American Journal of Medical Genetics Part C: Seminars in Medical Genetics最新文献

Neurofibromatosis type 1 (NF1) is a progressive multisystem condition that is characterized by a wide range of clinical manifestations and clinical variability. Individuals with NF1 can be significantly impacted by NF1-related complications, and targeted therapies are emerging. Currently, MEK inhibitors selumetinib and mirdametinib are the only FDA-approved targeted therapies for NF1-related symptomatic or progressive, inoperable plexiform neurofibromas. Several additional MEK inhibitors are being investigated in clinical trials for the treatment of plexiform neurofibromas. Additional therapies are currently under investigation for the treatment of malignant peripheral nerve sheath tumors, low-grade gliomas, skeletal manifestations, cutaneous neurofibromas, and other NF1-related complications.

Usher syndrome, the most common form of deaf-blindness, displays extensive genetic, allelic, and phenotypic heterogeneity. The dual sensory impairment associated with this autosomal recessive disorder makes Usher syndrome an important target for gene therapy, with dozens of published preclinical studies targeting multiple Usher syndrome genes and using multiple gene therapy strategies. Nine genes have been conclusively linked to Usher syndrome; however, data on the prevalence and contribution of specific genetic variants is lacking. Such information is essential to choosing a favorable target gene or therapeutic approach during clinical trial design. Here, we used large genomic databases to systematically evaluate the genomics of Usher syndrome. We ascertained pathogenic Usher syndrome variants from three clinical databases and determined the occurrence of these pathogenic Usher syndrome variants within: (1) a publicly available dataset including worldwide populations (GnomAD), (2) a cohort of 3888 children without hearing loss, and (3) 637 children with hearing loss. Results show significant variability in the frequency of Usher syndrome variants by gene and genetic ancestry. 1% of control subjects carry a pathogenic USH variant. Pathogenic variants in USH2A are the most prevalent, at 1 in 150 individuals (0.0062). Calculated general population prevalence for all Usher syndrome subtypes is 1 in ~29,000, indicating that 30,405 individuals in the United States and 721,769 individuals worldwide are affected. We estimate that 324 babies in the United States and 12,090 worldwide are born with Usher syndrome each year. We identify key targets for genetic therapy based on population-level prevalence including a focus on alternatives to gene replacement therapies, specifically for USH2A.

Rare diseases impact approximately 1 in 10 people worldwide, and yet, less than 5% of all rare diseases currently have an approved treatment option available. This is due to many challenges unique to rare diseases, including small, diverse patient populations, the cost of drug development that is not proportionate to the number of patients who could potentially benefit from treatment, and difficulty with clinical trial design to validate new therapeutics. As a result, drug repurposing has become an increasingly promising option for finding treatment options for rare diseases. First described in 2018, Bachmann-Bupp Syndrome (BABS) is a rare neurodevelopmental disorder that is caused by gain-of-function variants in the ornithine decarboxylase (ODC1) gene and is characterized by developmental delay, hypotonia, and alopecia. Through collaboration and the use of a unique drug repurposing strategy, the first patient identified with BABS was treated with the repurposed drug eflornithine, also known as α-difluoromethylornithine (DFMO), in just 16 months. Currently, five additional patients with BABS are being treated with DFMO. This model of drug repurposing of an FDA-approved drug for use in another indication can serve as an example of what is possible in the scope of other rare diseases, specifically in other polyaminopathies.

Myhre syndrome is a rare connective tissue disorder characterized by skeletal, cardiopulmonary, dermatologic, neurocognitive changes, and a predisposition to exaggerated fibrosis in response to mechanical stress. We report monozygotic male twins with Myhre syndrome caused by the recurrent SMAD4 gain-of-function variant c.1498A>G (p.Ile500Val), identified by targeted next-generation sequencing of peripheral blood. Proband 1 presented at age 37 years for evaluation of symptomatic aortic stenosis. Clinical recognition of Myhre syndrome prompted deferral of transesophageal echocardiography, and molecular diagnosis informed subsequent conservative management. His co-twin, Proband 2, underwent posterior pharyngeal flap surgery and right-heart catheterization with pulmonary artery stenting in childhood; later, he developed progressive pulmonary arterial hypertension and died at 31 years. We report on the differing outcomes of the twins and the possibility that invasive airway and cardiac procedures may have accelerated fibro-proliferative complications of Proband 2. Early recognition of Myhre syndrome allows selection of alternatives to high-risk procedures, longitudinal monitoring, and may reduce morbidity and mortality.

Myhre syndrome (MIM #139210) is a rare multisystem disorder first described in 1981, characterized by short stature, neurodevelopmental delay, joint contractures, and cardiopulmonary complications. Its molecular basis, recurrent pathogenic variants in SMAD4, was not discovered until 2011. This narrative is based on a review of medical records, personal experiences in the care of a remarkable patient, and family interviews. It traces the life of a young man from rural Montana whose diagnosis was delayed for over two decades, despite early evaluations by renowned specialists. The absence of a unifying diagnosis profoundly shaped his and his family's experience-emotionally, medically, and socially. When the diagnosis of Myhre syndrome was finally established via whole exome sequencing in adulthood, it brought both clarity and new uncertainties. Through his story, we examine the psychosocial toll of diagnostic delay, the transformative potential of genomic medicine, and the resilience of individuals and families living with complex, undiagnosed conditions. The narrative also underscores the ongoing systemic barriers to care and inclusion for individuals with lifelong rare disorders. Lastly, this account offers a reflection on the philosophical framework of Maurice Merleau-Ponty, whose phenomenology of the lived body versus the body-object provides a lens to understand the subjective and embodied dimensions of living with an undiagnosed condition.

Myhre syndrome is a rare progressive genetic disorder characterized by hearing loss, cardiovascular and joint problems, neoplasia, and neuropsychologic disabilities. Parents of children with Myhre syndrome and adults themselves face unique challenges, stresses, and fears associated with this diagnosis. Reflective writing in the form of journaling can provide psychosocial support and help individuals cope with this diagnosis. Adult patients and parents whose children were evaluated at the Massachusetts General Hospital Myhre Syndrome Clinic were invited to participate in a three-month journaling intervention. Participation in the study required the completion of a series of surveys prior to starting and upon completion of the study. Data from these surveys were analyzed to assess for change in mental well-being. Eleven individuals participated, six of whom completed the three-month journaling intervention and post-journaling surveys. Three participants indicated that journaling had an impact on their mental well-being, and of these, two planned to continue journaling. However, there was no statistically significant difference in mental well-being scores pre- and post-journaling intervention. The very small size of the study limits interpretation, but we think it is reasonable to suggest that expressive writing through journaling may be a coping mechanism and means of improving well-being for some individuals in the Myhre syndrome community.

It is evident that Turner syndrome (TS) impacts almost all developmental stages of the fetal heart with congenital heart disease (CHD) being seen in 23%–50% of individuals. Although the spectrum of CHDs in TS is well-established, with left-sided lesions predominating, the influence of specific karyotypes on the prevalence and types of CHDs remains incompletely understood. The primary objective of this systematic review/meta-analysis was to quantitatively synthesize the existing evidence on the association between specific karyotypes in TS and the risk of various CHDs. A systematic literature search was conducted through December 2023 to identify studies reporting the prevalence of CHDs in relation to TS karyotype. The quality of the individual studies was assessed using the Joanna Briggs Institute critical appraisal tools for systematic reviews. The overall estimates were pooled using both fixed- and random-effects models. Sensitivity and subgroup analysis were performed. Twenty-five studies were included in the analysis. TS individuals with a 45,X karyotype showed a significantly higher likelihood of bicuspid aortic valve (BAV) (pooled OR, 3.14 [95% CI: 2.49–3.94]), aortic coarctation (CoA) (pooled OR, 4.16 [95% CI: 2.74–6.31]), and partial anomalous pulmonary venous return (PAPVR) (pooled OR, 4.86 [2.31–10.2]) compared with TS individuals with a non-45,X karyotype. In addition, TS individuals with a 45,X karyotype also showed a significantly higher likelihood of BAV (pooled OR, 2.72 [95% CI: 1.62–4.56]) when compared with TS individuals with 45,X/46,XX mosaicism. TS individuals with a 45,X karyotype showed a significantly higher risk of BAV (pooled OR, 2.13 [95% CI: 1.42–3.21]) and CoA (pooled OR, 4.52 [95% CI: 1.58–13.0]) when compared with TS individuals with an isochromosome Xq. A significantly higher likelihood of BAV was also found in 45,X compared to other karyotypes (e.g., 45,X/46,XY and TS karyotypes with ring X chromosome). Some heterogeneity was evident, but publication was low. This meta-analysis confirms a strong association between the 45,X karyotype and increased prevalence of BAV, CoA, and PAPVR in TS. While 45,X/46,XX mosaicism and karyotypes with an isochromosome Xq mitigate risk, the findings emphasize the need for large-scale studies to refine risk assessment and management strategies.

This research review of Myhre syndrome is a summary of published articles which provide a valuable resource for readers, researchers, and future authors. It traces the evolution of the Laryngotracheal-Arthropathy-Prognathism-Short Stature (LAPS) syndrome to the current eponym of Myhre syndrome. These allelic disorders are caused by pathogenic variants in SMAD4. After the initial report over 40 years ago, the steady publication of case reports and small series was accelerated following the discovery of the pathogenic variants in SMAD4. The articles in this review include numerous case reports and small series, reports about basic science, the discovery of the causative gene, the emergence of the natural history in larger studies, and articles about specific features, especially the cardiovascular system and airways. We hope this analysis provides a foundation for future research that may extend symptom-based treatment to genetic-based therapy.

Turner syndrome (TS) continues to present a diagnostic challenge to healthcare professionals. The diagnostic challenges associated with TS result in delayed treatment and clinical care. Here we provide an update of the physical appearance of girls and women with TS by presenting clinical photographs and detailed clinical descriptions of 25 Danish girls and women with TS. Our data highlight the wide variation in physical appearance and clinical phenotype seen in girls and women with TS.