American Journal of Medical Genetics Part A最新文献

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.

Autosomal recessive spinocerebellar ataxia type 20 (SCAR20) is a rare neurodevelopmental disorder caused by biallelic variants in the SNX14 gene and characterized by developmental delay, hypotonia, cerebellar atrophy, and hearing loss. This study aimed to characterize the clinical, radiological, and genetic presentation of affected individuals in a consanguineous Omani population. We conducted a retrospective and partly prospective case series involving 17 patients from seven consanguineous families seen at the Royal Hospital, Oman. Data were collected between September and November 2024, with historical assessments extending over the past decade. Clinical data were extracted from electronic records, and neuroimaging was reviewed. Whole exome sequencing of seven probands was performed, and familial segregation was confirmed through targeted Sanger sequencing. Variants were classified according to American College of Medical Genetics and Genomics (ACMG) guidelines. The most common variant was SNX14 c.647_648del (p.Glu216Valfs24), identified in seven patients. Four patients carried the c.1132C>T (p.Arg378) variant, while two had a novel splice-site mutation, c.613-1G>A. One case involved a contiguous gene deletion affecting NT5E. Patient ages ranged from 1 month to 21 years. This report expands the mutational and clinical spectrum of SCAR20 in the Middle East and highlights the importance of early genetic testing, diagnostic vigilance, and multidisciplinary care in consanguineous populations.

Neurofibromatosis 1 (NF1) is caused by pathogenic variants of the NF1 gene and increases the risk of tumor development. Phyllodes tumors are rare fibroepithelial neoplasms of the breast, for which the malignant forms exhibit high recurrence and metastasis rates. Herein, we report the case of a 19-year-old female with NF1 who developed a malignant phyllodes tumor of the breast. She noticed a breast mass 3 years before referral, which was diagnosed as a fibroadenoma. However, rapid tumor growth was observed 3 months prior to her hospital visit. Magnetic resonance imaging of the breast revealed a 9-cm tumor, and lumpectomy confirmed the malignancy. Recurrence necessitated a total mastectomy and pectoralis major resection. One year after surgery, metastases were detected in the left axillary lymph nodes and femoral head, requiring surgical intervention and denosumab treatment. No relapses were observed after 18 months. Comprehensive genomic profiling revealed a germline NF1 nonsense variant with loss of heterozygosity (LOH) in tumor cells. Additional somatic variants of TP53 and SMARCB1 have been identified. The TP53 variant is listed in the Catalogue of Somatic Variants in Cancer as a breast cancer-associated variant, whereas a splice site variant in SMARCB1 and LOH suggests a loss of SMARCB1 function. This case highlights the increased risk of malignancy in NF1 patients and underscores the need for comprehensive genomic profiling.

To evaluate the prevalence of psychiatric signs and symptoms and describe psychotherapeutic and psychopharmacological interventions among children with osteogenesis imperfecta (OI). PRISMA guidelines were followed, and the study was registered in PROSPERO (CRD42024588284). Studies (n = 1419) were identified across five databases. Eligible studies, identified by independent reviewers, included peer-reviewed research on psychiatric comorbidities or interventions in children with OI. Data extraction included study design, population characteristics, mental health outcomes, and treatment effectiveness, with all studies assessed for quality and bias. Findings were synthesized to evaluate the prevalence of psychiatric comorbidities and intervention effectiveness. Five articles met inclusion criteria after screening and full-text review. Although the included studies varied in design and outcome measures, they reported elevated signs and symptoms of anxiety and depression in children with OI, particularly those with severe phenotypes. Qualitative findings highlighted subclinical psychosocial burdens, including emotional distress and social isolation. No studies evaluated psychotherapeutic or psychopharmacological interventions. This systematic review provides the first comprehensive analysis of psychiatric comorbidities in children with OI, revealing a critical lack of research on psychiatric comorbidities in children with OI. These gaps highlight an urgent need for targeted mental health studies to inform screening and integrated care for this population.

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.

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.

Elective genomic testing (EGT) for medically actionable disease predispositions may help adopted individuals (adoptees) with limited knowledge of family health history (FHH) information understand their inherited risks. In this prospective cohort study, patients who participated in Sanford Health's EGT program were surveyed at the time of enrollment between August 2020 and April 2022 about their motivations for pursuing EGT and perceived risks for three conditions. Data from self-reported adoptees and nonadoptees were analyzed using bivariate analyses. Of the 5799 eligible patients, 197 (3.4%) reported that they were adopted. Adoptees were more likely than nonadoptees to report lack of information about FHH as a very important motivation for pursuing EGT (81% vs. 32%, p < 0.001) and were more likely to rate it as their most important motivation (45% vs. 5%; p < 0.001). Other motivations, including learning about personal disease risk (72% vs. 61%; p = 0.016) and providing disease risk information to children (69% vs. 57%; p = 0.003), were also more likely to be rated as very important by adoptees than by nonadoptees, respectively. No differences in risk perceptions were observed. A lack of FHH information is an important reason why adoptees pursue EGT. Adoptees may hope that EGT will identify inherited risks for disease.

Hereditary sensory and autonomic neuropathy type IV (HSAN4) is a rare neurological disorder characterized by anhidrosis and congenital insensitivity to pain caused by biallelic pathogenic variants in NTRK1. The condition develops because of dorsal root and autonomic ganglion neurodegeneration, which ultimately results in reduced sensation and autonomic neurological dysfunction. We ascertained several neuropathic patients and performed genetic testing using gene panels and exome sequencing (ES). Genetic variants were confirmed by Sanger sequencing. Thirteen families, each with a single affected individual, participated in this study. Genetic testing revealed that all patients carried disease-causing variants in NTRK1. We identified seven different variants within our cohort, including two novel variants (c.1922T>C:p.Leu641Pro and c.1071_1072insTGCC:p.Asn358Cysfs*45). While some variants suggest a possible founder effect, the identification of new variants reflects the genetic diversity within the Saudi population. In addition to the cardinal clinical feature of HSAN4, patients exhibited various other symptoms like motor difficulties, microcephaly, recurrent hip dislocation, dystrophic nails, hypotrichosis, and various dysmorphic features. This study provides clinical information on a large number of patients, updates the prevalence and epidemiologic data in our population, and further expands the understanding of the disease's genetic and clinical spectrum within a highly consanguineous population.

The World Health Organization defines health as "a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity." Medical interventions are often studied for effectiveness in carefully controlled clinical trials, but the parent-perceived, real-world helpfulness of medical management steps on health is less studied. As part of a broader study to create a valid, reliable health measure in DS, we surveyed caregivers of individuals aged 0-21 with Down syndrome (DS) about activities that were helpful for managing their children's health. From February 2023 to February 2024, we received 542 complete survey responses from a national sample. We present caregiver-reported information on actions that caregivers perceived as helpful to address medical conditions in individuals with DS, medical providers seen, and correlations with general health status. Caregiver reports revealed variable health management actions and diverse perceived helpfulness across health domains. Certain actions for constipation prevention and mental health management correlated with higher overall health scores. The utilization of primary care providers and specialists highlights the importance of interprofessional care and communication. Trial Registration: ClinicalTrials.gov: NCT04631237.

Craniosynostosis is characterized by premature fusion of cranial sutures, often with a complex genetic basis. While multiple genes have been implicated, the role of TGFBR3 mutations remains largely uncharacterized in human craniosynostosis. We report two Kuwaiti male siblings, born to consanguineous parents, who presented with syndromic features including craniosynostosis involving the lambdoid and posterior sagittal sutures, hypertelorism, midface hypoplasia, bilateral low-set ears, undescended testes, and developmental hip dysplasia. Duo whole exome sequencing research re-analysis identified a novel homozygous nonsense variant segregating with the phenotype in TGFBR3 (NM_003243.4: c.2418G>A, p.Trp806Ter), which encodes the betaglycan protein. Functional studies were performed to assess the pathogenicity of the variant. Expression of the mutant TGFBR3 in HEK293T cells demonstrated correct plasma membrane localization but revealed a truncated protein lacking its intracellular C-terminus. The mutant receptor retained canonical co-receptor function. In luciferase reporter assays, both wild-type and mutant TGFBR3 enhanced TGF-β1, TGF-β2, and TGF-β3 signaling. Mutant TGFBR3 produced an increase in luciferase activity relative to wild type only at the highest TGFβ1 concentration tested (10 pM). At lower TGFβ1 concentrations (0.1 and 1 pM) and across all concentrations of TGFβ2 and TGFβ3, mutant and wild-type receptors behaved similarly. This is the first report implicating a biallelic TGFBR3 nonsense variant in a syndromic, autosomal recessive form of craniosynostosis in a Middle Eastern population. The premature stop codon truncates the C-terminal region of the protein, perhaps disrupting critical regulatory or interaction domains. Our results suggest that dysregulated TGFβ signaling via the intracellular C-terminus of the protein may represent a novel pathogenic mechanism in cranial suture biology.