Genetics in Medicine最新文献

Purpose: RAPGEF2 encodes a guanine nucleotide exchange factor (GEF) that activates small GTPases and has not been linked to a Mendelian disorder. RAPGEF2 is highly intolerant to loss-of-function variants. We report five de novo heterozygous variants in RAPGEF2 in unrelated individuals with developmental delay, attention deficit hyperactivity disorder, epilepsy, dysmorphic features, or other manifestations. We used a Drosophila model to assess the functional impact of the identified human variants.

Methods: We generated a Kozak-GAL4 null allele of the Drosophila ortholog of RAPGEF2, PDZ-GEF, and used the allele to determine the gene expression pattern as well as the LoF phenotypes. We expressed the reference and variant RAPGEF2 in PDZ-GEF mutant background to conduct "humanization" studies.

Results: Our experiments show that PDZ-GEF is expressed in the central nervous system. Loss of PDZ-GEF leads to severe locomotion defects, aberrant microtubular stability in motor neuron axons, and synaptic overgrowth at neuromuscular junctions in third instar larvae. Mutant animals are lethal at various developmental stages. Importantly, the neurodevelopmental phenotypes can be rescued by expression of the human RAPGEF2 reference cDNA but not by any of the variants.

Conclusion: Our findings provide functional evidence that the tested RAPGEF2 variants are LoF alleles and that the RAPGEF2 variants are associated with a neurodevelopmental disorder.

Purpose: Genomic disorders comprise a major source of human disease with survival into adulthood for most individuals, but data on adult outcomes are limited.

Methods: We conducted a formal search to identify studies of 14 clinically relevant, molecularly confirmed deletion syndromes with ≥5 adults reporting on prevalence of cardiovascular risk and other outcomes. Outcomes were pooled across deletion syndromes and by syndrome, using random-effects models.

Results: Of 1352 studies screened, 53 reported on nonoverlapping samples of 13 deletion syndromes. Estimated pooled prevalences, at age <30-40 for most, included 47% (95% CI 33-57%; n = 2076) for obesity, and for 10 deletion syndromes: diabetes 24% (95% CI 17-33%; n = 1739), hypertension 36% (95% CI 28-33%; n = 1314), and dyslipidemia 29% (95% CI 22-36%; n = 1127). High heterogeneity for each outcome was partly explained by a significant subgroup effect of individual syndrome. The few available mortality studies indicated premature mortality.

Conclusion: Pooled results suggest that, although there may be elevated prevalence of adult cardiovascular risk conditions, high heterogeneity indicates caution when considering rare deletion syndromes collectively. The paucity of data extending into later adulthood and using age-matched control comparisons supports the need for prospective studies of large, well-phenotyped cohorts to inform adult penetrance of treatable medical diseases in this emerging group of young adults.

Purpose: To report interim results from the ongoing, open-label, Phase 3 APHENITY Extension Study (NCT05166161), evaluating long-term treatment with sepiapterin in patients with phenylketonuria.

Methods: Participants received an age-based dose of oral sepiapterin daily; those with mean blood phenylalanine (Phe) levels <360 μmol/L (<5.95 mg/dL) after 2 weeks underwent a 26-week dietary Phe tolerance assessment, wherein dietary Phe intake was adjusted and blood Phe levels monitored. Other participants continued treatment with optional diet liberalization. Primary endpoints included change from baseline to Week 26 in dietary Phe intake and treatment-emergent adverse events (TEAEs).

Results: As of September 2, 2024, 169 participants received sepiapterin (median [minimum, maximum] age: 14.0 [0.2, 55.0] years, median exposure: 72.9 weeks); 102 participants underwent dietary Phe tolerance assessments. Mean (SD) dietary Phe intake increased from 27.6 (18.0) mg/kg/day at baseline to 62.5 (41.5) mg/kg/day at Week 26 (least-squares mean change [SE], 36.4 [2.8] mg/kg/day from baseline) (P<0.0001 from post hoc analysis). The incidence of treatment-related TEAEs was 29.0%; 3 participants (1.8%) discontinued treatment owing to treatment-related TEAEs. There were no treatment-related serious TEAEs or deaths.

Conclusion: Interim results support the long-term safety of sepiapterin and demonstrate the potential for diet liberalization in adults and children with phenylketonuria.

Purpose: We characterized dimensions of clinical utility in a prospective, observational cohort of patients with rare diseases undergoing genome sequencing (GS).

Methods: Clinical utility data (diagnostic, clinical management and research recommended, avoided, or pursued for index cases and relatives) were collected from medical records and summarized using descriptive statistics. A multivariable regression model characterized factors associated with each type of utility, reported as odds ratios with 95% confidence intervals.

Results: Among 715 cases who underwent GS, results triggered diagnostic investigations in 17.5%, clinical management activities in 35.8%, research opportunities in 30.8%, and genetic counseling/testing for relatives in 19.0%. Results also limited diagnostic investigations in 87.9%. Regression analyses identified clinical, geographic, and ethnicity-related factors as significantly associated with utility. Diagnostic/potentially diagnostic results increased odds of changes in diagnostic investigations, management and genetic testing recommendations for relatives. Patients from larger sites had higher odds of management or research recommendations and patients of non-European ethnicity were less likely to pursue recommendations.

Conclusions: Our findings provide evidence that GS has clinical utility beyond diagnostic care, including management, research, as well as familial care and preventing unnecessary medical activity. To determine which factors are associated with utility, multiple dimensions of care and broad sociodemographic factors warrant consideration.

Purpose: Biallelic pathogenic variants in YARS1 cause tyrosyl-tRNA synthase (TyrRS) deficiency that compromises the loading of tyrosine to its tRNA. YARS1 deficiency is characterized by impairment of neurological development, growth, liver function and hematopoiesis. For other aminoacyl-tRNA synthetase deficiencies, supplementation of the respective amino acid and high-protein diet improved outcome. Whether tyrosine supplementation is effective in YARS1 deficiency is not known.

Methods: Nine individuals with YARS1 deficiency received tyrosine (seven with and two without high-protein diet). Aminoacylation was measured in patient-derived fibroblasts.

Results: Since supplementation, cooperation, endurance and motor skills improved in 8/9 children. Two children demonstrated significant progress in active language skills. Weight gain improved in 6/9, and vomiting stopped in all cases. In 4/9 children hematological parameters improved. In vitro, the TyrRS activity determined in three fibroblast cell lines homozygous for p.(Arg367Trp) was significantly reduced (0%, 6%, 24%) at 100 μM tyrosine (physiological blood concentration). At 500 μM tyrosine, TyrRS activity increased to almost normal activity relative to controls at 100 μM.

Conclusion: Given the positive cost/risk-benefit ratio, we advocate the therapeutic trial with tyrosine supplementation and high-protein diet for YARS1 deficiency. Further studies should aim to determine variant-specific differences, and long-term outcomes in comparison to natural history.