10 research outputs found

    Genetics workforce: distribution of genetics services and challenges to health care in California

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    PurposeAccess to genetics health-care services is often complicated by the distance to hospitals, workforce shortages, and insurance coverage. Despite technological advances and decreasing costs of genetic sequencing, the benefits of personalized medicine may be inaccessible to many patients. To assess potential disparities in care, we examined the genetics workforce in California and geographical issues that people encounter in seeking care.MethodsData on all board-certified genetics providers were analyzed including medical geneticists (MGs) and genetic counselors (GCs) in California. To assess distance traveled for care, we computed the distance patients traveled for n = 288 visits to University of California-San Francisco (UCSF) Medical Genetics. We performed geographic optimization to minimize the distance to genetics providers.ResultsThe provider-to-patient ratio in California is 1:330,000 for MGs, 1:100,000 for GCs, and 1:1,520,000 for biochemical MGs. Genetics providers are concentrated in major metropolitan areas in California. People travel up to 386 miles for genetics care within the state (mean = 76.6 miles).ConclusionThere are substantial geographic barriers to genetics care that could increase disparities. Our findings highlight a challenging genetics workforce shortage. The shortage may be even greater due to care subspecialization or lack of full-time equivalency and staffing. We are currently promoting efforts to increase remote health-care options, training, and modified models of care

    Heterozygous nonsense variants in the ferritin heavy-chain gene FTH1 cause a neuroferritinopathy

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    Summary: Ferritin, the iron-storage protein, is composed of light- and heavy-chain subunits, encoded by FTL and FTH1, respectively. Heterozygous variants in FTL cause hereditary neuroferritinopathy, a type of neurodegeneration with brain iron accumulation (NBIA). Variants in FTH1 have not been previously associated with neurologic disease. We describe the clinical, neuroimaging, and neuropathology findings of five unrelated pediatric patients with de novo heterozygous FTH1 variants. Children presented with developmental delay, epilepsy, and progressive neurologic decline. Nonsense FTH1 variants were identified using whole-exome sequencing, with a recurrent variant (p.Phe171∗) identified in four unrelated individuals. Neuroimaging revealed diffuse volume loss, features of pontocerebellar hypoplasia, and iron accumulation in the basal ganglia. Neuropathology demonstrated widespread ferritin inclusions in the brain. Patient-derived fibroblasts were assayed for ferritin expression, susceptibility to iron accumulation, and oxidative stress. Variant FTH1 mRNA transcripts escape nonsense-mediated decay (NMD), and fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. C-terminal variants in FTH1 truncate ferritin’s E helix, altering the 4-fold symmetric pores of the heteropolymer, and likely diminish iron-storage capacity. FTH1 pathogenic variants appear to act by a dominant, toxic gain-of-function mechanism. The data support the conclusion that truncating variants in the last exon of FTH1 cause a disorder in the spectrum of NBIA. Targeted knockdown of mutant FTH1 transcript with antisense oligonucleotides rescues cellular phenotypes and suggests a potential therapeutic strategy for this pediatric neurodegenerative disorder

    Rubinstein-Taybi syndrome in diverse populations

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    Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by loss-of-function variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, and intellectual disability. RSTS phenotype has been well characterized in individuals of European descent but not in other populations. In this study, individuals from diverse populations with RSTS were assessed by clinical examination and facial analysis technology. Clinical data of 38 individuals from 14 different countries were analyzed. The median age was 7 years (age range: 7 months to 47 years), and 63% were females. The most common phenotypic features in all population groups included broad thumbs and/or halluces in 97%, convex nasal ridge in 94%, and arched eyebrows in 92%. Face images of 87 individuals with RSTS (age range: 2 months to 47 years) were collected for evaluation using facial analysis technology. We compared images from 82 individuals with RSTS against 82 age- and sex-matched controls and obtained an area under the receiver operating characteristic curve (AUC) of 0.99 (p < .001), demonstrating excellent discrimination efficacy. The discrimination was, however, poor in the African group (AUC: 0.79; p = .145). Individuals with EP300 variants were more effectively discriminated (AUC: 0.95) compared with those with CREBBP variants (AUC: 0.93). This study shows that clinical examination combined with facial analysis technology may enable earlier and improved diagnosis of RSTS in diverse populations
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