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The Myelin Regulator Factor (MYRF) is a master regulator governing myelin formation and maintenance in the central nervous system. The conservation of MYRF across metazoans and its broad tissue expression suggest it has functions extending beyond the well-established role in myelination. Loss of MYRF results in developmental lethality in both invertebrates and vertebrates, and MYRF haploinsufficiency in humans causes MYRF-related Cardiac Urogenital Syndrome, underscoring its importance in animal development; however, these mechanisms are largely unexplored. MYRF, an unconventional transcription factor, begins embedded in the membrane and undergoes intramolecular chaperone mediated trimerization, which triggers self-cleavage, allowing its N-terminal segment with an Ig-fold DNA-binding domain to enter the nucleus for transcriptional regulation. Recent research suggests developmental regulation of cleavage, yet the mechanisms remain enigmatic. While some parts of MYRF's structure have been elucidated, others remain obscure, leaving questions about how these motifs are linked to its intricate processing and function., (© 2024 Wiley Periodicals LLC.)

Background: Kinase D-interacting substrate of 220 kDa (KIDINS220) is a multifunctional scaffolding protein essential for neuronal development. It has been implicated in neurological diseases with either autosomal dominant (AD) or autosomal recessive (AR) inheritance patterns. The molecular mechanisms underlying the AR/AD dual nature of KIDINS220 remain elusive, posing challenges to genetic interpretation and clinical interventions. Moreover, increased KIDINS220 exhibited neurotoxicity, but its role in neurodevelopment remains unclear., Objective: The aim was to investigate the genotype-phenotype correlations of KIDINS220 and elucidate its pathophysiological role in neuronal development., Methods: Whole-exome sequencing was performed in a four-generation family with cerebral palsy. CRISPR/Cas9 was used to generate KIDINS220 mutant cell lines. In utero electroporation was employed to investigate the effect of KIDINS220 variants on neurogenesis in vivo., Results: We identified in KIDINS220 a pathogenic nonsense variant (c.4177C > T, p.Q1393*) that associated with AD cerebral palsy. We demonstrated that the nonsense variants located in the terminal exon of KIDINS220 are gain-of-function (GoF) variants, which enable the mRNA to escape nonsense-mediated decay and produce a truncated yet functional KIDINS220 protein. The truncated protein exhibited significant resistance to calpain and consequently accumulated within cells, resulting in the hyperactivation of Rac1 and defects in neuronal development., Conclusions: Our findings demonstrate that the location of variants within KIDINS220 plays a crucial role in determining inheritance patterns and corresponding clinical outcomes. The proposed interaction between Rac1 and KIDINS220 provides new insights into the pathogenesis of cerebral palsy, implying potential therapeutic perspectives. © 2023 International Parkinson and Movement Disorder Society., (© 2023 International Parkinson and Movement Disorder Society.)

Background A neurodevelopmental syndrome was recently reported in four patients with SOX4 heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome. Methods We newly identified 17 patients with SOX4 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes. Results All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the SOX11-related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS. Conclusion These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes. [ABSTRACT FROM AUTHOR]

Acute encephalopathy typically affects previously healthy children and often results in death or severe neurological sequelae. Acute encephalopathy is a group of multiple syndromes characterized by various clinical symptoms, such as loss of consciousness, motor and sensory impairments, and status convulsions. However, there is not only localized encephalopathy but also progression from localized to secondary extensive encephalopathy and to encephalopathy, resulting in a heterogeneous clinical picture. Acute encephalopathy diagnosis has advanced over the years as a result of various causes such as infections, epilepsy, cerebrovascular disorders, electrolyte abnormalities, and medication use, and new types of acute encephalopathies have been identified. In recent years, various tools, including neuroradiological diagnosis, have been developed as methods for analyzing heterogeneous acute encephalopathy. Encephalopathy caused by genetic abnormalities such as CPT2 and SCN1A is also being studied. Researchers were able not only to classify acute encephalopathy from image diagnosis to typology by adjusting the diffusion-weighted imaging/ADC value in magnetic resonance imaging diffusion-weighted images but also fully comprehend the pathogenesis of vascular and cellular edema. Acute encephalopathy is known as a very devastating disease both medically and socially because there are many cases where lifesaving is sometimes difficult. The overall picture of childhood acute encephalopathy is becoming clearer with the emergence of the new acute encephalopathies. Treatment methods such as steroid pulse therapy, immunotherapy, brain hypothermia, and temperature control therapy have also advanced. Acute encephalopathy in children is the result of our predecessor's zealous pursuit of knowledge. It is reasonable to say that it is a field that has advanced dramatically over the years. We would like to provide a comprehensive review of a pediatric acute encephalopathy, highlighting advancements in diagnosis and treatment based on changing disease classification scenarios from the most recent clinical data. [ABSTRACT FROM AUTHOR]

A clinical quiz on a case of a child patient with growth retardation and late-onset hypertension is presented.

Background: Pathogenic mutations in genes that control chromatin function have been implicated in rare genetic syndromes. These chromatin modifiers exhibit extraordinary diversity in the scale of the epigenetic changes they affect, from single basepair modifications by DNMT1 to whole genome structural changes by PRM1/2. Patterns of DNA methylation are related to a diverse set of epigenetic features across this full range of epigenetic scale, making DNA methylation valuable for mapping regions of general epigenetic dysregulation. However, existing methods are unable to accurately identify regions of differential methylation across this full range of epigenetic scale directly from DNA methylation data. Results: To address this, we developed DMRscaler, a novel method that uses an iterative windowing procedure to capture regions of differential DNA methylation (DMRs) ranging in size from single basepairs to whole chromosomes. We benchmarked DMRscaler against several DMR callers in simulated and natural data comparing XX and XY peripheral blood samples. DMRscaler was the only method that accurately called DMRs ranging in size from 100 bp to 1 Mb (pearson's r = 0.94) and up to 152 Mb on the X-chromosome. We then analyzed methylation data from rare-disease cohorts that harbor chromatin modifier gene mutations in NSD1, EZH2, and KAT6A where DMRscaler identified novel DMRs spanning gene clusters involved in development. Conclusion: Taken together, our results show DMRscaler is uniquely able to capture the size of DMR features across the full range of epigenetic scale and identify novel, co-regulated regions that drive epigenetic dysregulation in human disease. [ABSTRACT FROM AUTHOR]

Idiopathic scoliosis (IS) is a multifactorial disease with a genetic background. The association of Ladybird Homeobox 1 (LBX1) polymorphisms with IS has been proven in multiple studies. However, the epigenetic mechanisms have not been evaluated. This study aimed to evaluate the LBX1 methylation level in deep paravertebral muscles in order to analyze its association with IS occurrence and/or IS severity. Fifty-seven IS patients and twenty non-IS patients were examined for the paravertebral muscles' methylation level of the LBX1 promoter region. There was no significant difference in methylation level within paravertebral muscles between patients vs. controls, except for one CpG site. The comparison of the paravertebral muscles' LBX1 promoter region methylation level between patients with a major curve angle of ≤70° vs. >70° revealed significantly higher methylation levels in 17 of 23 analyzed CpG sequences at the convex side of the curvature in patients with a major curve angle of >70° for the reverse strand promoter region. The association between LBX1 promoter methylation and IS severity was demonstrated. In patients with severe IS, the deep paravertebral muscles show an asymmetric LBX1 promoter region methylation level, higher at the convex scoliosis side, which reveals the role of locally acting factors in IS progression. [ABSTRACT FROM AUTHOR]

The Schuurs–Hoeijmakers syndrome (SHMS) or PACS1 Neurodevelopment Disorder (PACS1-NDD) is a rare autosomal dominant disease caused by mutations in the PACS1 gene. To date, only 87 patients have been reported and, surprisingly, most of them carry the same variant (c.607C>T; p.R203W). The most relevant clinical features of the syndrome include neurodevelopment delay, seizures or a recognizable facial phenotype. Moreover, some of these characteristics overlap with other syndromes, such as the PACS2 or Wdr37 syndromes. The encoded protein phosphofurin acid cluster sorting 1 (PACS-1) is able to bind to different client proteins and direct them to their subcellular final locations. Therefore, although its main function is protein trafficking, it could perform other roles related to its client proteins. In patients with PACS1-NDD, a gain-of-function or a dominant negative mechanism for the mutated protein has been suggested. This, together with the fact that most of the patients carry the same genetic variant, makes it a good candidate for novel therapeutic approaches directed to decreasing the toxic effect of the mutated protein. Some of these strategies include the use of antisense oligonucleotides (ASOs) or targeting of its client proteins. [ABSTRACT FROM AUTHOR]

The normal structure of the spinal vertebrae is important for maintaining posture and the normal function of the thoracoabdominal organs and nervous system. Kyphoscoliosis occurs when the spinal vertebrae curve excessively beyond their physiological curvature to the back and side. Congenital kyphoscoliosis, a type of kyphoscoliosis, develops in the fetal period and is present in early childhood. However, neither the mechanism of pathogenesis nor the responsible gene has been identified. The lack of established animal models is a significant hurdle that limits the study of congenital kyphoscoliosis. Over the past 15 years, we have been accumulating data on this issue using rat models, based on the idea that the development of congenital kyphoscoliosis is caused by the abnormal expression of genes involved in normal bone formation. We hypothesize that analysis of an animal model of congenital kyphoscoliosis will provide a basis for the treatment of this disease in humans. The present review aimed to introduce molecules and mechanisms associated with the pathogenesis of kyphoscoliosis and to discuss the usefulness of studying this disease using model rats that develop kyphoscoliosis. [ABSTRACT FROM AUTHOR]

De novo variants in the myelin regulatory factor (MYRF), a transcription factor involved in the differentiation of oligodendrocytes, have been linked recently to the cardiac and urogenital syndrome, while familiar variants are associated with nanophthalmos. Here, we report for the first time on a patient with a de novo stop-gain variant in MYRF (p.Q838*) associated with Scimitar syndrome, 46,XY partial gonadal dysgenesis (GD) and severe hyperopia. Since variants in MYRF have been described in both 46,XX and 46,XY GD, we assumed a role of MYRF in the early development of the bipotential gonad. We used publicly available single cell sequencing data of human testis and ovary from different developmental stages and analysed them for MYRF expression. We identified MYRF expression in the subset of coelomic epithelial cells at stages of gonadal ridge development in 46,XX and 46,XY individuals. Differential gene expression analysis revealed significantly upregulated genes. Within these, we identified CITED2 as a gene containing a MYRF binding site. It has been shown that Cited2−/− mice have gonadal defects in both testis and ovary differentiation, as well as defects in heart development and establishment of the left–right axis. This makes MYRF a potential candidate as an early regulator of gonadal and heart development via upregulation of the transcriptional cofactor CITED2. [ABSTRACT FROM AUTHOR]

Background: Congenital cataract is causing one‐third of blindness worldwide. Congenital cataract is heterogeneous in its inheritance patterns. The current study is aimed to explore the unknown genetic causes underlying congenital cataracts. Methods: Blood samples from affected and normal individuals of n = 25 Pakistani families identified with congenital cataracts were collected. Genomic DNA was extracted and Sanger sequencing was performed to identify novel pathogenic variants in the FYCO1 (MIM#607182) gene. Later structural bioinformatics tools and molecular dynamics simulations were performed to analyze the impact of these variants on protein structure and function. Results: Sanger sequencing resulted in the identification of a novel splice site mutation (NM_024513.3: c.3151‐29_3151‐7del) segregating in an autosomal recessive manner. This novel variant was confirmed to be absent in the n = 300 population controls. Further, bioinformatics tools revealed the formation of a mutant protein with a loss of the Znf domain. In addition, we also found a previously known (c.4127 T > C; p.Leu1376Pro) mutation in four families. We also report a novel heterozygous variant (c.3419G > A; p.Arg1140Gln) in another family. Conclusions: In conclusion, we report a novel deletion (NM_024513.3: c.3151‐29_3151‐7del) in one family and a frequent homozygous missense mutation (c.4127 T > C; p.Leu1376Pro) in four Pakistani families. The current research highlights the importance of autophagy in lens development and maintaining its transparency. [ABSTRACT FROM AUTHOR]

Background: As precision medicine gradually played an inaccessible role in cancer treatment, there was an urgent need to explore biomarkers or signatures for predicting cancer prognosis. Currently, little was known about the associations between COLGALT1 and kidney renal clear cell carcinoma (KIRC). Hence, this study was performed to reveal its roles in KIRC and to identify potential mechanisms of competing endogenous RNA (ceRNA) networks. Methods: R 4.1.1 software was utilized to conduct bioinformatics analyses with the data derived from online databases. Difference analysis, survival analysis, univariate/multivariate cox regression analysis and correlation analysis were carried out successively in this article. Besides, we also investigated potential effects and mechanisms of COLGALT1 in KIRC. Results: COLGALT1 expression was overexpressed in KIRC samples compared with the normal samples and it was associated with poor OS (P < 0.001). COLGALT1 was also found to be significantly related to clinicopathological characteristics such as grade, T, N, M, stage and Cox regression analysis with univariate and multivariate data suggested it might be an independent prognostic parameter in KIRC (P < 0.001). Furthermore, Seven significantly enriched pathways were identified. Interestingly, correlation analyses revealed an association between COLGALT1 and microsatellite instability (MSI), tumor mutational burden (TMB) and immunity (P < 0.001). In addition, we used TIDE and TCIA databases to predict the immune response of COLGALT1 in KIRC and it suggested low expression of COLGALT1 is more likely to benefit from immunotherapy. Besides, we identified a ceRNA network of SLC16A1-AS1/hsa-mir-502-3p/COLGALT1 for its potential mechanism. Finally, experiments in vitro indicated that COLGALT1 was significantly related to cell proliferation. Conclusions: COLGALT1 could act as a valid immune-related prognostic indicator for KIRC and participated in a ceRNA network of SLC16A1-AS1/hsa-mir-502-3p/COLGALT1, offering one potential biomarker to investigate the mechanism and clinical therapeutic value of KIRC. [ABSTRACT FROM AUTHOR]

The importance of mitochondria in mammalian cells is widely known. Several biochemical reactions and pathways take place within mitochondria: among them, there are those involving the biogenesis of the iron–sulfur (Fe-S) clusters. The latter are evolutionarily conserved, ubiquitous inorganic cofactors, performing a variety of functions, such as electron transport, enzymatic catalysis, DNA maintenance, and gene expression regulation. The synthesis and distribution of Fe-S clusters are strictly controlled cellular processes that involve several mitochondrial proteins that specifically interact each other to form a complex machinery (Iron Sulfur Cluster assembly machinery, ISC machinery hereafter). This machinery ensures the correct assembly of both [2Fe-2S] and [4Fe-4S] clusters and their insertion in the mitochondrial target proteins. The present review provides a structural and molecular overview of the rare diseases associated with the genes encoding for the accessory proteins of the ISC machinery (i.e., GLRX5, ISCA1, ISCA2, IBA57, FDX2, BOLA3, IND1 and NFU1) involved in the assembly and insertion of [4Fe-4S] clusters in mitochondrial proteins. The disease-related missense mutations were mapped on the 3D structures of these accessory proteins or of their protein complexes, and the possible impact that these mutations have on their specific activity/function in the frame of the mitochondrial [4Fe-4S] protein biogenesis is described. [ABSTRACT FROM AUTHOR]

Congenital anomalies (CA) affect 3–5% of newborns, representing the second-leading cause of infant mortality in Argentina. Multiple congenital anomalies (MCA) have a prevalence of 2.26/1000 births in newborns, while congenital heart diseases (CHD) are the most frequent CA with a prevalence of 4.06/1000 births. The aim of this study was to identify the genetic causes in Argentinian patients with MCA and isolated CHD. We recruited 366 patients (172 with MCA and 194 with isolated CHD) born between June 2015 and August 2019 at public hospitals. DNA from peripheral blood was obtained from all patients, while karyotyping was performed in patients with MCA. Samples from patients presenting conotruncal CHD or DiGeorge phenotype (n = 137) were studied using MLPA. Ninety-three samples were studied by array-CGH and 18 by targeted or exome next-generation sequencing (NGS). A total of 240 patients were successfully studied using at least one technique. Cytogenetic abnormalities were observed in 13 patients, while 18 had clinically relevant imbalances detected by array-CGH. After MLPA, 26 patients presented 22q11 deletions or duplications and one presented a TBX1 gene deletion. Following NGS analysis, 12 patients presented pathogenic or likely pathogenic genetic variants, five of them, found in KAT6B, SHH, MYH11, MYH7 and EP300 genes, are novel. Using an algorithm that combines molecular techniques with clinical and genetic assessment, we determined the genetic contribution in 27.5% of the analyzed patients. [ABSTRACT FROM AUTHOR]

Prune exopolyphosphatase‐1 (PRUNE1) encodes a member of the aspartic acid–histidine–histidine (DHH) phosphodiesterase superfamily that regulates cell migration and proliferation during brain development. In 2015, biallelic PRUNE1 loss‐of‐function variants were identified to cause the neurodevelopmental disorder with microcephaly, hypotonia, and variable brain abnormalities (NMIHBA, OMIM#617481). NMIHBA is characterized by the namesake features and structural brain anomalies including thinning of the corpus callosum, cerebral and cerebellar atrophy, and delayed myelination. To date, 47 individuals have been reported in the literature, but the phenotypic spectrum of PRUNE1‐related disorders and their causative variants remains to be characterized fully. Here, we report a novel homozygous PRUNE1 NM_021222.2:c.933G>A synonymous variant identified in a 6‐year‐old boy with intellectual and developmental disabilities, hypotonia, and spastic diplegia, but with the absence of microcephaly, brain anomalies, or seizures. Fibroblast RNA sequencing revealed that the PRUNE1 NM_021222.1:c.933G>A variant resulted in an in‐frame skipping of the penultimate exon 7, removing 53 amino acids from an important protein domain. This case represents the first synonymous variant and the third pathogenic variant known to date affecting the DHH‐associated domain (DHHA2 domain). These findings extend the genotypic and phenotypic spectrums in PRUNE1‐related disorders and highlight the importance of considering synonymous splice site variants in atypical presentations. [ABSTRACT FROM AUTHOR]

Background: Idiopathic Scoliosis (IS) is the most common spinal deformity in adolescents, accounting for 80% of all spinal deformities. However, the etiology remains uncertain in most cases, being identified as Adolescent Idiopathic Scoliosis (AIS). IS treatments range from observation and sport to bracing or surgery. Several risk factors including sex and familiarity, have been linked with IS. Although there are still many uncertainties regarding the cause of this pathology, several studies report a greater incidence of the defect in families in which at least one other first degree relative is affected. This study systematically reviews the available literature to identify the most significant genes or variants related to the development and onset of IS. Methods: The research question was formulated using a PIOS approach on the following databases: Medline, Embase, Cinahl, Scopus, Web of Science and Google Scholar. The search was performed from July to August 2021, and articles from the inception of the database to August 2021 were searched. Results: 24 of the 919 initially identified studies were included in the present review. The 24 included studies observed a total of 16,316 cases and 81,567 controls. All the considered studies stated either the affected gene and/or specific SNPs. CHD7, SH2B1, ESR, CALM1, LBX1, MATN1, CHL1, FBN1 and FBN2 genes were associated with IS development. Conclusions: Although association can be found in some candidate genes the field of research regarding genetic association with the onset of IS still requires more information. [ABSTRACT FROM AUTHOR]

We have previously reported that the valproic acid (VPA)‐induced disruption pattern of hippocampal adult neurogenesis differs between developmental and 28‐day postpubertal exposure. In the present study, we performed brain region‐specific global gene expression profiling to compare the profiles of VPA‐induced neurotoxicity between developmental and postpubertal exposure. Offspring exposed to VPA at 0, 667, and 2000 parts per million (ppm) via maternal drinking water from gestational day 6 until weaning (postnatal day 21) were examined, along with male rats orally administered VPA at 0, 200, and 900 mg/kg body weight for 28 days starting at 5 weeks old. Four brain regions—the hippocampal dentate gyrus, corpus callosum, cerebral cortex, and cerebellar vermis—were subjected to expression microarray analysis. Profiled data suggested a region‐specific pattern of effects after developmental VPA exposure, and a common pattern of effects among brain regions after postpubertal VPA exposure. Developmental VPA exposure typically led to the altered expression of genes related to nervous system development (Msx1, Xcl1, Foxj1, Prdm16, C3, and Kif11) in the hippocampus, and those related to nervous system development (Neurod1) and gliogenesis (Notch1 and Sox9) in the corpus callosum. Postpubertal VPA exposure led to the altered expression of genes related to neuronal differentiation and projection (Cd47, Cyr61, Dbi, Adamts1, and Btg2) in multiple brain regions. These findings suggested that neurotoxic patterns of VPA might be different between developmental and postpubertal exposure, which was consistent with our previous study. Of note, the hippocampal dentate gyrus might be a sensitive target of developmental neurotoxicants after puberty. Global gene expression profiling was performed in four different brain regions in rats after developmental or postpubertal 28‐day valproic acid (VPA) exposure. Developmental VPA exposure had specific effects on each of the four brain regions, while postpubertal VPA exposure had common effects among multiple brain regions. Our results suggested that the neurotoxic pattern of VPA might differ between developmental and postpubertal exposure. They also suggested that the hippocampal dentate gyrus might be particularly vulnerable to postpubertal exposure to developmental neurotoxicants. [ABSTRACT FROM AUTHOR]

Objective: Fetal intracranial hemorrhage (ICH) is associated with an increased risk of perinatal mortality and morbidity. Healthcare professionals often find it challenging to counsel parents due to its rarity and diverse presentation. The aim of this systematic review and meta-analysis was to investigate the perinatal outcome of fetuses with ICH.Methods: MEDLINE, EMBASE, ClinicalTrials.gov and The Cochrane Library databases were searched. Inclusion criteria were studies reporting the outcome of fetuses, newborns and infants diagnosed with ICH. The primary outcome was perinatal death (PND), defined as the sum of intrauterine (IUD) and neonatal death (NND). The secondary outcomes were stillbirth, NND, IUD, termination of pregnancy, need for surgery/shunting at birth, cerebral palsy (defined according to the European Cerebral Palsy Network and classified as diplegia, hemiplegia, quadriplegia, dyskinetic or mixed), neurodevelopmental delay and intact survival. All outcomes were explored in the included fetuses with ICH. A subgroup analysis according to the location of the hemorrhage (intra-axial and extra-axial) was also planned. Meta-analysis of proportions was used to combine data, and pooled proportions and their 95% CI were reported.Results: Sixteen studies (193 fetuses) were included in the meta-analysis. PND occurred in 14.6% (95% CI, 7.3-24.0%) of fetuses with ICH. Among liveborn cases, 27.6% (95% CI, 12.5-45.9%) required shunt placement or surgery after birth and 32.0% (95% CI, 22.2-42.6%) had cerebral palsy. Furthermore, 16.7% (95% CI, 8.4-27.2%) of cases had mild neurodevelopmental delay, while 31.1% (95% CI, 19.0-44.7%) experienced severe adverse neurodevelopmental outcome. Normal neurodevelopmental outcome was reported in 53.6% of fetuses. Subgroup analysis according to the location of ICH showed that PND occurred in 13.3% (95% CI, 5.7-23.4%) of fetuses with intra-axial bleeding and 26.7% (95% CI, 5.3-56.8%) of those with extra-axial bleeding. In fetuses with intra-axial hemorrhage, 25.2% (95% CI, 11.0-42.9%) required shunt placement or surgery after birth and 25.5% (95% CI, 15.3-37.2%) experienced cerebral palsy. In fetuses with intra-axial hemorrhage, mild and severe neurodevelopmental delay was observed in 14.9% (95% CI, 12.0-27.0%) and 32.8% (95% CI, 19.8-47.4%) of cases, respectively, while 53.2% (95% CI, 37.0-69.1%) experienced normal neurodevelopmental outcome. The incidence of mortality and postnatal neurodevelopmental outcome in fetuses with extra-axial hemorrhage could not be estimated reliably due to the small number of cases.Conclusions: Fetuses with a prenatal diagnosis of ICH are at high risk of perinatal mortality and adverse neurodevelopmental outcome. Postnatal shunt placement or surgery was required in 28% of cases and cerebral palsy was diagnosed in approximately one-third of infants. Due to the rarity of ICH, multicenter prospective registries are warranted to collect high-quality data. © 2021 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

Background: Previous large-scale studies of de novo variants identified a number of genes associated with neurodevelopmental disorders (NDDs); however, it was also predicted that many NDD-associated genes await discovery. Such genes can be discovered by integrating copy number variants (CNVs), which have not been fully considered in previous studies, and increasing the sample size. Methods: We first constructed a model estimating the rates of de novo CNVs per gene from several factors such as gene length and number of exons. Second, we compiled a comprehensive list of de novo single-nucleotide variants (SNVs) in 41,165 individuals and de novo CNVs in 3675 individuals with NDDs by aggregating our own and publicly available datasets, including denovo-db and the Deciphering Developmental Disorders study data. Third, summing up the de novo CNV rates that we estimated and SNV rates previously established, gene-based enrichment of de novo deleterious SNVs and CNVs were assessed in the 41,165 cases. Significantly enriched genes were further prioritized according to their similarity to known NDD genes using a deep learning model that considers functional characteristics (e.g., gene ontology and expression patterns). Results: We identified a total of 380 genes achieving statistical significance (5% false discovery rate), including 31 genes affected by de novo CNVs. Of the 380 genes, 52 have not previously been reported as NDD genes, and the data of de novo CNVs contributed to the significance of three genes (GLTSCR1, MARK2, and UBR3). Among the 52 genes, we reasonably excluded 18 genes [a number almost identical to the theoretically expected false positives (i.e., 380 × 0.05 = 19)] given their constraints against deleterious variants and extracted 34 "plausible" candidate genes. Their validity as NDD genes was consistently supported by their similarity in function and gene expression patterns to known NDD genes. Quantifying the overall similarity using deep learning, we identified 11 high-confidence (> 90% true-positive probabilities) candidate genes: HDAC2, SUPT16H, HECTD4, CHD5, XPO1, GSK3B, NLGN2, ADGRB1, CTR9, BRD3, and MARK2. Conclusions: We identified dozens of new candidates for NDD genes. Both the methods and the resources developed here will contribute to the further identification of novel NDD-associated genes. [ABSTRACT FROM AUTHOR]

Background: Homozygous or compound heterozygous PRUNE1 mutations cause a neurodevelopmental disorder with microcephaly, hypotonia, and variable brain malformations (NMIHBA) (OMIM #617481). The PRUNE1 gene encodes a member of the phosphoesterase (DHH) protein superfamily that is involved in the regulation of cell migration. To date, most of the described mutations in the PRUNE1 gene are clustered in DHH domain. Methods: We subjected 4 members (two affected and two healthy) of a consanguineous Iranian family in the study. The proband underwent whole-exome sequencing and a start loss identified variant was confirmed by Sanger sequencing. Co-segregation of the detected variant with the disease in family was confirmed. Results: By whole-exome sequencing, we identified the a start loss variant, NM_021222.3:c.3G>A; p.(Met1?), in the PRUNE1 in two patients of a consanguineous Iranian family with spastic quadriplegic cerebral palsy (CP), hypotonia, developmental regression, and cerebellar atrophy. Sanger sequencing confirmed the segregation of the variant with the disease in the family. Protein structure analysis also revealed that the variant probably leads to the deletion of DHH (Asp-His-His) domain, the active site of the protein, and loss of PRUNE1 function. Conclusion: We identified a start loss variant, NM_021222.3:c.3G>A; p.(Met1?) in the PRUNE1 gene in two affected members as a possible cause of NMIHBA in an Iranian family. We believe that the study adds a new pathogenic variant in spectrum of mutations in the PRUNE1 gene as a cause of PRUNE1-related syndrome. [ABSTRACT FROM AUTHOR]

Au-Kline syndrome is a severe multisystemic syndrome characterized by several congenital defects, including intellectual disability. Loss-of-function and missense variants in the HNRNPK gene are associated with a range of dysmorphic features. This report describes an eleven-year-old Chinese boy with intellectual disability and developmental delays. Family-based whole-exome and Sanger sequencing identified a de novo missense variant in HNRNPK (NM_002140.3: c.143T > A, p. Leu48Val). In silico analysis predicted that this variant would be damaged in a highly conserved residue in the K homology 1 (KH1) domain. Bioinformatic analysis showed that the affinity change (ΔΔG) caused by this variant was -0.033 kcal/mol, indicating that it would have reduced affinity for RNA binding. Transcript analysis of the peripheral blood from this case found 42 aberrantly expressed and 86 aberrantly spliced genes (p -value <0.01). Functional enrichment analysis confirmed that the biological functions of these genes, including protein binding and transcriptional regulation, are associated with HNRNPK. In summary, this study identifies the first Chinese patient with a novel de novo heterozygous HNRNPK gene variant that contributes to Au-Kline syndrome and expands current knowledge of the clinical spectrum of HNRNPK variants. [ABSTRACT FROM AUTHOR]

The proper connection between the pre- and post-synaptic nervous cells depends on any element constituting the synapse: the pre- and post-synaptic membranes, the synaptic cleft, and the surrounding glial cells and extracellular matrix. An alteration of the mechanisms regulating the physiological synergy among these synaptic components is defined as "synaptopathy." Mutations in the genes encoding for proteins involved in neuronal transmission are associated with several neuropsychiatric disorders, but only some of them are associated with Developmental and Epileptic Encephalopathies (DEEs). These conditions include a heterogeneous group of epilepsy syndromes associated with cognitive disturbances/intellectual disability, autistic features, and movement disorders. This review aims to elucidate the pathogenesis of these conditions, focusing on mechanisms affecting the neuronal pre-synaptic terminal and its role in the onset of DEEs, including potential therapeutic approaches. [ABSTRACT FROM AUTHOR]

Cytosolic phosphoenolpyruvate carboxykinase (PEPCK‐C) deficiency due to the homozygous PCK1 variant has recently been associated with childhood‐onset hypoglycemia with a recognizable pattern of abnormal urine organic acids. In this study, 21 children and 3 adult patients with genetically confirmed PEPCK‐C deficiency were diagnosed during the years 2016 to 2019 and the available biochemical and clinical data were collected. All patients were ethnic Finns. Most patients (22 out of 24) had a previously published homozygous PCK1 variant c.925G>A. Two patients had a novel compound heterozygous PCK1 variant c.925G>A and c.716C>T. The laboratory results showed abnormal urine organic acid profile with increased tricarboxylic acid cycle intermediates and inadequate ketone body production during hypoglycemia. The hypoglycemic episodes manifested predominantly in the morning. Infections, fasting or poor food intake, heavy exercise, alcohol consumption, and breastfeeding were identified as triggering factors. Five patients presented with neonatal hypoglycemia. Hypoglycemic seizures occurred in half of the patients (12 out of 24). The first hypoglycemic episode often occurred at the age of 1‐2 years, but it sometimes presented at a later age, and could re‐occur during school age or adulthood. This study adds to the laboratory data on PEPCK‐C deficiency, confirming the recognizable urine organic acid pattern and identifying deficient ketogenesis as a novel laboratory finding. The phenotype is expanded suggesting that the risk of hypoglycemia may continue into adulthood if predisposing factors are present. [ABSTRACT FROM AUTHOR]

Electrical activity plays crucial roles in neural circuit formation and remodeling. During neocortical development, neurons are generated in the ventricular zone, migrate to their correct position, elongate dendrites and axons, and form synapses. In this review, we summarize the functions of ion channels and transporters in neocortical development. Next, we discuss links between neurological disorders caused by dysfunction of ion channels (channelopathies) and neocortical development. Finally, we introduce emerging optical techniques with potential applications in physiological studies of neocortical development and the pathophysiology of channelopathies. [ABSTRACT FROM AUTHOR]

Study Question: Do bi-allelic variants in the genes encoding the MSH4/MSH5 heterodimer cause male infertility?Summary Answer: We detected biallelic, (likely) pathogenic variants in MSH5 (4 men) and MSH4 (3 men) in six azoospermic men, demonstrating that genetic variants in these genes are a relevant cause of male infertility.What Is Known Already: MSH4 and MSH5 form a heterodimer, which is required for prophase of meiosis I. One variant in MSH5 and two variants in MSH4 have been described as causal for premature ovarian insufficiency (POI) in a total of five women, resulting in infertility. Recently, pathogenic variants in MSH4 have been reported in infertile men. So far, no pathogenic variants in MSH5 had been described in males.Study Design, Size, Duration: We utilized exome data from 1305 men included in the Male Reproductive Genomics (MERGE) study, including 90 males with meiotic arrest (MeiA). Independently, exome sequencing was performed in a man with MeiA from a large consanguineous family.Participants/materials, Setting, Methods: Assuming an autosomal-recessive mode of inheritance, we screened the exome data for rare, biallelic coding variants in MSH4 and MSH5. If possible, segregation analysis in the patients' families was performed. The functional consequences of identified loss-of-function (LoF) variants in MSH5 were studied using heterologous expression of the MSH5 protein in HEK293T cells. The point of arrest during meiosis was determined by γH2AX staining.Main Results and the Role Of Chance: We report for the first time (likely) pathogenic, homozygous variants in MSH5 causing infertility in 2 out of 90 men with MeiA and overall in 4 out of 902 azoospermic men. Additionally, we detected biallelic variants in MSH4 in two men with MeiA and in the sister of one proband with POI. γH2AX staining revealed an arrest in early prophase of meiosis I in individuals with pathogenic MSH4 or MSH5 variants. Heterologous in vitro expression of the detected LoF variants in MSH5 showed that the variant p.(Ala620GlnTer9) resulted in MSH5 protein truncation and the variant p.(Ser26GlnfsTer42) resulted in a complete loss of MSH5.Large Scale Data: All variants have been submitted to ClinVar (SCV001468891-SCV001468896 and SCV001591030) and can also be accessed in the Male Fertility Gene Atlas (MFGA).Limitations, Reasons For Caution: By selecting for variants in MSH4 and MSH5, we were able to determine the cause of infertility in six men and one woman, leaving most of the examined individuals without a causal diagnosis.Wider Implications Of the Findings: Our findings have diagnostic value by increasing the number of genes associated with non-obstructive azoospermia with high clinical validity. The analysis of such genes has prognostic consequences for assessing whether men with azoospermia would benefit from a testicular biopsy. We also provide further evidence that MeiA in men and POI in women share the same genetic causes.Study Funding/competing Interest(s): This study was carried out within the frame of the German Research Foundation sponsored Clinical Research Unit 'Male Germ Cells: from Genes to Function' (DFG, CRU326), and supported by institutional funding of the Research Institute Amsterdam Reproduction and Development and funds from the LucaBella Foundation. The authors declare no conflict of interest. [ABSTRACT FROM AUTHOR]

An estimated 5–11% of patients with neurofibromatosis type-1 (NF1) harbour large deletions encompassing the NF1 gene and flanking regions. These NF1 microdeletions are subclassified into type 1, 2, 3 and atypical deletions which are distinguishable from each other by their extent and by the number of genes included within the deletion regions as well as the frequency of mosaicism with normal cells. Most common are type-1 NF1 deletions which encompass 1.4-Mb and 14 protein-coding genes. Type-1 deletions are frequently associated with overgrowth, global developmental delay, cognitive disability and dysmorphic facial features which are uncommon in patients with intragenic pathogenic NF1 gene variants. Further, patients with type-1 NF1 deletions frequently exhibit high numbers of neurofibromas and have an increased risk of malignant peripheral nerve sheath tumours. Genes located within the type-1 NF1 microdeletion interval and co-deleted with NF1 are likely to act as modifiers responsible for the severe disease phenotype in patients with NF1 microdeletions, thereby causing the NF1 microdeletion syndrome. Genotype/phenotype correlations in patients with NF1 microdeletions of different lengths are important to identify such modifier genes. However, these correlations are critically dependent upon the accurate characterization of the deletions in terms of their extent. In this review, we outline the utility as well as the shortcomings of multiplex ligation-dependent probe amplification (MLPA) to classify the different types of NF1 microdeletion and indicate the importance of high-resolution microarray analysis for correct classification, a necessary precondition to identify those genes responsible for the NF1 microdeletion syndrome. [ABSTRACT FROM AUTHOR]

Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and weakness in the lower extremities. To date, a total of 88 types of SPG are known. To diagnose HSP, multiple technologies, including microarray, direct sequencing, multiplex ligation-dependent probe amplification, and short-read next-generation sequencing, are often chosen based on the frequency of HSP subtypes. Exome sequencing (ES) is commonly used. We used ES to analyze ten cases of HSP from eight families. We identified pathogenic variants in three cases (from three different families); however, we were unable to determine the cause of the other seven cases using ES. We therefore applied long-read sequencing to the seven undetermined HSP cases (from five families). We detected intragenic deletions within the SPAST gene in four families, and a deletion within PSEN1 in the remaining family. The size of the deletion ranged from 4.7 to 12.5 kb and involved 1-7 exons. All deletions were entirely included in one long read. We retrospectively performed an ES-based copy number variation analysis focusing on pathogenic deletions, but were not able to accurately detect these deletions. This study demonstrated the efficiency of long-read sequencing in detecting intragenic pathogenic deletions in ES-negative HSP patients., (© 2023. The Japan Society of Human Genetics.)

We analyze the fundamental functions of Prune_1 in brain pathophysiology. We discuss the importance and maintenance of the function of Prune_1 and how its perturbation influences both brain pathological conditions, neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA; OMIM: 617481), and tumorigenesis of medulloblastoma (MB) with functional correlations to other tumors. A therapeutic view underlying recent discoveries identified small molecules and cell penetrating peptides to impair the interaction of Prune_1 with protein partners (e.g., Nm23-H1), thus further impairing intracellular and extracellular signaling (i.e., canonical Wnt and TGF-β pathways). Identifying the mechanism of action of Prune_1 as responsible for neurodevelopmental disorders (NDDs), we have recognized other genes which are found overexpressed in brain tumors (e.g., MB) with functional implications in neurodevelopmental processes, as mainly linked to changes in mitotic cell cycle processes. Thus, with Prune_1 being a significant target in NDDs, we discuss how its network of action can be dysregulated during brain development, thus generating cancer and metastatic dissemination. [ABSTRACT FROM AUTHOR]

Progressive myoclonic epilepsy is a group of neurodegenerative diseases with complex clinical and genetic heterogeneity, which is associated with spontaneous or action-induced myoclonus and progressive neurodegeneration. Since 2020, 4 families with progressive myoclonic epilepsy-11 [OMIM#618876] have been reported with a very limited spectrum of SEMA6B pathogenic variants. In our study, whole-exome sequencing was used in a proband from a nonconsanguineous Chinese family presenting with growth retardation and recurrent atonic seizures. A deletion mutation (c.1960_1978del, p.Leu654Argfs*25) in the last exon of SEMA6B was detected, which is a de novo variant and pathogenic. The new genetic evidence we reported here strengthened the gene-disease relationship, and the gene curation level between SEMA6B and progressive myoclonic epilepsy-11 became "strong" following the ClinGen SOP. Therefore, the results of this study broaden the mutation spectrum of SEMA6B in different ethnic groups and strengthen the gene-disease relationship between SEMA6B and progressive myoclonic epilepsy-11. [ABSTRACT FROM AUTHOR]

PRUNE1 is linked to a wide range of neurodevelopmental and neurodegenerative phenotypes. Multiple pathogenic missense and stop‐gain PRUNE1 variants were identified in its DHH and DHHA2 phosphodiesterase domains. Conversely, a single splice alteration was previously reported. We investigated five patients from two unrelated consanguineous Sudanese families with an inherited severe neurodevelopmental disorder using whole‐exome sequencing coupled with homozygosity mapping, segregation, and haplotype analysis. We identified a founder haplotype transmitting a homozygous canonical splice‐donor variant (NM_021222.3:c.132+2T > C) in intron 2 of PRUNE1 segregated with the phenotype in all the patients. This splice variant possibly results in an in‐frame deletion in the DHH domain or premature truncation of the protein. The phenotypes of the affected individuals showed phenotypic similarities characterized by remarkable pyramidal dysfunction and prominent extrapyramidal features (severe dystonia and bradykinesia). In conclusion, we identified a novel founder variant in PRUNE1 and corroborated abnormal splicing events as a disease mechanism in PRUNE1‐related disorders. Given the phenotypes' consistency coupled with the founder effect, canonical and cryptic PRUNE1 splice‐site variants should be carefully evaluated in patients presenting with prominent dystonia and pyramidal dysfunction. [ABSTRACT FROM AUTHOR]

Panax ginseng is one of the most popular herbs which have been used as an important traditional Chinese medicine since ancient times. Yuan ginseng and Shizhu ginseng,which belong to P. ginseng, are widely used as substitutes for wild ginseng in clinical practice. Clinical practice has proved that the clinical efficacy of Shizhu ginseng is better than Yuan ginseng. However, current research cannot completely explain this phenomenon. Considering that small RNA may be one of the pharmacodynamic substances of P. ginseng, it is challenging to investigate differential miRNAs between Shizhu ginseng and Yuan ginseng. In this study, the transcriptome, small RNAome and degradome of P. ginseng were studied by high-throughput sequencing. A total of 63,875 unigenes and 43,950,137 small RNA clean reads were obtained from the roots of P. ginseng. Among 3206 differentially expressed genes, 1190 genes were up-regulated in Yuan ginseng when compared with Shizhu ginseng. 24 known differential miRNAs and 7 novel differential miRNAs were obtained. The 304 targets of 24 differentially expressed miRNA (17 known and 7 novel) families are mainly related to energy metabolism, biotic stress and disease immunity in ginseng itself. Through the association analysis of mRNA and miRNA, our work gives a better understanding of the difference between Yuan ginseng and Shizhu ginseng. Considering the cross-kingdom regulation of plant miRNAs, our results may provide a foundation for understanding the miRNA-dependent clinical efficacy in P. ginseng. [ABSTRACT FROM AUTHOR]

Warburg‐Micro syndrome (WARBM) is a rare autosomal recessively inherited neuro‐ophthalmologic syndrome. Although WARBM shows genetic heterogeneity, the pathogenic variants in RAB3GAP1 were the most common cause of WARBM. In this study, we aimed to evaluate the detailed clinical and dysmorphic features of seven WARBM1 patients and overview the variant spectrum of RAB3GAP1 in comparison with the literature who were referred due to congenital cataracts. A previously reported homozygous variant (c.2187_2188delGAinsCT) was identified in three of these patients, while the other four had three novel variants (c.251_258delAGAA, c.2606+1G>A, and c.2861_2862dupGC). Congenital cataract and corpus callosum hypo/agenesia are pathognomonic for WARBM, which could be distinguished from other similar syndromes with additional typical dysmorphic facial features. Although there is no known phenotype and genotype correlation in any type of WARBM, RAB3GAP1 gene analysis should be previously requested as the first step of genetic diagnosis in clinically suspicious patients when it is not possible to request a multi‐gene panel. [ABSTRACT FROM AUTHOR]

PACS1 neurodevelopmental disorder (PACS1 -NDD) is a category of rare disorder characterized by intellectual disability, speech delay, dysmorphic facial features, and developmental delay. Other various physical abnormalities of PACS1 -NDD might involve all organs and systems. Notably, there were only two unique missense mutations [c.607C > T (p.Arg203Trp) and c.608G > A (p.Arg203Gln)] in PACS1 that had been identified as pathogenic variants for PACS1 -NDD or Schuurs-Hoeijmakers syndrome (SHMS). Previous reports suggested that these common missense variants were likely to act through dominant-negative or gain-of-function effects manner. It is still uncertain whether the intragenic deletion or duplication in PACS1 will be disease-causing. By using whole-exome sequencing, we first identified a novel heterozygous multi-exon deletion covering exons 12–24 in PACS1 (NM_018026) in four individuals (two brothers and their father and grandfather) in a three-generation family. The younger brother was referred to our center prenatally and was evaluated before and after the birth. Unlike SHMS, no typical dysmorphic facial features, intellectual problems, and structural brain anomalies were observed among these four individuals. The brothers showed a mild hypermyotonia of their extremities at the age of 3 months old and recovered over time. Mild speech and cognitive delay were also noticed in the two brothers at the age of 13 and 27 months old, respectively. However, their father and grandfather showed normal language and cognitive competence. This study might supplement the spectrum of PACS1 -NDD and demonstrates that the loss of function variation in PACS1 displays no contributions to the typical SHMS which is caused by the recurrent c.607C > T (p.Arg203Trp) variant. [ABSTRACT FROM AUTHOR]

Thiamine metabolism dysfunction syndrome 2 (THMD2) is a rare metabolic disorder caused by SLC19A3 mutations, inherited in autosomal recessive pattern. As a treatable disease, early diagnosis and therapy with vitamin supplementation is important to improve the prognosis. So far, the reported cases were mainly from Saudi Arab regions, and presented with relatively simple clinical course because of the hot spot mutation (T422A). Rare Chinese cases were described until now. In this study, we investigated 18 Chinese THMD2 patients with variable phenotypes, and identified 23 novel SLC19A3 mutations, which expanded the genetic and clinical spectrum of the disorder. Meanwhile, we reviewed all 146 reported patients from different countries. Approximately 2/3 of patients presented with classical BTBGD, while 1/3 of patients manifested as much earlier onset and poor prognosis, including infantile Leigh-like syndrome, infantile spasms, neonatal lactic acidosis and infantile BTBGD. Literature review showed that elevated lactate in blood and CSF, as well as abnormal OXPHOS activities of muscle or skin usually correlated with infantile phenotypes, which indicated poor outcome. Brainstem involvement on MRI was more common in deceased cases. Thiamine supplementation is indispensable in the treatment of THMD2, whereas combination of biotin and thiamine is not superior to thiamine alone. But biotin supplementation does work in some patients. Genotypic-phenotypic correlation remains unclear which needs further investigation, and biallelic truncated mutations usually led to more severe phenotype. [ABSTRACT FROM AUTHOR]

We present a female patient in her early twenties with global development delay, progressive ataxia, epilepsy, and myoclonus caused by a stop mutation in the SEMA6B gene. Truncating DNA variants located in the last exon of SEMA6B have recently been identified as a cause of autosomal dominant progressive myoclonus epilepsy. In many cases, myoclonus in the context of progressive myoclonic epilepsy is refractory to medical treatment. In the present case, treatment with zonisamide caused clinical improvement, particularly of positive and negative truncal myoclonus, considerably improving patient's gait and thus mobility. [ABSTRACT FROM AUTHOR]

Genetic variants in growth factor-independent 1B (GFI1B), encoding transcription factor GFI1B, are causative of platelet-type bleeding disorder-17. Presently, 53 cases of GFI1B associated inherited thrombocytopenia (IT) have been published, however only three were homozygous. The bleeding- and platelet phenotypes of these patients depend on location and inheritance pattern of the GFI1B variant. We report a novel homozygous GFI1B (Thr174Ile) variant located in the first Zinc finger domain of GFI1B in two sisters of Palestinian ancestry born to consanguineous parents. They experienced severe bleeding tendency at moderately reduced platelet counts. Flow cytometry and immunofluorescent microscopy confirmed the diagnostic features of GFI1B associated IT: a reduced content of alpha granules and aberrant expression of the stem cell marker CD34 on platelets. Transcription factor GFI1B is differentially expressed during hemato- and lymphopoiesis. In addition, to platelet function investigations, we present results of lymphoid subgroup analyses and deformability of red cells measured by ektacytometry. [ABSTRACT FROM AUTHOR]

Background Cilia are dynamic cellular extensions that generate and sense signals to orchestrate proper development and tissue homeostasis. They rely on the underlying polarisation of cells to participate in signalling. Cilia dysfunction is a well-known cause of several diseases that affect multiple organ systems including the kidneys, brain, heart, respiratory tract, skeleton and retina. Methods Among individuals from four unrelated families, we identified variants in discs large 5 (DLG5) that manifested in a variety of pathologies. In our proband, we also examined patient tissues. We depleted dlg5 in Xenopus tropicalis frog embryos to generate a loss-of-function model. Finally, we tested the pathogenicity of DLG5 patient variants through rescue experiments in the frog model. Results Patients with variants of DLG5 were found to have a variety of phenotypes including cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations. We also observed a loss of cilia in cystic kidney tissue of our proband. Knockdown of dlg5 in Xenopus embryos recapitulated many of these phenotypes and resulted in a loss of cilia in multiple tissues. Unlike introduction of wildtype DLG5 in frog embryos depleted of dlg5, introduction of DLG5 patient variants was largely ineffective in restoring proper ciliation and tissue morphology in the kidney and brain suggesting that the variants were indeed detrimental to function. Conclusion These findings in both patient tissues and Xenopus shed light on how mutations in DLG5 may lead to tissue-specific manifestations of disease. DLG5 is essential for cilia and many of the patient phenotypes are in the ciliopathy spectrum. [ABSTRACT FROM AUTHOR]

Background: Bilateral striatal necrosis (BSN) is characterized by symmetrical degeneration, predominantly of the caudate and putamen nucleus, in the basal ganglia. It is associated with numerous acquired and hereditary neuro-developmental and motor dysfunction-related pathological conditions. BSN results in high morbidity and mortality among infants and children, and its diagnosis is clinically challenging due to several overlapping disease phenotypes. Therefore, a precise genetic diagnosis is urgently needed for accurate genetic counseling and improved prognostic outcomes as well. Objective: To identify novel missense mutations in the NDUFAF5 gene as a cause of childhood BSN in members of a Chinese family and summarize the clinical characteristics of patients with the NDUFAF5 gene mutations. Methods: This study included a large family living in a remote northwestern area of China. Three siblings developed a neurological disorder characterized by generalized dystonia within the first decade of their lives. Cerebral computed tomography (CT) and magnetic resonance imaging (MRI) showed bilateral lesions of the putamen. Biochemical and genetic approaches were used to identify the cause of BSN. Results: Sequence analysis showed no pathogenic variation in PANK2, SLC25A19, SLC19A3 , and NUP62 genes and in the entire mitochondrial genome as well. Whole-exome sequencing revealed compound heterozygous mutations consisting of NDUFAF5 :c.425A > C(p.E142A) and c.836T > G (p.M279R). The father, a healthy sister, and a healthy brother of the affected siblings carried the c.836T > G mutation, and the mother carried the c.425A > C mutation. These variants were absent in 100 ethnically matched non-BSN controls. In silico analysis demonstrated that the E142A and M279R mutations in NDUFAF5 protein significantly perturbed the normal conformation of the protein due to alterations in the hydrogen bonding patterns around the evolutionarily conserved catalytic domains, leading to its loss of function in the early stage of mitochondrial complex I assembly. Conclusions: We identified a novel compound heterozygous mutation (c.425A > C and c.836T > G) in the NDUFAF5 gene as the potential cause of autosomal recessive childhood BSN, which extended the pathogenic variation spectrum of the NDUFAF5 gene. This study provides substantial evidence for further improvement of genetic counseling and better clinical management of BSN affected individuals. [ABSTRACT FROM AUTHOR]

Background: During the last decade, remarkable progress with massive sequencing has been made in the identification of disease-associated genes for AIDs using next-generation sequencing technologies (NGS). An international group of experts described the ideal genetic screening method which should give information about SNVs, InDels, Copy Number Variations (CNVs), GC rich regions. We aimed to develop and validate a molecular diagnostic method in conjunction with the NGS platform as an inexpensive, extended and uniform coverage and fast screening tool which consists of nine genes known to be associated with various AIDs. Methods: For the validation of basic and expanded panels, long-range multiplex models were setup on healthy samples without any known variations for MEFV, MVK, TNFRSF1A, NLRP3, PSTPIP1, IL1RN, NOD2, NLRP12 and LPIN2 genes. Patients with AIDs who had already known causative variants in these genes were sequenced for analytical validation. As a last step, multiplex models were validated on patients with pre-diagnosis of AIDs. All sequencing steps were performed on the Illumina NGS platform. Validity steps included the selection of related candidate genes, primer design, development of screening methods, validation and verification of the product. The GDPE (Gentera) bioinformatics pipeline was followed. Results: Although there was no nonsynonymous variation in 21 healthy samples, 107 synonymous variant alleles and some intronic and UTR variants were detected. In 10 patients who underwent analytical validation, besides the 11 known nonsynonymous variant alleles, 11 additional nonsynonymous variant alleles and a total of 81 synonymous variants were found. In the clinical validation phase, 46 patients sequenced with multiplex panels, genetic and clinical findings were combined for diagnosis. Conclusion: In this study, we describe the development and validation of an NGS-based multiplex array enabling the "long-amplicon" approach for targeted sequencing of nine genes associated with common AIDs. This screening tool is less expensive and more comprehensive compared to other methods and more informative than traditional sequencing. The proposed panel offers advantages to WES or hybridization probe equivalents in terms of CNV analysis, high sensitivity and uniformity, GC-rich region sequencing, InDel detection and intron covering. [ABSTRACT FROM AUTHOR]

A case of a missense RBM10 variant in an adult with mild to moderate intellectual disability. Now, with two reported cases, distinct phenotypic traits unique to I RBM10 i missense variants, in addition to intellectual disability, remain to be clarified. [Extracted from the article]

Background: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype–phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. Methods: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. Results: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188–221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs. Conclusions: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics. [ABSTRACT FROM AUTHOR]