Dysmorphic Research Articles

The Phenotypic Spectrum of Desanto-Shinawi Syndrome: A Comparative Report of the First Reported Case in Turkey.

DeSanto-Shinawi syndrome (DESSH, OMIM #616708) is a rare genetic disorder caused by pathogenic variants in the WAC gene. This syndrome is characterized by a wide range of physical and neurological symptoms including dysmorphic features, developmental delay, intellectual disability, and behavioral abnormalities. DESSH was described by DeSanto in 2015, and since then, only a few dozen cases have been reported worldwide. Recent research has focused on identifying the underlying genetic cause of the syndrome as well as exploring potential treatments. In this report, we describe a female case who had dysmorphic features including long palpebral fissures, depressed nasal root, mild bulbous nasal tip, thin upper lip, hypertrichosis, short fingers, and intellectual disability, speech delay, and motor retardation. In addition, she had behavioral abnormalities such as agitation, anxiety, and attention deficit hyperactivity disorder (ADHD). Clinical exome sequencing showed a pathogenic heterozygous nonsense variant in exon 13 of the WAC gene c.1837C>T, p.(Arg613Ter) with de novo inheritance. To the best of our knowledge, this is the first case of DESSH reported from Turkey. We aimed to report this rare syndrome and compare the clinical findings of our case with previously reported cases in the literature.

Anesthesia management for a child with the Koolen-de Vries syndrome: a case report

BackgroundThe Koolen-de Vries syndrome (KdVS) is a relatively new rare disease caused by micro-deletion of 17q21.31 which was first reported by Koolen in 2006. Typical phenotypes for KdVS include hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Up to now, there was only one case report about anesthesia management of patient diagnosed KdVS. It was a 2-year-old girl who experienced an MRI exam under anesthesia.Case presentationWe described a 21-month-old boy who planned to undergo an orchidopexy under general anesthesia diagnosed with KdVS. He had an intellectual disability, characteristic facial dysmorphism, tracheo/laryngomalacia, patent foramen ovale, and cryptorchidism related to KdVS. Due to the complex condition especially the presence of tracheo/laryngomalacia, we took some special measures, including reducing the amount of long-acting opioid, keeping the spontaneous breath, performing a caudal block, and applying the laryngeal mask. But the laryngeal mask was changed to an endotracheal tube because it failed to provide adequate ventilation. The boy experienced mild laryngeal spasm and hypoxia after extubation, but lateral position and etomidate eased his breathing problem and re-intubation was avoided. It is indicated that anesthesia management for patients with orphan disease is a real challenge for all anesthesia providers.ConclusionsThe Koolen-de Vries syndrome is a relatively new orphan disease involving multiple systems. Keeping spontaneous breath, evaluating airway potency to anesthetics, applying endotracheal tube, and post-extubation lateral or prone position may be helpful for airway management for patient with hypotonia and tracheo/laryngomalacia. KdVS patient needs prolonged post-anesthesia monitoring and/or medication for airway complications.

Further evidence supporting the role of GTDC1 in glycine metabolism and neurodevelopmental disorders.

Copy number variants (CNVs) represent the genetic cause of about 15-20% of neurodevelopmental disorders (NDDs). We identified a ~67 kb de novo intragenic deletion on chromosome 2q22.3 in a female individual showing a developmental encephalopathy characterised by epilepsy, severe intellectual disability, speech delay, microcephaly, and thin corpus callosum with facial dysmorphisms. The microdeletion involved exons 5-6 of GTDC1, encoding a putative glycosyltransferase, whose expression is particularly enriched in the nervous system. In a previous study, a balanced de novo translocation encompassing GTDC1 was reported in a male child with global developmental delay and delayed speech and language development. Based on these premises, we explored the transcriptomic profile of our proband to evaluate the functional consequences of the novel GTDC1 de novo intragenic deletion in relation to the observed neurodevelopmental phenotype. RNA-seq on the proband's lymphoblastoid cell line (LCL) showed expression changes of glycine/serine and cytokine/chemokine signalling pathways, which are related to neurodevelopment and epileptogenesis. Subsequent analysis by ELISA (enzyme-linked immunosorbent assay) and HPLC (high-performance liquid chromatography) revealed increased levels of glycine in the proband's LCL and serum compared to matched controls. Given that an increased level of glycine has been observed in the plasma samples of individuals with Rett syndrome, a condition sharing epilepsy, microcephaly, and intellectual disability with our proband, we proposed that the GTDC1 downregulation is implicated in neurodevelopmental impairment by altering glycine metabolism. Furthermore, our findings expanded the phenotypic spectrum of the novel GTDC1-related condition, including microcephaly and epilepsy among relevant clinical features.

Body Image, Nutrition, and Mental Health

Classical examples of disorders associated with body image disturbances are eating disorders (EDs) such as anorexia nervosa (AN) and bulimia nervosa (BN), as well as body dysmorphic disorder (BDD) [...]

The Impact of Prenatal Alcohol Exposure on the Autonomic Nervous System and Cardiovascular System in Rats in a Sex-Specific Manner

Background: Fetal Alcohol Spectrum Disorder (FASD) is a consequence of prenatal alcohol exposure (PAE) associated with a range of effects, including dysmorphic features, prenatal and/or postnatal growth problems, and neurodevelopmental difficulties. Despite advances in treatment methods, there are still gaps in knowledge that highlight the need for further research. The study investigates the effect of PAE on the autonomic system, including sex differences that may aid in early FASD diagnosis, which is essential for effective interventions. Methods: During gestational days 5 to 20, five pregnant female Wistar rats were orally administered either glucose or ethanol. After 22 days, 26 offspring were born and kept with their mothers for 21 days before being isolated. Electrocardiographic recordings were taken on the 29th and 64th day. Heart rate variability (HRV) parameters were collected, including heart rate (HR), standard deviation (SD), standard deviation of normal-to-normal intervals (SDNN), and the root mean square of successive differences between normal heartbeats (RMSSD). Additionally, a biochemical analysis of basic serum parameters was performed on day 68 of the study. Results: The study found that PAE had a significant impact on HRV. While electrolyte homeostasis remained mostly unaffected, sex differences were observed across various parameters in both control and PAE groups, highlighting the sex-specific effects of PAE. Specifically, the PAE group had lower mean heart rates, particularly among females, and higher SDNN and RMSSD values. Additionally, there was a shift towards parasympathetic activity and a reduction in heart rate entropy in the PAE group. Biochemical changes induced by PAE were also observed, including elevated levels of alanine transaminase (ALT) and aspartate aminotransferase (AST), especially in males, increased creatinine concentration in females, and alterations in lipid metabolism. Conclusions: PAE negatively affects the development of the autonomic nervous system, resulting in decreased heart rate and altered sympathetic activity. PAE also induces cardiovascular abnormalities with sex-specific effects, highlighting a relationship between PAE consequences and sex. Elevated liver enzymes in the PAE group may indicate direct toxic effects, while increased creatinine levels, particularly in females, may suggest an influence on nephrogenesis and vascular function. The reduced potassium content may be linked to hypothalamus–pituitary–adrenal axis overactivity.

Exploring genetic testing requests, genetic alterations and clinical associations in a cohort of children with autism spectrum disorder.

Several studies show great heterogeneity in the type of genetic test requested and in the clinicopathological characteristics of patients with ASD. The following study aims, firstly, to explore the factors that might influence professionals' decisions about the appropriateness of requesting genetic testing for their patients with ASD and, secondly, to determine the prevalence of genetic alterations in a representative sample of children with a diagnosis of ASD. Methods: We studied the clinical factors associated with the request for genetic testing in a sample of 440 children with ASD and the clinical factors of present genetic alterations. Even though the main guidelines recommend genetic testing all children with an ASD diagnosis, only 56% of children with an ASD diagnosis were genetically tested. The prevalence of genetic alterations was 17.5%. These alterations were more often associated with intellectual disability and dysmorphic features. There are no objective data to explicitly justify the request for genetic testing, nor are there objective data to justify requesting one genetic study versus multiple studies. Remarkably, only 28% of males were genetically tested with the recommended tests (fragile X and CMA). Children with dysmorphic features and organic comorbidities were more likely to be genetic tested than those without. Previous diagnosis of ASD (family history of ASD) and attendance at specialist services were also associated with Genetically tested Autism Spectrum Disorder GTASD. Our findings emphasize the importance of establishing algorithms to facilitate targeted genetic consultation for individuals with ASD who are likely to benefit, considering clinical phenotypes, efficiency, ethics, and benefits.

Oxidative Effects in Early Stages of Embryo Development Due to Alcohol Consumption.

Alcohol, a widely consumed drug, exerts significant toxic effects on the human organism. This review focuses on its impact during fetal development, when it leads to a spectrum of disorders collectively termed Fetal Alcohol Spectrum Disorders (FASD). Children afflicted by FASD exhibit distinct clinical manifestations, including facial dysmorphism, delayed growth, and neurological and behavioral disorders. These behavioral issues encompass diminished intellectual capacity, memory impairment, and heightened impulsiveness. While the precise mechanisms underlying alcohol-induced fetal damage remain incompletely understood, research indicates a pivotal role for reactive oxygen species (ROS) that are released during alcohol metabolism, inciting inflammation at the cerebral level. Ethanol metabolism amplifies the generation of oxidant molecules, inducing through alterations in enzymatic and non-enzymatic systems responsible for cellular homeostasis. Alcohol consumption disrupts endogenous enzyme activity and fosters lipid peroxidation in consumers, potentially affecting the developing fetus. Addressing this concern, administration of metformin during the prenatal period, corresponding to the third trimester of human pregnancy, emerges as a potential therapeutic intervention for mitigating FASD. This proposed approach holds promise for ameliorating the adverse effects of alcohol exposure on fetal development and warrants further investigation.

Comparison of Aesthetic and Functional Rhinoplasty Outcomes Between Patients with Body Dysmorphic Disorder and Normal Individuals.

Rhinoplasty is among the top five most popular cosmetic surgical procedures worldwide. Among rhinoplasty candidates, the most common mental health disorder is body dysmorphic disorder. (BDD). The present study aimed to assess the prevalence of BDD among rhinoplasty candidates, its association with the patient's self-assessment of aesthetic outcome and nasal functional, post-rhinoplasty compared to applicants with negative screening for BDD. The following study is a cross-sectional, comparative study. Out of the 209 rhinoplasty candidates screened by the BDDQ questionnaire, 39 were positive for BDD. From the remaining 170 patients who screened negative for BDD, 39 participants were randomly selected as the control group for the comparative analysis. Rhinoplasty outcome evaluation (ROE) and standardized cosmesis and health nasal outcomes survey-cosmetic (SCHNOS-C) questionnaires were used for assessment of patient satisfaction with the cosmetic outcome of rhinoplasty. Nasal obstruction symptom evaluation (NOSE) and standardized cosmesis and health nasal outcomes survey-obstruction (SCHNOS-O) were used for the assessment of satisfaction with functional outcomes between groups of patients screened positive and negative for BDD. The prevalence of BDD was 18.66% among rhinoplasty candidates. The average age of patients screened positive for BDD was 31.41. The mean ROE score was significantly lower (i.e. lower satisfaction) in patients screened positive for BDD (15.69 versus 19.08, P = 0.001), regardless of confounding variables, such as age, sex, and marital status. SCHNOS-C score was higher (i.e. less satisfaction) among patients with BDD (47.01 versus 34.96, P = 0.021) and was significantly associated with higher odds of severe aesthetic concern post-rhinoplasty (OR (95%CI) = 5.000 (1.135-22.022), P = 0.033). Patients screened positive for BDD had significantly higher NOSE scores (i.e. less satisfaction with functional outcome) compared to participants negative for BDD (49.74 versus 37.82, P = 0.012). SCHNOS-O score had no significant association with BDD (P = 0.053). Furthermore, there was no significant association between BDD and NOSE or SCHNOS-O score after adjustment for the confounders. Patients screened positive for BDD were significantly less satisfied with the cosmetic outcome of the rhinoplasty compared to those screened negative for BDD. Assessment of BDD among rhinoplasty candidates before surgery, could potentially be beneficial for both patients and surgeons. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

A hierarchy of visual processing deficits in body dysmorphic disorder: a conceptual review and empirical investigation

ABSTRACT Objective Abnormal visual processing has been proposed as a mechanism underlying excessive focus on minor appearance flaws in body dysmorphic disorder (BDD). Existing BDD research has not differentiated the various stages of face processing (featural, first-order configural, holistic and second-order configural) that are required for higher-order processes such as emotion recognition. This study investigated a hierarchical visual processing model to examine the nature of abnormalities in face processing in BDD. Method Thirty BDD participants and 27 healthy controls completed the Navon task, a featural and configural face processing task and a facial emotion labelling task. Results BDD participants performed similarly to controls when processing global and local non-face stimuli on the Navon task, when detecting subtle changes in the features and spacing of a target face, and when labelling emotional faces. However, BDD participants displayed poorer performance when viewing inverted faces, indicating difficulties in configural processing. Conclusions The findings only partially support prior work. However, synthesis of results with previous findings indicates that heterogenous task methodologies may contribute to inconsistent findings. Recommendations are provided regarding the task parameters that appear most sensitive to abnormalities in BDD.

Domain-specific phenotypes in LINS1-related disorder-A Chinese family with the Q92X variant and literature review.

LINS1 is the human homolog of the Drosophila segment polarity gene that encodes an essential regulator of the wingless/Wnt signaling. By 2011, only seven pedigrees (16 patients) with eight causative variants in LINS1 gene have been reported. These cases mainly presented with infancy-/child-onset neurodevelopmental disorders, facial dysmorphia, and other clinical features, and a wide spectrum of clinically distinct phenotypes were also manifested. In our study, two brothers in a family were admitted and diagnosed with child-onset movement disorders, slight intellectual disability, psychological symptoms, eye problems, urinary and bowel dysfunction, mitral value prolapse, and Q-T prolongation. By exome sequencing, we identified a nonsense homozygous pathogenic variant (LINS1: c.274C > T (p.Q92X)), which had been reported in a case diagnosed with intellectual disability and psychiatric disorders (such as schizophrenia and anxiety). Compared with this case, the clinical features of our cases were distinct. In particular, our cases displayed unusual features of heart and blood system. Furthermore, the genotype-phenotype relationship analysis suggested that distinct phenotypes presented in cases carrying variants in different domains of the LINS1 gene. In conclusions, our findings suggest the high clinical variations in the LINS1 variants-related disorders. Moreover, the Q92X might be a recurrent variant in Hans of Southern China.

Recurrent myocardial injury in a de novo SON mutation ZTTK syndrome patient: a case report

BackgroundZhu-Tokita-Takenouchi-Kim syndrome (ZTTK syndrome) is a severe multi-systemic developmental disorder, caused by variants in the SON gene. A patient diagnosed with ZTTK syndrome who carried a de novo SON mutation and exhibited recurrent myocardial injury was described in this case.Case presentationA 7-year-old girl was admitted to the Cardiology Department of Beijing Children’s Hospital in November 2019 due to myocardial injury following respiratory infection. She displayed elevated myocardial enzymes and severe T-wave changes on electrocardiogram. Over the past three years, she had experienced myocardial injury on three occasions. Additionally, she exhibited intellectual disability, congenital amblyopia, and dysmorphic facial features. Genetic analysis revealed a de novo heterozygous mutation c.3852_3856delGGTAT in the SON gene, which was confirmed by Sanger sequencing of her parents. She received anti-infection treatment and was administered metoprolol orally. Her condition was stable at the time of discharge. Over a 42-month follow-up period at the outpatient clinic, she complained intermittent fatigue and palpitation.ConclusionsThe identified SON mutation, which plays a crucial role in heart development and mitochondrial function, may be associated with an increased susceptibility to myocardial injury or cardiomyopathy. This case report contributes novel insights into this rare condition and suggests the expansion of the ZTTK syndrome phenotype.

Is it possible for a procedure to be just ‘skin deep’?

Dr Deborah Auer discusses why practitioners should consider a robust assessment process This piece discusses the complexities that sometimes underlie a patient's request for procedures, highlighting the importance of practitioners having a robust and ethical assessment process in place. Research that links psychology with requests for procedures, more often than not, will consider how to assess for body dysmorphia in particular. This does have benefits in identifying patients for whom having a procedure may result in a poor outcome. However, often these measures and/or screening tools do not highlight the more nuanced difficulties a patient may have regarding their relationship with their body. Procedures have a twofold impact: firstly, on the external body that is shown to the world, and secondly, the internal part — an individual's psyche, self-esteem, body image and confidence ( Auer, 2018 ). Therefore, it is paramount that practitioners consider both the physical and psychological wellbeing of their patients.

Phenotypic Description of A Patient with ODLURO Syndrome and Functional Characterization of the Pathogenetic Role of A Synonymous Variant c.186G>A in KMT2E Gene

O’Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant disorder caused by mutations in the KMT2E gene. The clinical phonotype of the affected individuals is typically characterized by global developmental delay, autism, epilepsy, hypotonia, macrocephaly, and very mild dysmorphic facial features. In this report, we describe the case of a 6-year-old boy with ODLURO syndrome who is a carrier of the synonymous mutation c.186G>A (p.Ala62=) in the KMT2E gene, predicted to alter splicing by in silico tools. Given the lack of functional studies on the c.186G>A variant, in order to assess its potential functional effect, we sequenced the patient’s cDNA demonstrating its impact on the mechanism of splicing. To the best of our knowledge, our patient is the second to date reported carrying this synonymous mutation, but he is the first whose functional investigation has confirmed the deleterious consequence of the variant, resulting in exon 4 skipping. Additionally, we suggest a potential etiological mechanism that could be responsible for the aberrant splicing mechanism in KMT2E.

Genome Sequencing of Idiopathic Speech Delay

Genetic investigations of people with speech and language disorders can provide windows into key aspects of human biology. Most genomic research into impaired speech development has so far focused on childhood apraxia of speech (CAS), a rare neurodevelopmental disorder characterized by difficulties with coordinating rapid fine motor sequences that underlie proficient speech. In 2001, pathogenic variants of FOXP2 provided the first molecular genetic accounts of CAS aetiology. Since then, disruptions in several other genes have been implicated in CAS, with a substantial proportion of cases being explained by high-penetrance variants. However, the genetic architecture underlying other speech-related disorders remains less well understood. Thus, in the present study, we used systematic DNA sequencing methods to investigate idiopathic speech delay, as characterized by delayed speech development in the absence of a motor speech diagnosis (such as CAS), a language/reading disorder, or intellectual disability. We performed genome sequencing in a cohort of 23 children with a rigorous diagnosis of idiopathic speech delay. For roughly half of the sample (ten probands), sufficient DNA was also available for genome sequencing in both parents, allowing discovery of de novo variants. In the thirteen singleton probands, we focused on identifying loss-of-function and likely damaging missense variants in genes intolerant to such mutations. We found that one speech delay proband carried a pathogenic frameshift deletion in SETD1A, a gene previously implicated in a broader variable monogenic syndrome characterized by global developmental problems including delayed speech and/or language development, mild intellectual disability, facial dysmorphisms, and behavioural and psychiatric symptoms. Of note, pathogenic SETD1A variants have been independently reported in children with CAS in two separate studies. In other probands in our speech delay cohort, likely pathogenic missense variants were identified affecting highly conserved amino acids in key functional domains of SPTBN1 and ARF3. Overall, this study expands the phenotype spectrum associated with pathogenic SETD1A variants, to also include idiopathic speech delay without CAS or intellectual disability, and suggests additional novel potential candidate genes that may harbour high-penetrance variants that can disrupt speech development.

A Case of Chromosome 17q12 Deletion Syndrome with Type 2 Mayer–Rokitansky–Küster–Hauser Syndrome and Maturity-Onset Diabetes of the Young Type 5

Chromosome 17q12 deletion syndrome (OMIM #614527) is a rare genetic disorder associated with a heterozygous 1.4–1.5 Mb deletion at chromosome 17q12, leading to a spectrum of clinical manifestations, including kidney abnormalities, neurodevelopmental delay, maturity-onset diabetes of the young type 5 (MODY5), and Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome. We present the case of a 14-year-old Korean female diagnosed with chromosome 17q12 deletion syndrome, confirmed by chromosomal microarray analysis. The patient exhibited MODY5 with pancreatic agenesis, MRKH syndrome, dysmorphic facial features, developmental delay, kidney rotation anomaly, portal vein thrombosis with liver hypoplasia, short stature, and scoliosis. Management involved the initiation of multiple daily insulin injections for diabetes control, gynecological evaluation for MRKH syndrome, and multidisciplinary care for associated complications. This case highlights the complexity and varied organ involvement in chromosome 17q12 deletion syndrome. A comprehensive and multidisciplinary approach is crucial for the management of affected individuals, including regular monitoring, tailored interventions across various medical specialties, and providing psychosocial support.

Screening for Body Dysmorphic Disorder in Plastic Surgery Patients.

The Australian medical board, the Australian Health Practitioner Regulation Agency (AHPRA) has recently introduced new regulations mandating providers of cosmetic surgery undertake a clinical screen for body dysmorphic disorder (BDD) in all potential cosmetic surgery patients. The assessment must be conducted by the surgeon using a validated psychological screening tool. The aims of this paper are to discuss the key clinical characteristics of BDD before reviewing currently validated screening tools that would meet this new regulatory requirement, and which may be most applicable to a busy plastic surgery practice. A literature search identified 1164 titles, of which 229 titles were retrieved for abstract screening. Six studies were identified that validated BDD screening tools in a setting relevant to cosmetic plastic surgery. Six validated screening were identified: BDD Questionnaire (BDDQ), BDD Questionnaire Dermatology Version (BDDQ-DV), BDD Questionnaire Aesthetic Surgery (BDDQ-AS), Cosmetic Procedure Screening Questionnaire (COPS), Body Dysmorphia Symptom Scale (BDSS) and the BDD Screening Test (BDD-ST). Our group practice has chosen to adopt the BDDQ-AS to meet the AHPRA regulator requirement for BDD screening based on its robust validation and ease of use in clinical practice, consisting of a seven-item self-report questionnaire that can be reliably completed in 1-2 minutes in most cases. Of the six screening tools for body dysmorphic disorder available for use in clinical practice that have been validated in a cosmetic population setting, we have chosen to use the BDD Questionnaire Aesthetic Surgery (BDDQ-AS). To date all available validated screening tools are based on the DSM-IV, and further work to develop a validated screening tool based on the revised definition of BDD in the DSM-V is recommended, with a particular focus on items relating to repetitive physical or mental behaviours. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Atlantoaxial Instability due to Os Odontoideum in a Child with Christianson Syndrome

<b><i>Introduction:</i></b> Christianson syndrome is a rare neurodevelopmental disorder associated with mutations in the <i>SLC9A6</i> gene located on the chromosome X. It is characterized by intellectual disability, developmental delay, speech and language impairments, dysmorphic features, seizures, ataxia, and neurobehavioral problems. <b><i>Case Presentation:</i></b> A 5-year-old boy was presented with respiratory failure and then progressive muscle weakness in all four extremities. He manifested acquired microcephaly, intellectual disability, global developmental delay, distinct dysmorphic facial features, seizures, spastic tetraparesis, truncal hypotonia, speech impairment, failure to thrive, malnutrition, recurrent lung infections, self-mutilation, primary hyperparathyroidism, medullary nephrocalcinosis, and atlantoaxial instability due to os odontoideum. Brain magnetic resonance imaging revealed atlantoaxial instability due to os odontoideum, a narrow foramen magnum, myelopathy due to spinal cord compression, and cerebral and cerebellar atrophy. <b><i>Discussion:</i></b> This report highlights a significant contribution by introducing a child with Christianson syndrome describing atlantoaxial instability due to os odontoideum, a previously undocumented phenomenon. This report suggests a potential link between Christianson syndrome and atlantoaxial instability. In children with Christianson syndrome experiencing increased muscle weakness in all extremities during follow-up, consideration of underlying myelopathy due to os odontoideum is advised.

Adams–Oliver syndrome: About a case

Key Clinical MessageWe report the case of a newborn with aplasia cutis congenita characterized by the absence of skin in the left parietal region, superficial dilatation of the scalp veins, facial dysmorphia, limb anomalies, and severe intrauterine growth retardation. Maternal milk enabled the baby to gain weight, and dermatological treatment was performed for scarring of the vertex. Psychomotor development and stature were spectacular. This case illustrates the clinical variability of this condition and the need for multidisciplinary management.

De novo missense variants in exon 9 of SEPHS1 cause a neurodevelopmental condition with developmental delay, poor growth, hypotonia, and dysmorphic features

Selenophosphate synthetase (SEPHS) plays an essential role in selenium metabolism. Two mammalian SEPHS paralogues, SEPHS1 and SEPHS2, share high sequence identity and structural homology with SEPHS. Here, we report nine individuals from eight families with developmental delay, growth and feeding problems, hypotonia, and dysmorphic features, all with heterozygous missense variants in SEPHS1. Eight of these individuals had a recurrent variant at amino acid position 371 of SEPHS1 (p.Arg371Trp, p.Arg371Gln, and p.Arg371Gly); seven of these variants were known to be de novo. Structural modeling and biochemical assays were used to understand the effect of these variants on SEPHS1 function. We found that a variant at residue Trp352 results in local structural changes of the C-terminal region of SEPHS1 that decrease the overall thermal stability of the enzyme. In contrast, variants of a solvent-exposed residue Arg371 do not impact enzyme stability and folding but could modulate direct protein-protein interactions of SEPSH1 with cellular factors in promoting cell proliferation and development. In neuronal SH-SY5Y cells, we assessed the impact of SEPHS1 variants on cell proliferation and ROS production and investigated the mRNA expression levels of genes encoding stress-related selenoproteins. Our findings provided evidence that the identified SEPHS1 variants enhance cell proliferation by modulating ROS homeostasis. Our study supports the hypothesis that SEPHS1 plays a critical role during human development and provides a basis for further investigation into the molecular mechanisms employed by SEPHS1. Furthermore, our data suggest that variants in SEPHS1 are associated with a neurodevelopmental disorder.

Biallelic variants in GTF3C5, a regulator of RNA polymerase III-mediated transcription, cause a multisystem developmental disorder.

General transcription factor IIIC subunit 5 (GTF3C5) encodes transcription factor IIIC63 (TFIIIC63). It binds to DNA to recruit another transcription factor, TFIIIB, and RNA polymerase III (Pol III) to mediate the transcription of small noncoding RNAs, such as tRNAs. Here, we report four individuals from three families presenting with a multisystem developmental disorder phenotype with biallelic variants in GTF3C5. The overlapping features include growth retardation, developmental delay, intellectual disability, dental anomalies, cerebellar malformations, delayed bone age, skeletal anomalies, and facial dysmorphism. Using lymphoblastoid cell lines (LCLs) from two affected individuals, we observed a reduction in TFIIIC63 protein levels compared to control LCLs. Genome binding of TFIIIC63 protein is also reduced in LCL from one of the affected individuals. Additionally, approximately 40% of Pol III binding regions exhibited reduction in the level of Pol III occupancy in the mutant genome relative to the control, while approximately 54% of target regions showed comparable levels of Pol III occupancy between the two, indicating partial impairment of Pol III occupancy in the mutant genome. Yeasts with subject-specific variants showed temperature sensitivity and impaired growth, supporting the notion that the identified variants have deleterious effects. gtf3c5 mutant zebrafish showed developmental defects, including a smaller body, head, and eyes. Taken together, our data show that GTF3C5 plays an important role in embryonic development, and that biallelic variants in this gene cause a multisystem developmental disorder. Our study adds GTF3C5-related disorder to the growing list of genetic disorders associated with Pol III transcription machinery.