Neurodevelopmental disorders (NDDs) affect more than 3% of children and are attributable to single-gene mutations at more than 1000 loci. Traditional methods yield molecular diagnoses in less than ...one-half of children with NDD. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) can enable diagnosis of NDD, but their clinical and cost-effectiveness are unknown. One hundred families with 119 children affected by NDD received diagnostic WGS and/or WES of parent-child trios, wherein the sequencing approach was guided by acuity of illness. Forty-five percent received molecular diagnoses. An accelerated sequencing modality, rapid WGS, yielded diagnoses in 73% of families with acutely ill children (11 of 15). Forty percent of families with children with nonacute NDD, followed in ambulatory care clinics (34 of 85), received diagnoses: 33 by WES and 1 by staged WES then WGS. The cost of prior negative tests in the nonacute patients was $19,100 per family, suggesting sequencing to be cost-effective at up to $7640 per family. A change in clinical care or impression of the pathophysiology was reported in 49% of newly diagnosed families. If WES or WGS had been performed at symptom onset, genomic diagnoses may have been made 77 months earlier than occurred in this study. It is suggested that initial diagnostic evaluation of children with NDD should include trio WGS or WES, with extension of accelerated sequencing modalities to high-acuity patients.
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.
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.
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).
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.
Lysosomal storage diseases (LSDs) comprise a diverse group of over 40 clinically distinct inherited disorders. LSDs are progressive and may present at any age affecting any number of tissues and ...organ systems. They result from a genetic defect in cellular transport or metabolism of molecules within the lysosome. Treatment is directed toward symptomatic care of secondary complications for most of these diseases. For some individuals, hematopoietic stem cell transplantation or enzyme-replacement therapy can be effective. However, limitations in these therapies still exist. To date, there is no cure for any of the LSDs. Early diagnosis and treatment is essential for optimal treatment; this lends support to implementing mass newborn screening for LSDs.
Status epilepticus is not rare in critically ill intensive care unit patients, but its diagnosis is often delayed or missed. The mortality for convulsive status epilepticus is dependent on the ...underlying aetiologies and the age of the patients, and thus varies from study to study. In this context, effective molecular diagnosis in a pediatric patient with a genetically heterogeneous phenotype is essential. Homozygous or compound heterozygous variants in KPTN have been recently associated with a syndrome typified by macrocephaly, neurodevelopmental delay, and seizures. To identify the causative genetic defect in a 9 year old male with focal epilepsy, static encephalopathy, autism spectrum disorder, and macrocephaly of unknown etiology who died of status epilepticus. We describe a comprehensive investigation of a patient who was admitted to the intensive care unit. Clinical whole-genome sequencing revealed compound heterozygous variants in the KPTN gene. The first variant is a previously characterized 18-bp in-frame duplication (c.714_731dup) in exon 8, resulting in the protein change p.Met241_Gln246dup. The second variant, c.394+1G>A, affects the splice junction of exon 3. These results are consistent with a diagnosis of autosomal recessive KPTN-related disease. This is the forth clinical report for KPTN-deficiency, providing further evidence of a wider range of severity.
Primary carnitine deficiency impairs fatty acid oxidation and can result in hypoglycemia, hepatic encephalopathy, cardiomyopathy and sudden death. We diagnosed primary carnitine deficiency in six ...unrelated women whose unaffected infants were identified with low free carnitine levels (C0) by newborn screening using tandem mass spectrometry. Given the lifetime risk of morbidity or sudden death, identification of adult patients with primary carnitine deficiency is an added benefit of expanded newborn screening programs.
This study aimed to provide comprehensive diagnostic and candidate analyses in a pediatric rare disease cohort through the Genomic Answers for Kids program.
Extensive analyses of 960 families with ...suspected genetic disorders included short-read exome sequencing and short-read genome sequencing (srGS); PacBio HiFi long-read genome sequencing (HiFi-GS); variant calling for single nucleotide variants (SNV), structural variant (SV), and repeat variants; and machine-learning variant prioritization. Structured phenotypes, prioritized variants, and pedigrees were stored in PhenoTips database, with data sharing through controlled access the database of Genotypes and Phenotypes.
Diagnostic rates ranged from 11% in patients with prior negative genetic testing to 34.5% in naive patients. Incorporating SVs from genome sequencing added up to 13% of new diagnoses in previously unsolved cases. HiFi-GS yielded increased discovery rate with >4-fold more rare coding SVs compared with srGS. Variants and genes of unknown significance remain the most common finding (58% of nondiagnostic cases).
Computational prioritization is efficient for diagnostic SNVs. Thorough identification of non-SNVs remains challenging and is partly mitigated using HiFi-GS sequencing. Importantly, community research is supported by sharing real-time data to accelerate gene validation and by providing HiFi variant (SNV/SV) resources from >1000 human alleles to facilitate implementation of new sequencing platforms for rare disease diagnoses.
The nutrition guidelines for management of phenylketonuria (PKU or phenylalanine hydroxlyase PAH deficiency) are well developed. One missing component is the phenylalanine (Phe) requirements for the ...preterm infant with PAH deficiency. It has been found that preterm infants at a postmenstrual age (PMA) of 30 and 32 weeks have required a Phe intake as high as 100 mg/kg, well above the current clinical guidelines available for the term infant. Three case presentations illustrate modifications that the clinician may need to consider when caring for the preterm infant with PAH deficiency during the weeks leading up to 40 weeks of PMA.
PDF
