The current landscape of genetic test stewardship: A multi-center prospective study.

Genetic counselors (GCs) play a pivotal role in selecting clinically appropriate and cost-effective genetic testing. Several single-institution reports over the past decade provide evidence of the value GCs bring to this stewardship role across diverse settings in healthcare, including hospital laboratories, commercial laboratories, and insurance companies. This multi-center, prospective, and quantitative study describes the outcomes of GC review of genetic test requests over a four-week period at six hospital laboratories and three commercial laboratories, thus expanding our understanding of this emerging specialty in the genetic counseling field. This study also highlights the added value of utilizing GC expertise in stewardship efforts, namely selecting the most appropriate genetic testing and realizing significant cost savings. GC review of genetic test requests led to an average order modification rate of 22%-25%. It also resulted in significant cost savings to institutions. The projected average annual savings after GC review of genetic test requests approximated $665,600 for hospital laboratories and $1,651,000 for commercial laboratories. These study findings demonstrate the significant value of GC-led genetic test stewardship programs, allow for comparisons across institutions currently performing genetic test stewardship, and support the implementation of a GC-led stewardship program at institutions who currently do not have one.

Single-nucleotide polymorphism arrays and unexpected consanguinity: considerations for clinicians when returning results to families.

PURPOSE: The broad use of single-nucleotide polymorphism microarrays has increased identification of unexpected consanguinity. Therefore, guidelines to address reporting of consanguinity have been published for clinical laboratories. Because no such guidelines for clinicians exist, we describe a case and present recommendations for clinicians to disclose unexpected consanguinity to families. METHODS: In a boy with multiple endocrine abnormalities and structural birth defects, single-nucleotide polymorphism array analysis revealed ~23% autosomal homozygosity suggestive of a first-degree parental relationship. We assembled an interdisciplinary health-care team, planned the most appropriate way to discuss results of the single-nucleotide polymorphism array with the adult mother, including the possibility of multiple autosomal recessive disorders in her child, and finally met with her as a team. RESULTS: From these discussions, we developed four major considerations for clinicians returning results of unexpected consanguinity, all guided by the child's best interests: (i) ethical and legal obligations for reporting possible abuse, (ii) preservation of the clinical relationship, (iii) attention to justice and psychosocial challenges, and (iv) utilization of the single-nucleotide polymorphism array results to guide further testing. CONCLUSION: As single-nucleotide polymorphism arrays become a common clinical diagnostic tool, clinicians can use this framework to return results of unexpected consanguinity to families in a supportive and productive manner.

Practices and policies of clinical exome sequencing providers: analysis and implications.

Exome and whole genome sequencing (ES/WGS) offer potential advantages over traditional approaches to diagnostic genetic testing. Consequently, use of ES/WGS in clinical settings is rapidly becoming commonplace. Yet there are myriad moral, ethical, and perhaps legal implications attached to the use of ES and health care professionals and institutions will need to consider these implications in the context of the varied practices and policies of ES service providers. We developed "core elements" of content and procedures for informed consent, data sharing, and results management and a quantitative scale to assess the extent to which research protocols met the standards established by these core elements. We then used these tools to evaluate the practices and policies of each of the 6 U.S. CLIA-certified labs offering clinical ES. Approaches toward informed consent, data sharing, and results return vary widely among ES providers as do the overall potential merits and disadvantages of each, and more importantly, the balance between the two.

Evaluation of Exome Sequencing Criteria for Hospital Stewardship and Insurance Authorization at a Pediatric Hospital.

CONTEXT.­: Genomic molecular testing practices in a pediatric tertiary care institution can vary in utility by patient indication. OBJECTIVE.­: To evaluate exome sequencing (ES) ordering practices and the effects of applying criteria to support ES stewardship. Exome sequencing can provide molecular diagnostic information for patients with known or suspected genetic diseases, but it is relatively expensive, and the cost is often borne by patients, institutions, and payers. DESIGN.­: We examined ordering patterns of ES approved by board-certified geneticists at our tertiary pediatric care center, as well as preauthorization outcomes for ES requests. We compared positivity rates among patients by patient phenotype, composite insurance coverage criteria, and insurance preauthorization outcome. RESULTS.­: Patients who met composite coverage criteria were more likely to receive a positive result from ES compared to patients who did not meet composite coverage criteria, though this trend was not statistically significant. There was no significant difference in ES results between patients who were denied or not denied preauthorization by insurance payers. CONCLUSIONS.­: Insurance payers should consider implementing and/or expanding coverage criteria for ES, and institutions should implement stewardship programs to support appropriate ES practices.

Preventing Genetic Testing Order Errors With a Laboratory Utilization Management Program.

OBJECTIVES: To characterize error rates for genetic test orders between medical specialties and in different settings by examining detailed order information. METHODS: We performed a retrospective analysis of a detailed utilization management case database, comprising 2.5 years of data and almost 1,400 genetic test orders. After review by multiple reviewers, we categorized order modifications and cancellations, quantified rates of positive results and order errors, and compared genetics with nongenetics providers and inpatient with outpatient orders. RESULTS: High cost or problems with preauthorization were the most common reasons for modification and cancellation, respectively. The cancellation rate for nongenetics providers was three times the rate for geneticists, but abnormal result rates were similar between the two groups. The approval rate for inpatient orders was not significantly lower than outpatient orders, and abnormal result rates were similar for these two groups as well. Order error rates were approximately 8% among tests recommended by genetics providers in the inpatient setting, and tests ordered or recommended by nongeneticists had error rates near 5% in both inpatient and outpatient settings. CONCLUSIONS: Clinicians without specialty training in genetics make genetic test order errors at a significantly higher rate than geneticists. A laboratory utilization management program prevents these order errors from becoming diagnostic errors and reaching the patient.

The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant.

The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.

Genetic testing utilization and the role of the laboratory genetic counselor.

Laboratory genetic counselors within hospital laboratories and genetic testing laboratories have an important role in increasing the appropriate utilization of genetic tests. This service is becoming more important as genetic testing becomes more complex and the demand for genetic testing in healthcare increases. Additionally genetic tests are among the most expensive assays in the clinical laboratory test catalog. Laboratory genetic counselors are able to increase genetic test utilization through review and assessment of the appropriateness of the ordered testing, developing protocols, and by increasing communication with ordering providers.

Improving the value of costly genetic reference laboratory testing with active utilization management.

CONTEXT: Tests that are performed outside of the ordering institution, send-out tests, represent an area of risk to patients because of complexity associated with sending tests out. Risks related to send-out tests include increased number of handoffs, ordering the wrong or unnecessary test, specimen delays, data entry errors, preventable delays in reporting and acknowledging results, and excess financial liability. Many of the most expensive and most misunderstood tests are send-out genetic tests. OBJECTIVE: To design and develop an active utilization management program to reduce the risk to patients and improve value of genetic send-out tests. DESIGN: Send-out test requests that met defined criteria were reviewed by a rotating team of doctoral-level consultants and a genetic counselor in a pediatric tertiary care center. RESULTS: Two hundred fifty-one cases were reviewed during an 8-month period. After review, nearly one-quarter of genetic test requests were modified in the downward direction, saving a total of 2% of the entire send-out bill and 19% of the test requests under management. Ultimately, these savings were passed on to patients. CONCLUSIONS: Implementing an active utilization strategy for expensive send-out tests can be achieved with minimal technical resources and results in improved value of testing to patients.

A novel missense mutation in POMT1 modulates the severe congenital muscular dystrophy phenotype associated with POMT1 nonsense mutations.

Mutations in POMT1 lead to a group of neuromuscular conditions ranging in severity from Walker-Warburg syndrome to limb girdle muscular dystrophy. We report two male siblings, ages 19 and 14, and an unrelated 6-year old female with early onset muscular dystrophy and intellectual disability with minimal structural brain anomalies and no ocular abnormalities. Compound heterozygous mutations in POMT1 were identified including a previously reported nonsense mutation (c.2167dupG; p.Asp723Glyfs*8) associated with Walker-Warburg syndrome and a novel missense mutation in a highly conserved region of the protein O-mannosyltransferase 1 protein (c.1958C>T; p.Pro653Leu). This novel variant reduces the phenotypic severity compared to patients with homozygous c.2167dupG mutations or compound heterozygous patients with a c.2167dupG mutation and a wide range of other mutant POMT1 alleles.

De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot.

Tetralogy of Fallot (TOF), the most common severe congenital heart malformation, occurs sporadically, without other anomaly, and from unknown cause in 70% of cases. Through a genome-wide survey of 114 subjects with TOF and their unaffected parents, we identified 11 de novo copy number variants (CNVs) that were absent or extremely rare (<0.1%) in 2,265 controls. We then examined a second, independent TOF cohort (n = 398) for additional CNVs at these loci. We identified CNVs at chromosome 1q21.1 in 1% (5/512, P = 0.0002, OR = 22.3) of nonsyndromic sporadic TOF cases. We also identified recurrent CNVs at 3p25.1, 7p21.3 and 22q11.2. CNVs in a single subject with TOF occurred at six loci, two that encode known (NOTCH1, JAG1) disease-associated genes. Our findings predict that at least 10% (4.5-15.5%, 95% confidence interval) of sporadic nonsyndromic TOF cases result from de novo CNVs and suggest that mutations within these loci might be etiologic in other cases of TOF.