Impact of dental restorations and removable prostheses on potentially malignant oral mucosal disorders in the general population.

STATEMENT OF PROBLEM: Dental restorations and removable dental prostheses have been considered as risk factors for potentially malignant disorders of the oral mucosa. It remains unclear whether amalgam, composite resins, and prosthesis materials can induce potentially malignant disorders. PURPOSE: The purpose of this clinical study was to determine the relationship between the presence of amalgam and composite resin restorations, crowns and fixed partial dentures, and removable prostheses in potentially malignant disorders. MATERIAL AND METHODS: The data of 6041 participants in the population-based Studies of Health in Pomerania (SHIP) were accessed. Potentially malignant disorders had been clinically diagnosed by calibrated dentists and documented with photographs. Dental treatment was subdivided into restored and replaced teeth. Dental restorations were subclassified as buccal composite resin or amalgam restorations. Prosthetic treatment was subclassified into removable partial or complete prostheses and definitive restorations with crowns and fixed partial dentures. RESULTS: In the maxilla, participants with removable prostheses had a higher incidence of potentially malignant disorders than participants not undergoing treatment with removable prostheses (OR 2.12; 95% CI: 1.08-4.18), but not in the mandible (OR 1.30; 95% CI: 0.67-2.53). The surfaces with composite resin restorations were associated with a slightly higher risk of mucosal lesions than those without the restorations (OR 1.04; 95% CI: 1.01-1.07). No significant association was found between amalgam restorations and mucosal lesions. CONCLUSIONS: Participants with removable prostheses have a higher risk of potentially malignant disorders. Composite resin restorations are associated with a higher risk of mucosal lesions, whereas no significant association was found between amalgam restorations and mucosal lesions.

Prevalence of SARS-CoV-2 IgG antibodies among dental teams in Germany.

OBJECTIVES: During the corona pandemic, dental practices temporarily closed their doors to patients except for emergency treatments. Due to the daily occupational exposure, the risk of SARS-CoV-2 transmission among dentists and their team is presumed to be higher than that in the general population. This study examined this issue among dental teams across Germany. MATERIALS AND METHODS: In total, 2784 participants provided usable questionnaires and dry blood samples. Dry blood samples were used to detect IgG antibodies against SARS-CoV-2. The questionnaires were analyzed to investigate demographic data and working conditions during the pandemic. Multivariable logistic mixed-effects models were applied. RESULTS: We observed 146 participants with positive SARS-CoV-2 IgG antibodies (5.2%) and 30 subjects with a borderline finding (1.1%). Seventy-four out of the 146 participants with SARS-CoV-2 IgG antibodies did not report a positive SARS-CoV-2 PCR test (50.7%), while 27 participants without SARS-CoV-2 IgG antibodies reported a positive SARS-CoV-2 PCR test (1.1%). Combining the laboratory and self-reported information, the number of participants with a SARS-CoV-2 infection was 179 (6.5%). Though after adjustment for region, mixed-effects models indicated associations of use of rubber dams (OR 1.65; 95% CI: 1.01-2.72) and the number of protective measures (OR 1.16; 95% CI: 1.01-1.34) with increased risk for positive SARS-CoV-2 status, none of those variables was significantly associated with a SARS-CoV-2 status in fully adjusted models. CONCLUSIONS: The risk of SARS-CoV-2 transmission was not higher among the dental team compared to the general population. CLINICAL RELEVANCE: Following hygienic regulations and infection control measures ensures the safety of the dental team and their patients.

Dominant KPNA3 Mutations Cause Infantile-Onset Hereditary Spastic Paraplegia.

OBJECTIVE: Hereditary spastic paraplegia (HSP) is a highly heterogeneous neurologic disorder characterized by lower-extremity spasticity. Here, we set out to determine the genetic basis of an autosomal dominant, pure, and infantile-onset form of HSP in a cohort of 8 patients with a uniform clinical presentation. METHODS: Trio whole-exome sequencing was used in 5 index patients with infantile-onset pure HSP to determine the genetic cause of disease. The functional impact of identified genetic variants was verified using bioinformatics and complementary cellular and biochemical assays. RESULTS: Distinct heterozygous KPNA3 missense variants were found to segregate with the clinical phenotype in 8 patients; in 4 of them KPNA3 variants had occurred de novo. Mutant karyopherin-α3 proteins exhibited a variable pattern of altered expression level, subcellular distribution, and protein interaction. INTERPRETATION: Our genetic findings implicate heterozygous variants in KPNA3 as a novel cause for autosomal dominant, early-onset, and pure HSP. Mutant karyopherin-α3 proteins display varying deficits in molecular and cellular functions, thus, for the first time, implicating dysfunctional nucleocytoplasmic shuttling as a novel pathomechanism causing HSP. ANN NEUROL 2021;90:738-750.

KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating.

Here, we report on six unrelated individuals, all presenting with early-onset global developmental delay, associated with impaired motor, speech and cognitive development, partly with developmental epileptic encephalopathy and physical dysmorphisms. All individuals carry heterozygous missense variants of KCND2, which encodes the voltage-gated potassium (Kv) channel α-subunit Kv4.2. The amino acid substitutions associated with the variants, p.(Glu323Lys) (E323K), p.(Pro403Ala) (P403A), p.(Val404Leu) (V404L) and p.(Val404Met) (V404M), affect sites known to be critical for channel gating. To unravel their likely pathogenicity, recombinant mutant channels were studied in the absence and presence of auxiliary ß-subunits under two-electrode voltage clamp in Xenopus oocytes. All channel mutants exhibited slowed and incomplete macroscopic inactivation, and the P403A variant in addition slowed activation. Co-expression of KChIP2 or DPP6 augmented the functional expression of both wild-type and mutant channels; however, the auxiliary ß-subunit-mediated gating modifications differed from wild type and among mutants. To simulate the putative setting in the affected individuals, heteromeric Kv4.2 channels (wild type + mutant) were studied as ternary complexes (containing both KChIP2 and DPP6). In the heteromeric ternary configuration, the E323K variant exhibited only marginal functional alterations compared to homomeric wild-type ternary, compatible with mild loss-of-function. By contrast, the P403A, V404L and V404M variants displayed strong gating impairment in the heteromeric ternary configuration, compatible with loss-of-function or gain-of-function. Our results support the etiological involvement of Kv4.2 channel gating impairment in early-onset monogenic global developmental delay. In addition, they suggest that gain-of-function mechanisms associated with a substitution of V404 increase epileptic seizure susceptibility.

Prevalence and risk factors of potentially malignant disorders of the mucosa in the general population: Mucosa lesions a general health problem?

AIM: Oral cancer mostly develops from oral mucosa regions with morphological alterations transforming malignant. These visible precancerous mucosa lesions are named potentially malignant disorders (PMD). We aimed to analyze the prevalence of PMD and its risk factors for PMD in a population-based sample in Northern Germany. MATERIAL AND METHODS: Data of 6078 individuals from the population-based Study of Health in Pomerania (SHIP) was used. PMD were photographically documented and periodontal health was assessed in a standardized procedure. RESULTS: PMD were observed in 54 individuals (0.9%). The most prevalent PMD was homogenous leukoplakia (n = 37) followed by Lichen ruber (n = 9). Smoking (Odds Ratio (OR) 2.70; 95% confidence interval (CI): 1.24-5.87), male sex (OR 3.32; 95%-CI: 1.77-6.21), type 2 diabetes mellitus (OR 2.07; 95%-CI: 1.08-3.98) and body mass index (OR 1.09; CI 1.04-1.14) were significantly associated with PMD, with the corresponding area under the curve (AUC) being 0.696 (CI: 0.655; 0.737). CONCLUSION: Our results suggest a clinically relevant prevalence of PMD in the population. We identified male sex, type 2 diabetes mellitus, current smoking, and obesity as risk factors. We recommend photographic documentation and intensified training of medical and dental staff to detect and monitor PMD.

SHIP-MR and Radiology: 12 Years of Whole-Body Magnetic Resonance Imaging in a Single Center.

The Study of Health in Pomerania (SHIP), a population-based study from a rural state in northeastern Germany with a relatively poor life expectancy, supplemented its comprehensive examination program in 2008 with whole-body MR imaging at 1.5 T (SHIP-MR). We reviewed more than 100 publications that used the SHIP-MR data and analyzed which sequences already produced fruitful scientific outputs and which manuscripts have been referenced frequently. Upon reviewing the publications about imaging sequences, those that used T1-weighted structured imaging of the brain and a gradient-echo sequence for R2* mapping obtained the highest scientific output; regarding specific body parts examined, most scientific publications focused on MR sequences involving the brain and the (upper) abdomen. We conclude that population-based MR imaging in cohort studies should define more precise goals when allocating imaging time. In addition, quality control measures might include recording the number and impact of published work, preferably on a bi-annual basis and starting 2 years after initiation of the study. Structured teaching courses may enhance the desired output in areas that appear underrepresented.

Effects of cold physical plasma on oral lichen planus: An in vitro study (Effects of CAP on OLP).

OBJECTIVES: In the search for more effective and safe treatment avenues, we investigated cold physical plasma as a new treatment modality for therapy of oral lichen planus (OLP). MATERIAL AND METHODS: Healthy and diseased human mucosal tissue samples with a size of 3 mm in diameter obtained from OLP patients were subjected to plasma treatment ex vivo or were left untreated. Tissue sections were quantified for immune-infiltration of CD4+ , CD8+ , CD45RA+ , and CD45R0+ T cells. Moreover, the tissues' inflammatory profile was assessed by analyzing 12 different cytokines in the surrounding media. RESULTS: A significantly increased infiltrate of CD8+ and CD45-R0+ T cells was detected in OLP tissue samples when compared to healthy tissue. A higher concentration of interleukin (IL) 1ß, IL6, IL8, and granulocyte macrophage-colony stimulating factor (GM-CMF) was detected in OLP samples compared to healthy mucosal tissue. For all cytokines and chemokines investigated, 23 out of 24 comparisons showed a decrease in tendency (significant for IL1ß, IL2, IL10, and GM-CSF) in response to plasma treatment. In ex vivo-treated tissue, a decrease of T-cell infiltrate in OLP lesions compared with healthy tissue was observed. CONCLUSION: Our findings suggest cold physical plasma can be a promising therapeutic option for OLP that requires further validation in vivo.

Germline AGO2 mutations impair RNA interference and human neurological development.

ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development.

Are third molars associated with orofacial pain? Findings from the SHIP study.

OBJECTIVES: To examine the association between third molars and orofacial pain. We hypothesized that impacted third molars are a cause of orofacial pain. METHODS: Magnetic resonance images of 1808 participants from two population-based cohorts from Northeastern Germany were analysed to define the status of third molars according to the Pell and Gregory classification. A self-reported questionnaire and a clinical dental examination were used to detect chronic and acute complaints of orofacial pain, masticatory muscle pain, migraine and other types of headache. Logistic regression models were used to analyse the associations between third molar status and orofacial pain. RESULTS: Individuals with impacted third molars in the maxilla had a higher chance of chronic orofacial pain than those with erupted third molars (odds ratio 2.19; 95% CI 1.19-4.02). No such association was detected for third molars in the lower jaw. Third molars were not associated with masticatory muscle pain, migraine or other types of headache. CONCLUSIONS: Impacted maxillary third molars might be a cause of chronic orofacial pain. Thus, physicians should consider the eruption/impaction status of third molars in their decision-making process when treating patients who complain of orofacial pain.

Does craniofacial morphology affect third molars impaction? Results from a population-based study in northeastern Germany.

OBJECTIVES: It is still not clear why impaction of third molars occurs. Craniofacial morphology and facial parameters have been discussed to be strong predictors for third molar impaction. Thus, this study aimed to investigate the effect of craniofacial morphology on erupted or impacted third molars in a German population sample. MATERIALS AND METHODS: Erupted and impacted third molars in 2,484 participants from the Study of Health in Pomerania were assessed by whole-body magnetic resonance imaging. Markers of facial morphology were determined in 619 individuals of those participants in whose 421 participants (16.7%) had at least one impacted third molar. Craniofacial morphology was estimated as linear measurements and was associated in a cross-sectional study design with impacted and erupted third molars by multinomial logistic regression models. Erupted third molars were used as reference outcome category and regression models were adjusted for age and sex. RESULTS: Maximum Cranial Width (Eurion-Eurion distance) was significantly associated with impacted third molars (RR: 1.079; 95% confidence interval 1.028-1.132). This association was even more pronounced in the mandible. Individuals with a lower total anterior facial height (Nasion-Menton distance) and a lower facial index also have an increased risk for impacted third molars in the mandible (RR 0.953; 95% confidence interval 0.913-0.996 and RR: 0.943; 95% confidence interval 0.894-0.995). No significant associations of third molar status with facial width (Zygion-Zygion distance), and sagittal cranial dimension (Nasion-Sella distance; Sella-Basion distance) were observed. CONCLUSION: Individuals with an increased maximal cranial width have a higher risk for impaction of third molars in the mandible and in the maxilla. Individuals with a lower anterior total anterior facial height and lower facial index also have an increased risk for third molars impaction in the mandible. These findings could help orthodontic dentists, oral surgeons and oral and maxillofacial surgeons in decision-making for third molars removal in their treatment. These findings highlight the necessity of an additional analysis of the maximal cranial width by the Eurion- Eurion distance.

Do Third Molars Contribute to Systemic Inflammation? Results From a Population-Based Study From Northeast Germany.

PURPOSE: Erupted and impacted third molars have been reported to contribute to systemic inflammation. This study investigated the systemic effect of third molars on serum levels of inflammatory parameters and on inflammatory messenger peptide hormones in a general population sample. MATERIALS AND METHODS: Data of 2,151 participants from the Study of Health in Pomerania were included in this study. Erupted or impacted third molars were assessed with whole-body magnetic resonance imaging at 1.5 T and associated with biomarkers of inflammation, lipid metabolism, glucose metabolism, and peptide hormones by linear regression. Models were adjusted for age, gender, smoking status, education, and type 2 diabetes mellitus. RESULTS: Neither erupted nor impacted third molars were associated with high-sensitivity C-reactive protein, white blood cell count, or fibrinogen as markers for systemic inflammation. Participants with erupted third molars had markedly lower serum levels of leptin (ß coefficient, -2.47; 95% confidence interval [CI], -4.47 to -0.48), angiopoietin-2 (ß coefficient, -135.1; 95% CI, 248.6 to -21.5), and ratio of angiopoietin-2 to tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2 (ß coefficient, -6.57; 95% CI, -13.06 to -00.7) than participants without third molars. No such associations were observed for impacted third molars. CONCLUSION: The present results did not substantiate a relation between third molars and an increase in systemic inflammatory markers. Therefore, dental practitioners should be careful when considering this as the only indication for removal of third molars, especially in medically compromised patients. The results of this study showed that participants with erupted third molars had lower levels of messenger peptide hormones, such as leptin and angiopoetin-2.

Association of anthropometric markers with globe position: A population-based MRI study.

PURPOSE: Exophthalmometry is a common examination in ophthalmology. For example it is relevant for diagnosis or follow-up of thyroid eye disease. However, exophthalmometry is affected by several factors such as ethnicity, sex and age. The purpose of this study was to determine the globe position by magnetic resonance imaging (MRI) and to investigate its correlates among the general Northeast German adult population. METHODS: A total of 3030 subjects aged between 20 and 89 from the population-based Study of Health in Pomerania (SHIP) underwent a standardised whole-body MRI. Axial length and globe position were determined in axial T1-weighted images of the orbit. The image had to include the corneal apex as well as the optic nerve head. Study participants were excluded from imaging analysis if there was no plane available that included both structures. Further exclusion criterion was a lateral deviation of the subject's viewing direction. Images with inadequate quality due to motion artefacts or other technical reasons were excluded as well. Globe position was defined as the perpendicular distance between the interzygomatic line and the posterior surface of the cornea (exophthalmometric value). The distance between the posterior surface of the cornea and the posterior pole of the eyeball, at the boundary with orbital fat, was defined as axial length. We used posterior surface of the cornea for our measurements, because it seemed to be less vulnerable for motion artefacts than the anterior one. Moreover body measurements including body mass index (BMI), waist and hip circumferences were determined. Associations between anthropometric measurements with exophthalmometric outcomes were analysed by linear regressions adjusted for age and stratified by sex. P-values <0.05 were considered as statistically significant. To assess intra-reader variability intra-class correlation coefficients (ICC) were computed for repeated measurements of the MRI scans of 25 subjects. RESULTS: After considering the exclusion criteria 1926 evaluable subjects remained. There was no significant difference between means of right and left eyes. The mean exophthalmometric value was significantly higher in men (16.5 +/- 2.2 mm) than in women (15.3 +/- 2.1 mm). The mean MRI-axial length was 23.4 +/- 0.8 mm for men and 22.8 +/- 0.9 mm for women. BMI, waist and hip circumferences were positively correlated with exophthalmometric value (p<0.001). Difference of mean MRI-based exophthalmometric value for obese subjects (BMI ≥30 kg/m2) and non-overweight (BMI <25 kg/m2) was 2.1 mm for men and 1.6 mm for women. ICC between 0.97 and 0.99 indicate excellent repeatability of our method. CONCLUSION: We conclude that MRI-based exophthalmometric values are positively correlated with BMI, waist- and hip-circumference among the general Northeast German adult population. This association is independent from age and axial length. Consequently bodyweight of patients should be regarded to interpret exophthalmometric values correctly. MRI-exophthalmometry seems to be a suitable method to determine globe position. Considering the large number of study participants, exophthalmometric values of our study could be used as comparative values for exophthalmometry of people of Western European descent in future.

New insights in the link between malocclusion and periodontal disease.

AIM: We aimed to investigate associations between malocclusions and periodontal disease by comparing it to that of smoking in subjects recruited from the population-based cross-sectional study "Study of Health in Pomerania." MATERIALS AND METHODS: Sagittal intermaxillary relationship, variables of malocclusion and socio-demographic parameters of 1,202 dentate subjects, 20-39 years of age, were selected. Probing depth (PD) and attachment loss (AL) were assessed at four sites by tooth in a half-mouth design. Analyses were performed with multilevel models on subject, jaw and tooth level. RESULTS: Distal occlusion determined in the canine region, ectopic position of canines, anterior spacing, deep anterior overbite and increased sagittal overjet were associated with AL (p-value <0.05). Associations between malocclusions and PD: deep anterior overbite with gingival contact (odds ratio [OR] = 1.40, 95% CI: 1.08-1.82; p-value = 0.0101) and anterior crossbite (OR = 1.75, 95% CI: 1.29-2.38; p-value = 0.0003). Regarding crowding, only severe anterior crowding was compatible with a moderate to large association with PD (OR = 1.93, 95% CI: 0.89-4.20). Compared to smoking, the overall effect of malocclusions was about one half for AL and one-third for PD. CONCLUSION: Malocclusions or morphologic parameters were associated with periodontal disease.

Cognitive impairment and autistic-like behaviour in SAPAP4-deficient mice.

In humans, genetic variants of DLGAP1-4 have been linked with neuropsychiatric conditions, including autism spectrum disorder (ASD). While these findings implicate the encoded postsynaptic proteins, SAPAP1-4, in the etiology of neuropsychiatric conditions, underlying neurobiological mechanisms are unknown. To assess the contribution of SAPAP4 to these disorders, we characterized SAPAP4-deficient mice. Our study reveals that the loss of SAPAP4 triggers profound behavioural abnormalities, including cognitive deficits combined with impaired vocal communication and social interaction, phenotypes reminiscent of ASD in humans. These behavioural alterations of SAPAP4-deficient mice are associated with dramatic changes in synapse morphology, function and plasticity, indicating that SAPAP4 is critical for the development of functional neuronal networks and that mutations in the corresponding human gene, DLGAP4, may cause deficits in social and cognitive functioning relevant to ASD-like neurodevelopmental disorders.

Association Between Symptoms of Posttraumatic Stress Disorder and Signs of Temporomandibular Disorders in the General Population.

AIMS: To estimate the association between signs of temporomandibular disorders (TMD) and symptoms of posttraumatic stress disorder (PTSD) in a representative sample from the general population of northeastern Germany. METHODS: Signs of TMD were assessed with a clinical functional analysis that included palpation of the temporomandibular joints (TMJs) and masticatory muscles. PTSD was assessed with the PTSD module of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, ed 4. The change-in-estimate method for binary logistic regression models was used to determine the final model and control for confounders. RESULTS: After the exclusion of subjects without prior traumatic events, the sample for joint pain consisted of 1,673 participants with a median age of 58.9 years (interquartile range 24.8), and the sample for muscle pain consisted of 1,689 participants with a median age of 59.1 years (interquartile range 24.8). Of these samples, 84 participants had pain on palpation of the TMJ, and 42 participants had pain on palpation of the masticatory muscles. Subjects having clinical PTSD (n = 62) had a 2.56-fold increase in joint pain (odds ratio [OR] = 2.56; 95% confidence interval [CI]: 1.14 to 5.71, P = .022) and a 3.86-fold increase (OR = 3.86; 95% CI: 1.51 to 9.85, P = .005) in muscle pain compared to subjects having no clinical PTSD. CONCLUSION: These results should encourage general practitioners and dentists to acknowledge the role of PTSD and traumatic events in the diagnosis and therapy of TMD, especially in a period of international migration and military foreign assignments.

Alexithymia and temporomandibular joint and facial pain in the general population.

BACKGROUND: Associations of alexithymia with temporomandibular pain disorders (TMD), facial pain, head pain and migraine have been described, but the role of the different dimensions of alexithymia in pain development remained incompletely understood. OBJECTIVES: We sought to investigate the associations of alexithymia and its subfactors with signs of TMD and with facial pain, head pain and migraine in the general population. METHODS: A total of 1494 subjects from the general population completed the Toronto Alexithymia Scale-20 (TAS-20) and underwent a clinical functional examination with palpation of the temporomandibular joint and masticatory muscles. Facial pain, migraine and head pain were defined by questionnaire. A set of logistic regression analyses was applied with adjustment for age, sex, education, number of traumatic events, depressive symptoms and anxiety. RESULTS: Alexithymia was associated with TMD joint pain (Odds Ratio 2.63; 95% confidence interval 1.60-4.32 for 61 TAS-20 points vs the median of the TAS-20 score) and with facial pain severity (Odds Ratio 3.22; 95% confidence interval 1.79-5.79). Differential effects of the subfactors were discovered with difficulties in identifying feelings as main predictor for joint, facial, and head pain, and externally oriented thinking (EOT) as U-shaped and strongest predictor for migraine. CONCLUSION: Alexithymia was moderately to strongly associated with signs and symptoms of TMD. These results should encourage dental practioners using the TAS-20 in clinical practice, to screen TMD, facial or head pain patients for alexithymia and could also help treating alexithymic TMD, facial or head pain patients.

Third molars and periodontal damage of second molars in the general population.

AIM: The aim of this study was to clarify the association between impacted or erupted third molars and periodontal pathology, assessed by probing depth (PD) and clinical attachment levels (CAL), in adjacent second molars. MATERIALS AND METHODS: Data from the population-based Study of Health in Pomerania (SHIP) was used. This is the first project with whole-body magnetic resonance imaging (WB-MRI) application in a general population setting with dental issues. Calibrated and licensed dentists measured PD and CAL with a periodontal probe. RESULTS: In the mandible, individuals with erupted third molars had a 1.45-fold higher odds ratio (CI:1.03; 2.05; p = 0.031) and individuals with impacted third molars had a 2.37-fold higher odds ratio (CI:1.45; 3.85; p < 0.001) to have higher PD values in the adjacent distal site of second molar than individuals with missing third molars in the total population. These significant associations were even more pronounced in the population free of periodontitis disease. In participants with periodontitis in the maxilla, there was an association of erupted third molars with an increased PD of adjacent molars. CONCLUSION: In particular, in the mandible, those findings could guide dental practitioners more in the direction to remove the third molars after having evaluated the periodontium of the adjacent teeth.

De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder.

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.