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.

Collaborative efforts to improve genetic testing in the neonatal intensive care unit.

OBJECTIVE: To reduce unnecessary simultaneous karyotype analysis and chromosomal microarray (CMA) testing in the neonatal intensive care unit (NICU). STUDY DESIGN: This quality improvement study investigated the effect of collaborative efforts between the NICU, cytogenetics, and clinical genetics on numbers of genetic tests, rates of abnormal tests, and number of genetics consults comparing baseline and 5-month intervention periods. RESULTS: Simultaneous karyotype analyses and CMAs decreased due to a decrease in karyotype testing (11.3% [68/600] vs. 0.98% [6/614], p < 0.01). Karyotype analyses were more likely to be abnormal (13.8% [12/87] vs. 64.0% [16/25], p < 0.01). Frequency of genetics consultation did not change (7.0% [42/600] vs. 9.4% [58/614], p = 0.12). CONCLUSION: Collaborative efforts between the NICU, cytogenetics, and clinical genetics decreased redundant genetic testing, which demonstrated potential cost savings to our institution. Ongoing collaborative efforts could facilitate genetic testing practices in the NICU that readily evolve in tandem with genetic testing recommendations.

The D409H variant in GBA1: Challenges in predicting the Gaucher phenotype in the newborn screening era.

Gaucher disease (GD) is an autosomal recessive disorder resulting from glucocerebrosidase deficiency due to pathologic variants in GBA1. While clinically heterogeneous, GD encompasses three types, non-neuronopathic (GD1), acute neuronopathic (GD2), and chronic neuronopathic (GD3). Newborn screening (NBS), which has made remarkable inroads in detecting certain diseases before detrimental health consequences and fatality ensues, is now being piloted for GD in several states and countries. Early on, clinical features of GD2 can overlap with GD3; hence, predicting outcome is challenging. As NBS for GD becomes more available, the increased detection of GD in neonates is inevitable. As a result, health care providers and families will be faced with uncertainty with respect to clinical management. Since more severe GBA1 variants are generally associated with neuronopathic GD, there has been an increased dependence on genotypic information. We present an infant detected by NBS with genotype D409H(p.Asp448His)/RecNciI (p.Leu483Pro; p.Ala495Pro;p.Val499=). To assist in genetic counseling, we performed a retrospective review of other patients in our cohort carrying D409H and reviewed the literature. The study illustrates the challenges faced in counseling for infants with neuronopathic GD, even with known GBA1 variants, and the tough management decisions that can ensue from detection in newborns.

Beyond Trinucleotide Repeat Expansion in Fragile X Syndrome: Rare Coding and Noncoding Variants in FMR1 and Associated Phenotypes.

FMR1 (FMRP translational regulator 1) variants other than repeat expansion are known to cause disease phenotypes but can be overlooked if they are not accounted for in genetic testing strategies. We collected and reanalyzed the evidence for pathogenicity of FMR1 coding, noncoding, and copy number variants published to date. There is a spectrum of disease-causing FMR1 variation, with clinical and functional evidence supporting pathogenicity of five splicing, five missense, one in-frame deletion, one nonsense, and four frameshift variants. In addition, FMR1 deletions occur in both mosaic full mutation patients and as constitutional pathogenic alleles. De novo deletions arise not only from full mutation alleles but also alleles with normal-sized CGG repeats in several patients, suggesting that the CGG repeat region may be prone to genomic instability even in the absence of repeat expansion. We conclude that clinical tests for potentially FMR1-related indications such as intellectual disability should include methods capable of detecting small coding, noncoding, and copy number variants.

Use of dexamethasone in idiopathic, acute pediatric rhabdomyolysis.

Current rhabdomyolysis treatment guidelines vary based on the etiology and diagnosis, yet many cases evade conclusive diagnosis. In these cases, treatment options remain largely limited to fluids and supportive therapy. We present two cases of acute rhabdomyolysis diagnosed in the emergency department: a 5-year-old boy with sudden onset bilateral flank pain, and a 13-year-old boy with 2-3 days of worsening pectoral and shoulder pain. Each patient had a prior similar episode requiring hospitalization in the past. The 5-year-old had no inciting trauma or trigger, medication use, or illness. The 13-year-old previously had an upper respiratory infection during the week prior and had been strenuously exercising at the time of onset. Genetic testing results were unknown for both patients during their hospitalizations, and insurance and other barriers led to delay. Later results for the first patient revealed a heterozygous deletion in intron 19 on the LPIN1 gene interpreted as a variant of unknown significance. During their hospitalizations, both children were started on intravenous (i.v.) fluids, and creatine kinase (CK) initially trended downward, but then began to rise or plateau. After reviewing the cases, prior literature, and anecdotal evidence of benefit from corticosteroid therapy in rhabdomyolysis with our consultant metabolic physicians, dexamethasone was initiated. In both patients, dexamethasone use correlated with relief of patient symptoms, significantly decreased CK value, and our ability to discharge these patients home quickly. Our cases, discussion, and literature review all lead to the consideration of the use of dexamethasone in conjunction with standard therapy for acute rhabdomyolysis.

Clinical characteristics of individual organ system disease in non-motile ciliopathies.

Non-motile ciliopathies (disorders of the primary cilia) include autosomal dominant and recessive polycystic kidney diseases, nephronophthisis, as well as multisystem disorders Joubert, Bardet-Biedl, Alström, Meckel-Gruber, oral-facial-digital syndromes, and Jeune chondrodysplasia and other skeletal ciliopathies. Chronic progressive disease of the kidneys, liver, and retina are common features in non-motile ciliopathies. Some ciliopathies also manifest neurological, skeletal, olfactory and auditory defects. Obesity and type 2 diabetes mellitus are characteristic features of Bardet-Biedl and Alström syndromes. Overlapping clinical features and molecular heterogeneity of these ciliopathies render their diagnoses challenging. In this review, we describe the clinical characteristics of individual organ disease for each ciliopathy and provide natural history data on kidney, liver, retinal disease progression and central nervous system function.

Enlarged parietal foramina: a review of genetics, prognosis, radiology, and treatment.

INTRODUCTION: Enlarged parietal foramina are variable ossification defects in the parietal bones that present as symmetric radiolucencies on skull radiographs. In contrast to the normal small parietal foramina, enlarged parietal foramina are a hereditary condition and genes associated with it have been identified. METHODS: A literature review was performed to discuss the many known findings related to enlarged parietal foramina. CONCLUSIONS: Even though they remain asymptomatic in the majority of cases, they may be associated with other pathologies and occasionally become symptomatic. This article provides a comprehensive review of the current knowledge of enlarged parietal foramina.