American Journal of Medical Genetics Part A最新文献

A significant positive correlation between age and functional independence has been reported in pediatric patients with Prader-Willi Syndrome (PWS) using the Functional Independence Measure (FIM) for Children (WeeFIM). However, no previous study has evaluated the use of the FIM in adults with PWS. This study aimed to assess functional independence in adults with PWS using the FIM and to explore the effects of age and genetic subtype on functional outcomes. We conducted a retrospective, single-center study of 54 genetically confirmed patients with PWS of Japanese descent. No significant correlations were observed between age and FIM scores. Similarly, no significant differences were found between age groups or genetic subtypes in total, motor, or cognitive FIM domains. Radar chart analysis illustrated slightly lower FIM scores in older adults, although these differences were not statistically significant. These findings highlight the importance of individualized support plans tailored to age and specific functional needs. Early intervention in childhood, followed by continued support into adulthood, may be crucial for maintaining independence and enhancing quality of life in individuals with PWS.

The objective of this study was to evaluate the EHR user experience and satisfaction of clinicians in the medical genetics and genomics field. An anonymous survey was sent through genetic related listservs and LinkedIn to a broad range of genetics clinicians including physicians, advanced practice providers, and genetic counselors. Results showed a wide range of satisfaction levels among all types of genetic clinicians, reflecting the need for improved genetic EHR functionalities. Despite available EHR training being reported as helpful by most individuals who had completed some, the utilization was low. There was a striking difference between internally and externally sent test results regarding how difficult they are to find and import into clinical documentation. Despite available EHR tools, a high manual labor burden occurs for most during the documentation process. There is demand for more genetic functionalities, some which exist but institutions may not have implemented these features. Genomics EHR modules can improve EHR user experiences. Key themes for EHR usability include institutional support, interoperability and integration, ease of data access, streamlined documentation, centralized workflows, and clinical decision support. Future evaluation is needed to determine how to improve the interoperability of genetic testing with EHRs and increase accessibility to genetic related EHR functionalities.

Osteogenesis imperfecta type VI is a rare genetic disorder caused by biallelic disease-causing variants in SERPINF1. The phenotype is characterized by severe osteopenia, recurrent fractures, and moderate to severe skeletal deformities. We report an 11-year-old individual who presented with multiple fractures of the long bones of the upper and lower extremities, severe osteopenia, and skeletal deformities. Whole exome sequencing revealed compound heterozygous variants c.[-37C>A];[829_831del] in SERPINF1. To determine the functional consequence of the variants, quantitative real-time PCR and immunoblotting analyses in patient-derived fibroblasts were performed, which showed reduced expression of SERPINF1 transcript and protein levels.

Rahman syndrome (HIST1H1E-related neurodevelopmental syndrome, OMIM #617537) is a rare autosomal-dominant condition caused by truncating variants in the C-terminal domain of the HIST1H1E gene. It is characterized by macrocephaly, hypotonia, craniofacial anomalies, and multisystem anomalies. Although multisystem involvement has been increasingly described, respiratory manifestations remain sparsely documented. We report a female infant with mosaic HIST1H1E truncation (c.435dupC; p.Thr146Hisfs*50) who presented with severe mixed sleep apnea secondary to laryngomalacia, requiring two airway surgeries and multidisciplinary management. Despite surgical intervention, polysomnography demonstrated persistent mixed apneas, suggesting both structural and central components. Brain MRI revealed nonspecific ischemic changes that could contribute to the neurological phenotype. To contextualize this observation, we reviewed 70 published cases of Rahman syndrome. Respiratory involvement was reported in only 13.5% (neonatal respiratory distress), 2.8% (upper-airway anomalies), and 1.4% (sleep-disordered breathing), frequencies comparable to those in the general population, although most reports lacked systematic respiratory evaluation. These findings suggest that respiratory morbidity may be under-evaluated rather than absent in Rahman syndrome. The combination of hypotonia, craniofacial restriction, and possible brain-stem dysregulation provides a plausible pathophysiologic substrate for both central and obstructive apnea. We recommend considering airway assessment and polysomnography in affected individuals presenting with stridor, desaturations, or sleep-related breathing difficulties. This case further expands the phenotypic spectrum of HIST1H1E-related disorders and represents the first documented example of mosaicism associated with this condition.

Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic disorder that presents with severe chronic pain (CP) in adults. A limited number of NF1 research studies have evaluated behaviorally based interventions to address CP. The current study evaluated the efficacy of cognitive behavior therapy delivered via mobile application. The three-arm (treatment as usual [control], iCanCope only [iCC-NF], iCanCope + contingency management [iCC-NF + CM]) randomized clinical trial of 108 adults with NF1 and CP was completed during a 2-month intervention period. Significant improvements in pain interference (p = 0.005, d = 0.815) occurred in the iCC-NF + CM group when compared to the control group. Outcomes for pain self-efficacy (p = 0.009, d = 0.718), pain inflexibility (p = 0.026, d = 0.629), and chronic pain acceptance (p = 0.036, d = 0.653) significantly improved among the iCC-NF + CM group when compared to the control group. No significant differences were noted between iCC-NF + CM and iCC-NF. The current findings offer preliminary evidence of the added benefit of contingency management to mobile pain applications and provide an auxiliary treatment option for individuals with NF1. Trial Registration: ClinicalTrials.gov identifier: 2000029045.

Heterozygous de novo and inherited biallelic pathogenic variants in DNM1 have been reported in association with autosomal dominant (AD) and autosomal recessive (AR) developmental and epileptic encephalopathy, respectively, due to aberrant dynamin function or expression, with each inheritance pattern associated with a different mechanism of disease. We report an instance of DNM1-related early infantile developmental and epileptic encephalopathy due to compound heterozygous pathogenic variants with different functional effects: the de novo dominant negative-associated c.194C>A (p.Thr65Asn), and the maternally inherited loss of function-associated c.850C>T (p.Gln284*). We describe this patient's severe clinical presentation and disease progression as compared to those previously reported with either AD or AR DNM1-related disease. We hypothesize about the interactions and outcomes of the two variants at the molecular level following review of in vitro and in vivo functional data and demonstrate the utility of long-read genome sequencing for phasing the variants and confirming this individual's molecular diagnosis.

Translocation of newly synthesized proteins into the lumen of the endoplasmic reticulum (ER) is mediated by signal peptide recognition and cleavage. Here we report an individual with Simpson-Golabi-Behmel syndrome (SGBS) bearing a GPC3 missense variant at the signal peptide cleavage site of the glypican-3 protein. The c.71C>T; p.(Ala24Val) alteration in the key -1 position of the cleavage greatly reduces cleavage of the signal peptide, resulting in failure of the protein to efficiently exit the ER, and impaired glycosylation. Functional characterization of two other engineered variants at this position-one predicted to permit cleavage and the other to prevent it-corroborates our findings. This case highlights the potential for missense variants within the signal peptide cleavage site to underlie genetic disorders, and reinforces the idea that many of the missense variants in GPC3 that cause SGBS reside in motifs with high functional relevance to the processing and maturation of glypican-3.

Whilst biallelic variants in RTEL1 are an established cause of telomere biology disorder (TBD), the significance of heterozygous variants has been more challenging to establish. In this nationwide analysis, we describe 18 individuals with heterozygous pathogenic RTEL1 variants from seven families. All were identified during routine clinical genetic investigation for a variety of indications. Each family carried a different variant in RTEL1. Eight individuals had been diagnosed with a TBD-related disease (five with a hematological disorder, four with pulmonary fibrosis, overlap of one). No cases of clinically significant liver fibrosis had been detected. Cutaneous features of dyskeratosis congenita (abnormal skin pigmentation, oral leukoplakia, nail dysplasia and/or prematurely gray hair) were observed in four individuals. Telomere length (lymphocyte) was measured in nine individuals from six families and was below the 1st percentile in eight individuals. These cases illustrate the wide spectrum of disease and reduced penetrance associated with pathogenic RTEL1 variants, providing a real-world perspective on previous findings from research cohorts. We discuss the challenges surrounding incidental findings, clinical surveillance, and reproductive counseling in this context.