminase acting on RNA (Adar) enzyme have been linked to AGS type 6 (AGS6, Online Mendelian Inheritance in Man (OMIM) 615010). In knockout mouse models, loss of Adar activates the interferon (IFN) pathway and causes autoimmune pathogenesis in the brain or liver. Bilateral striatal necrosis (BSN) has previously been reported in case series of children with biallelic pathogenic variants in Adar We describe a unique, previously unreported case of a child with AGS6, with clinical manifestations of BSN and recurrent transient episodes of transaminitis. The case highlights the importance of Adar in protecting the brain and liver from IFN-induced inflammation. Adar-related disease should therefore be considered in the differential diagnosis of BSN accompanied by recurrent episodes of transaminitis.

An integrated genetic analysis of epileptogenic brain malformed lesions.

Focal cortical dysplasia is the most common malformation during cortical development, sometimes excised by epilepsy surgery and often caused by somatic variants of the mTOR pathway genes. In this study, we performed a genetic analysis of epileptogenic brain malformed lesions from 64 patients with focal cortical dysplasia, hemimegalencephy, brain tumors, or hippocampal sclerosis. Targeted sequencing, whole-exome sequencing, and single nucleotide polymorphism microarray detected four germline and 35 somatic variants, comprising three copy number variants and 36 single nucleotide variants and indels in 37 patients. One of the somatic variants in focal cortical dysplasia type IIB was an in-frame deletion in MTOR, in which only gain-of-function missense variants have been reported. In focal cortical dysplasia type I, somatic variants of MAP2K1 and PTPN11 involved in the RAS/MAPK pathway were detected. The in-frame deletions of MTOR and MAP2K1 in this study resulted in the activation of the mTOR pathway in transiently transfected cells. In addition, the PTPN11 missense variant tended to elongate activation of the mTOR or RAS/MAPK pathway, depending on culture conditions. We demonstrate that epileptogenic brain malformed lesions except for focal cortical dysplasia type II arose from somatic variants of diverse genes but were eventually linked to the mTOR pathway.

The Coexistence of Two Genetic Astrocytopathies-Megalencephalic Leukoencephalopathy and Vanishing White Matter Disease-in an Indian Child.

A 9-month-old male child, born of second-degree consanguinity, presented with a progressively enlarging head since early infancy. The child had normal early development, but further acquisition of milestones after 6 months was delayed. He had afebrile seizures at 9 months, followed by the appearance of appendicular spasticity. First magnetic resonance imaging (MRI) showed nonenhancing, diffuse, bilaterally symmetrical T1/fluid-attenuated inversion recovery (FLAIR) hypointensity and T2 hyperintensity of the cerebral white matter and anterior temporal cysts. Subsequently, the periventricular and deep white matter developed microcystic changes with a pattern of radial stripes. Next-generation sequencing revealed homozygous autosomal recessive variations in the MLC1 gene [c.188T > G, (p.Leu63Arg)] on exon 3 and also in the EIF2B3 gene [c.674G > A, (p.Arg225Gln)] on exon 7, the parents being heterozygous carriers for both variations. This article highlights the rare occurrence of two leukodystrophies of diverse pathogenesis in a child from a nonpredisposed community.

A case of Aicardi-Goutières syndrome caused by TREX1 gene mutation.

Aicardi-Goutières syndrome (AGS) is a rare genetic disorder involving the central nervous system and autoimmune abnormalities, leading to severe intellectual and physical disability with poor prognosis. AGS has a phenotype similar to intrauterine viral infection, which often leads to delays in genetic counseling. In this study, we report a case with a prenatal diagnosis of AGS. The first fetal ultrasound detected bilateral lateral ventricle cystic structures, and fetal MRI was performed to identify other signs. The right parietal lobe signal showed cerebral white matter abnormalities, and fetal brain development level was lower than that of normal fetuses of the same gestational age. Whole-exome sequencing revealed that the fetus carried the TREX1:NM_033629.6:exon2:c.294dup:p. C99Mfs*3 variant, suggesting that the c.294dup mutation of the TREX1 gene was the pathogenic mutation site, and the final comprehensive diagnosis was AGS1. In this article, we also reviewed the previous literature for possible phenotypes in the fetus and found that microcephaly and intrauterine growth retardation may be the first and most important markers of the intrauterine phenotype of AGS.

Second trimester fetal MRI of the brain: Through the ground glass.

Fetal MRI is an important tool for the prenatal diagnosis of brain malformations and is often requested after second-trimester ultrasonography reveals a possible abnormality. Despite the immature state of the fetal brain at this early stage, early suggestive signs of the presence of brain malformations can be recognized. To differentiate between the normal dynamics of the growing brain and the developing pathological conditions can be challenging and requires extensive knowledge of normal central nervous system developmental stages and their neuroradiological counterparts at those different stages. This article reviews the second-trimester appearances of some commonly encountered brain malformations, focusing on helpful tricks and subtle signs to aid in the diagnosis of such conditions as rhombencephalosynapsis, various causes of vermian rotation, molar tooth spectrum anomalies, diencephalic-mesencephalic junction dysplasia, ganglionic eminence anomalies, and the most common malformations of cortical development.

Zika virus induced microcephaly and aberrant hematopoietic cell differentiation modeled in novel neonatal humanized mice.

Introduction: Immunocompetent and immunocompromised murine models have been instrumental in answering important questions regarding ZIKV pathogenesis and vertical transmission. However, mimicking human congenital zika syndrome (CZS) characteristics in these murine models has been less than optimal and does not address the potential viral effects on the human immune system. Methods: Here, we utilized neonatal humanized Rag2-/-γc-/- mice to model CZS and evaluate the potential viral effects on the differentiation of human hematopoietic stem cells in vivo. Newborn Rag2-/-γc-/- mice were engrafted with ZIKV-infected hematopoietic stem cells (HSC) and monitored for symptoms and lesions. Results: Within 13 days, mice displayed outward clinical symptoms that encompassed stunted growth, hunched posture, ruffled fur, and ocular defects. Striking gross pathologies in the brain and visceral organs were noted. Our results also confirmed that ZIKV actively infected human CD34+ hematopoietic stem cells and restricted the development of terminally differentiated B cells. Histologically, there was multifocal mineralization in several different regions of the brain together with ZIKV antigen co-localization. Diffuse necrosis of pyramidal neurons was seen with collapse of the hippocampal formation. Discussion: Overall, this model recapitulated ZIKV microcephaly and CZS together with viral adverse effects on the human immune cell ontogeny thus providing a unique in vivo model to assess the efficacy of novel therapeutics and immune interventions.

Medullary Tegmental Cap Dysplasia: Fetal and Postnatal Presentations of a Unique Brainstem Malformation.

BACKGROUND AND PURPOSE: Medullary tegmental cap dysplasia is a rare brainstem malformation, first described and defined by James Barkovich in his book Pediatric Neuroimaging from 2005 as an anomalous mass protruding from the posterior medullary surface. We describe the neuroimaging, clinical, postmortem, and genetic findings defining this unique malformation. MATERIALS AND METHODS: This is a multicenter, international, retrospective study. We assessed the patients' medical records, prenatal ultrasounds, MR images, genetic findings, and postmortem results. We reviewed the medical literature for all studies depicting medullary malformations and evaluated cases in which a dorsal medullary protuberance was described. RESULTS: We collected 13 patients: 3 fetuses and 10 children. The medullary caps had multiple characteristics. Associated brain findings were a rotated position of the medulla, a small and flat pons, cerebellar anomalies, a molar tooth sign, and agenesis of the corpus callosum. Systemic findings included the following: polydactyly, hallux valgus, large ears, and coarse facies. Postmortem analysis in 3 patients revealed that the cap contained either neurons or white matter tracts. We found 8 publications describing a dorsal medullary protuberance in 27 patients. The syndromic diagnosis was Joubert-Boltshauser syndrome in 11 and fibrodysplasia ossificans progressiva in 14 patients. CONCLUSIONS: This is the first study to describe a series of 13 patients with medullary tegmental cap dysplasia. The cap has different shapes: distinct in Joubert-Boltshauser syndrome and fibrodysplasia ossificans progressive. Due to the variations in the clinical, imaging, and postmortem findings, we conclude that there are multiple etiologies and pathophysiology. We suggest that in some patients, the pathophysiology might be abnormal axonal guidance.

Molecular characterization of an intronic RNASEH2B variant in a patient with Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome (AGS) is a progressive multisystem disorder including encephalopathy with significant impacts on intellectual and physical abilities. An early diagnosis is becoming ever more crucial, as targeted therapies are emerging. A deep understanding of the molecular heterogeneity of AGS can help guide the early diagnosis and clinical management of patients, and inform recurrence risks. Here, we detail the diagnostic odyssey of a patient with an early presentation of AGS. Exome and genome sequencing detected an intronic RNASEH2B variant missed in a conventional leukodystrophy NGS gene panel. RNA studies demonstrated that a c.322-17 A > G variant affected splicing and caused 16-nucleotide intronic retention in the RNASEH2B transcript, introducing an out-of-frame early termination codon. RNASEH2B expression in the patient's blood was reduced when compared to controls. Our study highlights the pathogenicity of this intronic variant and the importance of its inclusion in variant assessment.

Neuromuscular and Neuromuscular Junction Manifestations of the PURA-NDD: A Systematic Review of the Reported Symptoms and Potential Treatment Options.

PURA-related neurodevelopmental disorders (PURA-NDDs) are a rare genetic disease caused by pathogenic autosomal dominant variants in the PURA gene or a deletion encompassing the PURA gene. PURA-NDD is clinically characterized by neurodevelopmental delay, learning disability, neonatal hypotonia, feeding difficulties, abnormal movements, and epilepsy. It is generally considered to be central nervous system disorders, with generalized weakness, associated hypotonia, cognitive and development deficits in early development, and seizures in late stages. Although it is classified predominantly as a central nervous syndrome disorder, some phenotypic features, such as myopathic facies, respiratory insufficiency of muscle origin, and myopathic features on muscle biopsy and electrodiagnostic evaluation, point to a peripheral (neuromuscular) source of weakness. Patients with PURA-NDD have been increasingly identified in exome-sequenced cohorts of patients with neuromuscular- and congenital myasthenic syndrome-like phenotypes. Recently, fluctuating weakness noted in a PURA-NDD patient, accompanied by repetitive nerve stimulation abnormalities, suggested the disease to be a channelopathy and, more specifically, a neuromuscular junction disorder. Treatment with pyridostigmine or salbutamol led to clinical improvement of neuromuscular function in two reported cases. The goal of this systematic retrospective review is to highlight the motor symptoms of PURA-NDD, to further describe the neuromuscular phenotype, and to emphasize the role of potential treatment opportunities of the neuromuscular phenotype in the setting of the potential role of PURA protein in the neuromuscular junction and the muscles.

Causes of death in children with congenital Zika syndrome in Brazil, 2015 to 2018: A nationwide record linkage study.

BACKGROUND: Children with congenital Zika syndrome (CZS) have severe damage to the peripheral and central nervous system (CNS), greatly increasing the risk of death. However, there is no information on the sequence of the underlying, intermediate, immediate, and contributing causes of deaths among these children. The aims of this study are describe the sequence of events leading to death of children with CZS up to 36 months of age and their probability of dying from a given cause, 2015 to 2018. METHODS AND FINDINGS: In a population-based study, we linked administrative data on live births, deaths, and cases of children with CZS from the SINASC (Live Birth Information System), the SIM (Mortality Information System), and the RESP (Public Health Event Records), respectively. Confirmed and probable cases of CZS were those that met the criteria established by the Brazilian Ministry of Health. The information on causes of death was collected from death certificates (DCs) using the World Health Organization (WHO) DC template. We estimated proportional mortality (PM%) among children with CZS and among children with non-Zika CNS congenital anomalies (CA) by 36 months of age and proportional mortality ratio by cause (PMRc). A total of 403 children with confirmed and probable CZS who died up to 36 months of age were included in the study; 81.9% were younger than 12 months of age. Multiple congenital malformations not classified elsewhere, and septicemia unspecified, with 18 (PM = 4.5%) and 17 (PM = 4.2%) deaths, respectively, were the most attested underlying causes of death. Unspecified septicemia (29 deaths and PM = 11.2%) and newborn respiratory failure (40 deaths and PM = 12.1%) were, respectively, the predominant intermediate and immediate causes of death. Fetuses and newborns affected by the mother's infectious and parasitic diseases, unspecified cerebral palsy, and unspecified severe protein-caloric malnutrition were the underlying causes with the greatest probability of death in children with CZS (PMRc from 10.0 to 17.0) when compared to the group born with non-Zika CNS anomalies. Among the intermediate and immediate causes of death, pneumonitis due to food or vomiting and unspecified seizures (PMRc = 9.5, each) and unspecified bronchopneumonia (PMRc = 5.0) were notable. As contributing causes, fetus and newborn affected by the mother's infectious and parasitic diseases (PMRc = 7.3), unspecified cerebral palsy, and newborn seizures (PMRc = 4.5, each) were more likely to lead to death in children with CZS than in the comparison group. The main limitations of this study were the use of a secondary database without additional clinical information and potential misclassification of cases and controls. CONCLUSION: The sequence of causes and circumstances involved in the deaths of the children with CZS highlights the greater vulnerability of these children to infectious and respiratory conditions compared to children with abnormalities of the CNS not related to Zika.

FREM2-related Fraser syndrome with popliteal pterygium and structural central nervous system anomalies.

Fraser syndrome (FS) is a rare multiple malformation disorder characterized by cryptophthalmos, characteristic craniofacial dysmorphism, cutaneous syndactyly, malformations of the respiratory and urinary tract, and anogenital anomalies. Although the characteristic presentation of FS can be detected prenatally, oligohydramnios often challenges the clinical diagnosis. Here we report on the atypical prenatal and postmortem findings of a fetus with FS caused by a novel homozygous frameshift variant in FREM2. Our study highlights the variable manifestations of the FS and expands the clinical spectrum to include popliteal pterygium and structural central nervous system anomalies.

A novel splice site CUL3 variant in a patient with neurodevelopmental delay.

BACKGROUND: CUL3-related neurodevelopmental disorder is a recently described rare genetic condition characterized by global developmental delay and intellectual disability. Five affected individuals have been reported worldwide. The molecular and phenotypic spectrum of the disorder has yet to be fully elucidated. Splice variants in CUL3 are a well-described cause of pseudohypoaldosteronism type IIE; however, splice variants have not been associated with the neurodevelopmental disorder. We report the first individual with a neurodevelopmental disorder attributed to a CUL3 splice site variant. CASE REPORT: The patient presented with congenital developmental dysplasia of the hip and global developmental delay. A de novo splice site variant (c.379-2A > G) was identified in CUL3 and is predicted to abolish the acceptor splice site. CONCLUSION: This is the first report of an individual with a splice site variant causing CUL3-related neurodevelopmental disorder and expands our understanding of this rare condition.

Abnormal degree centrality and functional connectivity in Down syndrome: A resting-state fMRI study

Background/Objective: Neuroimaging studies have shown brain abnormalities in Down syndrome (DS) but have not clarified the underlying mechanisms of dysfunction. Here, we investigated the degree centrality (DC) abnormalities found in the DS group compared with the control group, and we conducted seed-based functional connectivity (FC) with the significant clusters found in DC. Moreover, we used the significant clusters of DC and the seed-based FC to elucidate differences between brain networks in DS compared with controls.Method: The sample comprised 18 persons with DS (M = 28.67, SD = 4.18) and 18 controls (M = 28.56, SD = 4.26). Both samples underwent resting-state functional magnetic resonance imaging. Results: DC analysis showed increased DC in the DS in temporal and right frontal lobe, as well as in the left caudate and rectus and decreased DC in the DS in regions of the left frontal lobe. Regarding seed-based FC, DS showed increased and decreased FC. Significant differences were also found between networks using Yeo parcellations, showing both hyperconnectivity and hypoconnectivity between and within networks. Conclusions: DC, seed-based FC and brain networks seem altered in DS, finding hypo- and hyperconnectivity depending on the areas. Network analysis revealed between- and within-network differences, and these abnormalities shown in DS could be related to the characteristics of the population. (AU)

[Value of chromosomal microarray analysis for the diagnosis of fetuses with anomalies of central nervous system].

OBJECTIVE: To assess the value of chromosomal microarray analysis (CMA) for the diagnosis of fetuses with anomalies of the central nervous system (CNS) and summarize the outcome of the pregnancies and follow-up. METHODS: A total of 636 fetuses from June 2014 to December 2020 who were referred to the Prenatal Diagnosis Center of Nanjing Drum Tower Hospital due to abnormal CNS prompted by ultrasound were selected as the research subjects. Based on the ultrasound findings, the fetuses were divided into ventricular dilatation group (n = 441), choroid plexus cyst group (n = 41), enlarged posterior fossa group (n = 42), holoprosencephaly group (n = 15), corpus callosum hypoplasia group (n = 22), and other anomaly group (n = 75). Meanwhile, they were also divided into isolated (n = 504) and non-isolated (n = 132) groups based on the presence of additional abnormalities. Prenatal samples (amniotic fluid/chorionic villi/umbilical cord blood) or abortus tissue were collected for the extraction of genomic DNA and CMA assay. Outcome of the pregnancies and postnatal follow-up were summarized and subjected to statistical analysis. RESULTS: In total 636 fetuses with CNS anomalies (including 89 abortus tissues) were included, and 547 cases were followed up. The overall detection rate of CMA was 11.48% (73/636). The detection rates for the holoprosencephaly group, ACC group, choroid plexus cyst group, enlarged posterior fossa group, ventricular dilatation group and other anomaly group were 80% (12/15), 31.82% (7/22), 19.51% (8/41), 14.29% (6/42), 7.48% (33/441) and 9.33% (7/75), respectively. Compared with the isolated CNS anomaly group, the detection rate for the non-isolated CNS anomaly group was significantly higher (6.35% vs. 31.06%) (32/504 vs. 41/132) (χ² = 62.867, P < 0.001). Follow up showed that, for 52 fetuses with abnormal CMA results, 51 couples have opted induced labor, whilst 1 was delivered at full term with normal growth and development. Of the 434 fetuses with normal CMA results, 377 were delivered at full term (6 had developmental delay), and 57 couples had opted induced labor. The rate of adverse pregnancy outcome for non-isolated CNS abnormal fetuses was significantly higher than that of isolated CNS abnormal fetuses (26.56% vs. 10.54%) (17/64 vs. 39/370) (χ² = 12.463, P < 0.001). CONCLUSION: Fetuses with CNS anomaly should be tested with CMA to determine the genetic cause. Most fetuses with negative CMA result have a good prognosis, but there is still a possibility for a abnormal neurological phenotype. Fetuses with CNS abnormalities in conjunct with other structural abnormalities are at increased risk for adverse pregnancy outcomes.