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

GNB1-related disorder is characterized by intellectual disability, abnormal tone, and other variable neurologic and systemic features. GNB1 encodes the β1 subunit of the heterotrimeric G-protein, a complex with a key role in signal transduction. Consistent with its particularly high expression in rod photoreceptors, G_β1 forms a subunit of retinal transducin (G_αtβ1γ1), which mediates phototransduction. In mice, GNB1 haploinsufficiency has been associated with retinal dystrophy. In humans, however, although vision and eye movement abnormalities are common in individuals with GNB1-related disorder, rod-cone dystrophy is not yet an established feature of this condition. We expand the phenotype of GNB1-related disorder with the first confirmed report of rod-cone dystrophy in an affected individual, and contribute to a further understanding of the natural history of this condition in a mildly affected 45-year-old adult.

Beckwith–Wiedemann syndrome (BWS) is an overgrowth and epigenetic disorder caused by changes on chromosome 11p15. The primary features requiring management in childhood include macroglossia, omphalocele, lateralized overgrowth, hyperinsulinism, and embryonal tumors. Management guidelines have not been developed for adults with BWS and there have been few studies to assess the clinical needs of these patients. Furthermore, there have been few studies on the psychosocial implications of BWS in children or adults. Here, we present a descriptive summary of data gathered from two separate adult BWS cohorts. The first, a patient-based survey cohort, includes self-reported health information and recollections about BWS experiences, while the second provides results of a medical record-based assessment from patients in an overgrowth registry. Results highlight the clinical features and medical issues affecting two large independent cohorts of adults with BWS while noting similarities. Open-ended questions asked of the survey cohort yielded themes to guide future qualitative studies. Finally, the study demonstrated the reliability of patient-reported data and the utility of international partnerships in this context.

Dynamin 1 is a GTPase protein involved in synaptic vesicle fission, which facilitates the exocytosis of neurotransmitters necessary for normal signaling. Pathogenic variants in the DNM1 gene are associated with intractable epilepsy, often manifested as infantile spasms at onset, developmental delay, and a movement disorder, and are located in the GTPase and middle domains of the protein. We describe a 36-year-old man with autism and moderate intellectual disability who experienced only a few generalized seizures between the age 16 and 30 years. Using a whole sequencing approach, we identified the c.1994T>C p.(Leu665Pro) de novo novel missense pathogenic variant in the GTPase effector domain (GED) of the DNM1 protein. Structural analyses suggest that this substitution impairs both the stalk formation and its interactions, known to be important for the dynamin-1 physiological cellular function. Our data expand the spectrum of phenotypes associated with pathogenic variants in the DNM1 gene, linking a variant in the GED domain with autism and onset in the adolescence of mild epilepsy, a phenotypic presentation remarkably different from the early infantile epileptic encephalopathy associated with pathogenic variants in the GTPase or middle domains.

Little is known about the mental well-being of adults living with arthrogryposis multiplex congenita (AMC). The objectives of this study were to determine the incidence of depression in an international population of adults with AMC and to identify variables independently associated with depression. This cross-sectional study used independent samples t-test and hierarchical multiple regression. The mean Hospital Anxiety and Depression Scale—depression (HADS-D) score of our sample, which included 60 adults with AMC, was 4.0 ± 3.6, with 19% having some signs of depression. Occupation status, age, sex, physical independence, environmental factors, anxiety, and fatigue explained 52.2% of the variance in HADS-D. The prevalence of depression in an adult sample of individuals with AMC is similar to that of the general adult population in the United States. Beyond direct interventions to ameliorate depression, rehabilitation clinicians may also consider treatments and interventions to decrease anxiety and reduce fatigue and environmental barriers.

Bone marrow failure type 3 (BMFS3) (MIM:617052) is a subtype of inherited bone marrow failure syndromes (IBMFS) caused by homozygous pathogenic variants in DNAJC21. It was first defined in 2016, and to date, 19 patients have been reported. Here we report the first adult patient; a 20-year-old female with a novel frameshift variant in DNAJC21 presents with thrombocytopenia, dysmorphic findings, and ovarian agenesis. Our patient expands the clinical spectrum to the milder end and suggests that DNAJC21-related disorders can have relatively mild presentations. Investigation of DNAJC21 variants in both childhood and adult patients with persistent, non-progressive thrombocytopenia will allow to broaden the gene-related phenotypic and genotypic spectrum and elucidate the pathophysiology. Therefore, we encourage revisiting undiagnosed patients to offer whole exome sequencing (WES) in adulthood.

Research regarding caregivers for individuals with Down syndrome mainly focuses on outcomes for the pediatric population and not on the experience of caregivers themselves. Our objective was to understand caregiver-reported experiences and concerns for themselves and the individual they care for through a survey of caregivers of adults with Down syndrome. We conducted a survey of N = 438 caregivers of adults with Down syndrome and asked about the perspectives of the respondents surrounding caregiving and demographics. The most common concerns among caregivers were planning for future needs (72.1%) and what happens when they (the caregiver) are gone (68.3%). Concerns they had for the individual they cared for were employment (63.2%) and friendships/relationships (63.2%). We found no significant difference in responses based on caregiver education level. Our survey identified six themes for the feedback about what clinical and research professionals should know to better serve individuals with Down syndrome, their families, and those who support them. Many caregivers discussed topics including healthcare, coordination, competence, and ability. More efforts for research into the caregiver experience for adults with Down syndrome are needed.

Genetic conditions affect people throughout their entire lifespan; however, many clinical geneticists focus on the care of pediatric individuals. We analyzed the medical literature and related resources to help assess to what extent adults with genetic diseases were represented. This included general literature searches of PubMed (from 2001 through 2022), specific databases (the FDA orphan drug list and the Clinical Genomic Database) related to management and direct treatment of genetic conditions, and textbooks and morphology guides relevant to the diagnosis of genetic conditions. In the field of genetics/genomics in general, we overall detected a statistically significant emphasis on pediatric populations in the medical literature compared to select other disciplines and compared with the global population distribution. Clinical genetics articles about adults tended to focus on younger adult ages. In clinical genetics, management and treatments, as well as illustrations in several educational/diagnostic resources tended to focus on pediatric populations.

Cover image: Be Prepared Gene Targeted Therapy Ahead