Rare diseases, common barriers: disparities in pediatric clinical genetics outcomes.

BACKGROUND: Identifying a precise genetic diagnosis can improve outcomes for individuals with rare disease, though the resources required to do so may impede access and exacerbate healthcare disparities leading to inequitable care. Our objective was therefore to determine the effect of multiple sociodemographic factors on the yield of the diagnostic evaluation for genetics outpatients. METHODS: This is a retrospective cohort study from 2017 to 2019 of outpatient genetics referrals at a pediatric academic tertiary care center. Exposures included: primary language, insurance type, and neighborhood resources (via the Childhood Opportunity Index, COI). The primary outcome was identification of a genetic diagnosis within 2 years of the initial clinic visit. RESULTS: COI quintile was not significantly associated with the odds of diagnosis but was significantly associated with clinic attendance, with lower neighborhood resources leading to incomplete referrals. Limited English proficiency was associated with a higher odds of diagnosis, though at an older age. Public insurance was associated with increased access to genetic testing. CONCLUSIONS: Lower neighborhood resources are negatively associated with clinic attendance. Our findings further suggest delays in care and a referral bias for more severe phenotypes among families with limited English proficiency. Improved access to clinical genetics is needed to improve diagnostic equity. IMPACT: The resources required to identify a genetic diagnosis may impede access and exacerbate healthcare disparities leading to inequitable care. In an analysis of pediatric outpatient genetics referrals, we observed a significant association between neighborhood resources and clinic attendance but not diagnostic yield for those attending, and a higher diagnostic yield for families with limited English proficiency, suggesting referral bias for more severe phenotypes. Thus, the primary barrier to finding a genetic diagnosis was initiation of care, not the ensuing diagnostic odyssey. Further research efforts should be directed at increasing access to clinical genetics evaluations for children with rare disease.

Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.

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Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.

PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. METHODS: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. RESULTS: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. CONCLUSION: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy.

Aortopathy can be defined as aortic dilation, aneurysm, dissection, and tortuosity. Familial aortopathy may occur secondary to fibrillin-1 (FBN1) mutations in the setting of Marfan syndrome, or may occur as a result of other genetic defects with different, but occasionally overlapping, phenotypes. Because of the phenotypic overlap and genetic heterogeneity of disorders featuring aortopathy, we developed a next generation sequencing (NGS) assay and comparative genomic hybridization (CGH) array to detect mutations in 10 genes that cause thoracic aortic aneurysms (TAAs). Here, we report on the clinical and molecular findings in 175 individuals submitted for aortopathy panel testing at ARUP laboratories. Ten genes associated with heritable aortopathies were targeted using hybridization capture prior to sequencing. NGS results were analyzed, and variants were confirmed using Sanger sequencing. Array CGH was used to detect copy-number variation. Of 175 individuals, 18 had a pathogenic mutation and 32 had a variant of uncertain significance (VUS). Most pathogenic mutations (72%) were identified in FBN1. A novel large SMAD3 duplication and FBN1 deletion were identified. Over half who had TAAs or other aortic involvement tested negative for a mutation, suggesting that additional aortopathy genes exist. We anticipate that the clinical sensitivity of at least 10.3% will rise with VUS reclassification and as additional genes are identified and included in the panel. The aortopathy NGS panel aids in the timely molecular diagnosis of individuals with disorders featuring aortopathy and guides proper treatment.