Insurance denials and diagnostic rates in a pediatric genomic research cohort.

PURPOSE: This study aimed to assess the amount and types of clinical genetic testing denied by insurance and the rate of diagnostic and candidate genetic findings identified through research in patients who faced insurance denials. METHODS: Analysis consisted of review of insurance denials in 801 patients enrolled in a pediatric genomic research repository with either no previous genetic testing or previous negative genetic testing result identified through cross-referencing with insurance prior-authorizations in patient medical records. Patients and denials were also categorized by type of insurance coverage. Diagnostic findings and candidate genetic findings in these groups were determined through review of our internal variant database and patient charts. RESULTS: Of the 801 patients analyzed, 147 had insurance prior-authorization denials on record (18.3%). Exome sequencing and microarray were the most frequently denied genetic tests. Private insurance was significantly more likely to deny testing than public insurance (odds ratio = 2.03 [95% CI = 1.38-2.99] P = .0003). Of the 147 patients with insurance denials, 53.7% had at least 1 diagnostic or candidate finding and 10.9% specifically had a clinically diagnostic finding. Fifty percent of patients with clinically diagnostic results had immediate medical management changes (5.4% of all patients experiencing denials). CONCLUSION: Many patients face a major barrier to genetic testing in the form of lack of insurance coverage. A number of these patients have clinically diagnostic findings with medical management implications that would not have been identified without access to research testing. These findings support re-evaluation of insurance carriers' coverage policies.

Phenotypic expansion and variable expressivity in individuals with JARID2-related intellectual disability: A case series.

Loss of function variants in JARID2 were recently reported in 16 patients with a neurodevelopmental disorder characterized by delays, intellectual and learning disability, autism, behavioral abnormalities, and dysmorphic features. Most cases were de novo, with only one variant inherited from an affected parent. Here, we present seven additional individuals from five families with pathogenic or likely pathogenic JARID2 variants, confirming this gene-disease association and highlighting palatal abnormalities and heart defects as part of the phenotype. In addition, we report inheritance of JARID2 variants from mildly affected parents, demonstrating the variable expressivity of the disease. We also note the high prevalence of intragenic JARID2 copy number variants, emphasizing the importance of exon-level analysis.

Novel mosaic SRY gene deletions in three newborn males with variable genitourinary malformations.

Ambiguous genitalia in the newborn can present a diagnostic challenge in medical practice. In most cases, the causes of genitourinary anomalies are not well understood; both genetic and environmental factors are thought to play a role. In this study, we report mosaic SRY gene deletion identified by fluorescence in situ hybridization (FISH) analysis in three unrelated newborn male patients with genital anomalies. G-banded chromosomes and microarray analysis were normal for all three patients. One patient had microphallus, hypospadias, bifid scrotum, exstrophic perineal tissue identified as a rectal duplication, lumbar vertebral anomalies, scoliosis, and a dysmorphic sacrum. The other two patients had isolated epispadias with the urethral meatus close to the penopubic junction. All three had bilateral palpable gonads in the scrotum. While this is the first report of mosaic SRY deletions, mosaic SRY sequence variants have been described in patients with variable genitourinary anomalies. This study identifies FISH analysis as a reliable method for mosaic SRY deletion detection. We suggest SRY FISH analysis should be used in the clinical workup of patients with genitourinary ambiguity.

Hypotonia and intellectual disability without dysmorphic features in a patient with PIGN-related disease.

BACKGROUND: Defects in the human glycosylphosphatidylinositol anchor biosynthetic pathway are associated with inherited glycosylphosphatidylinositol (GPI)-deficiencies characterized by a broad range of clinical phenotypes including multiple congenital anomalies, dysmorphic faces, developmental delay, hypotonia, and epilepsy. Biallelic variants in PIGN, encoding phosphatidylinositol-glycan biosynthesis class N have been recently associated with multiple congenital anomalies hypotonia seizure syndrome. CASE PRESENTATION: Our patient is a 2 year old male with hypotonia, global developmental delay, and focal epilepsy. Trio whole-exome sequencing revealed heterozygous variants in PIGN, c.181G > T (p.Glu61*) and c.284G > A (p.Arg95Gln). Analysis of FLAER and anti-CD59 by flow-cytometry demonstrated a shift in this patient's granulocytes, confirming a glycosylphosphatidylinositol-biosynthesis defect, consistent with PIGN-related disease. CONCLUSIONS: To date, a total of 18 patients have been reported, all but 2 of whom have congenital anomalies and/or obvious dysmorphic features. Our patient has no significant dysmorphic features or multiple congenital anomalies, which is consistent with recent reports linking non-truncating variants with a milder phenotype, highlighting the importance of functional studies in interpreting sequence variants.

A patient with polymerase E1 deficiency (POLE1): clinical features and overlap with DNA breakage/instability syndromes.

BACKGROUND: Chromosome instability syndromes are a group of inherited conditions associated with chromosomal instability and breakage, often leading to immunodeficiency, growth retardation and increased risk of malignancy. CASE PRESENTATION: We performed exome sequencing on a girl with a suspected chromosome instability syndrome that manifested as growth retardation, microcephaly, developmental delay, dysmorphic features, poikiloderma, immune deficiency with pancytopenia, and myelodysplasia. She was homozygous for a previously reported splice variant, c.4444 + 3A > G in the POLE1 gene, which encodes the catalytic subunit of DNA polymerase E. CONCLUSION: This is the second family with POLE1-deficency, with the affected individual demonstrating a more severe phenotype than previously described.

Family history and clefting as major criteria for CHARGE syndrome.

CHARGE syndrome is an autosomal dominant malformation syndrome associated with mutations in CHD7. The condition is typically sporadic with few familial cases reported. The diagnosis of CHARGE syndrome is based on a combination of major and minor criteria comprised of structural and functional abnormalities, most of which are part of the original CHARGE acronym, although additional anomalies have been added. To date, family history has not been considered in the diagnostic criteria. Here we report a family with a previously unreported missense mutation in exon 31 of CHD7, in which family history played a role in the diagnosis of CHARGE syndrome. Given the tremendous phenotypic variability and the dominant nature of CHARGE syndrome, we propose that family history be included as a major diagnostic criterion. A positive family history would include any individual with an apparently isolated unilateral major CHARGE anomaly or someone with a few of the minor features. Our cases support this proposal; had family history not been considered in this case, CHD7 testing might not have been pursued, leading to incomplete medical follow-up and erroneous genetic counseling. Additionally, with the increased incidence of orofacial clefting in this family, as well as in the literature, we suggest that cleft lip and/or palate be added to the major diagnostic criteria for CHARGE syndrome.

Mindfulness-based interventions for cancer-related pain and depression: a narrative review of current evidence and future potential.

PURPOSE OF REVIEW: People with cancer commonly experience persistent pain and psychological distress. Interventions are needed which address the multifactorial nature of pain and depression, yet few studies have examined the impact of mindfulness-based interventions (MBIs) for cancer-related pain and depression. RECENT FINDINGS: MBIs for cancer-related pain and depression can be effectively delivered across a range of modalities and show promise for alleviating mood and some physical health symptoms, although not always pain. There is some evidence for the cost-effectiveness of MBIs. SUMMARY: The field of MBIs would benefit from greater methodological rigour and investigation into a broader range of cancer populations to increase the knowledge base and in turn the evidence base on which interventions can be developed to the benefit to patients with cancer-related pain and depression.