Muscular dystrophies and myopathies: the spectrum of mutated genes in the Czech Republic

Inherited neuromuscular disorder (NMD) is a wide term covering different genetic disorders affecting muscles, nerves, and neuromuscular junctions. Genetic and clinical heterogeneity is the main drawback in a routine gene‐by‐gene diagnostics. We present Czech NMD patients with a genetic cause identified using targeted next‐generation sequencing (NGS) and the spectrum of these causes. Overall 167 unrelated patients presenting NMD falling into categories of muscular dystrophies, congenital muscular dystrophies, congenital myopathies, distal myopathies, and other myopathies were tested by targeted NGS of 42 known NMD‐related genes. Pathogenic or probably pathogenic sequence changes were identified in 79 patients (47.3%). In total, 37 novel and 51 known disease‐causing variants were detected in 23 genes. In addition, variants of uncertain significance were suspected in 7 cases (4.2%), and in 81 cases (48.5%) sequence changes associated with NMD were not found. Our results strongly indicate that for molecular diagnostics of heterogeneous disorders such as NMDs, targeted panel testing has a high‐clinical yield and should therefore be the preferred first‐tier approach. Further, we show that in the genetic diagnostic practice of NMDs, it is necessary to take into account different types of inheritance including the occurrence of an autosomal recessive disorder in two generations of one family.     

Functional and isokinetic assessment of muscle strength in patients with idiopathic inflammatory myopathies

OBJECTIVE: To assess muscle strength in patients with idiopathic inflammatory myopathies (IIM) using neuromuscular scales and isokinetic testing. METHODS: Muscle function was evaluated in 27 IIM patients being followed at the Rheumatology Unit of the University of Pisa using: (i) a modified version of the grading system used to assess Duchenne dystrophy, (ii) the four-stage grading system of Henriksson and Sandstedt, (iii) an isokinetic muscle strength test (Kin Com, Chatanooga) and (iv) the Health Assessment Questionnaire (HAQ). RESULTS: The neuromuscular scales showed normal or only mildly impaired muscle strength in 60% (Duchenne scale) and 80% (Henriksson and Sandstedt scale) of the patients, respectively, whereas isokinetic testing detected moderate to severe reductions in muscle strength in almost 70% of the patients. No correlations were observed between muscle strength and disease activity, therapy, age at evaluation and disease duration. There was a correlation between the results of the HAQ and neuromuscular testing, but not the isokinetic test. CONCLUSIONS: Although less easy and more expensive to administer, isokinetic testing appears to be a more sensitive instrument than the standard neuromuscular tests for assessing muscle function in IIM patients. In particular, it can detect small reductions in muscle strength.     

Functional and isokinetic assessment of muscle strength in patients with idiopathic inflammatory myopathies

Objective: To assess muscle strength in patients with idiopathic inflammatory myopathies (IIM) using neuromuscular scales and isokinetic testing.

Methods: Muscle function was evaluated in 27 IIM patients being followed at the Rheumatology Unit of the University of Pisa using: (i) a modified version of the grading system used to assess Duchenne dystrophy, (ii) the four-stage grading system of Henriksson and Sandstedt, (iii) an isokinetic muscle strength test (Kin Com, Chatanooga) and (iv) the Health Assessment Questionnaire (HAQ).

Results: The neuromuscular scales showed normal or only mildly impaired muscle strength in 60% (Duchenne scale) and 80% (Henriksson and Sandstedt scale) of the patients, respectively, whereas isokinetic testing detected moderate to severe reductions in muscle strength in almost 70% of the patients. No correlations were observed between muscle strength and disease activity, therapy, age at evaluation and disease duration. There was a correlation between the results of the HAQ and neuromuscular testing, but not the isokinetic test.

Conclusions: Although less easy and more expensive to administer, isokinetic testing appears to be a more sensitive instrument than the standard neuromuscular tests for assessing muscle function in IIM patients. In particular, it can detect small reductions in muscle strength.     

Outcomes of prior authorization requests for genetic testing in outpatient pediatric genetics clinics

PurposeGenetic testing is an important diagnostic tool in pediatric genetics clinics, yet many patients face barriers to testing. We describe the outcomes of prior authorization requests (PARs) for genetic tests, one indicator of patient access to clinically recommended testing, in pediatric genetics clinics.MethodsWe retrospectively reviewed PARs for genetic tests (n = 4,535) recommended for patients <18 years of age (n = 2,798) by pediatric medical geneticists at two children’s hospitals in Texas, 2017–2018. We described PAR outcomes, accompanying diagnostic codes, and diagnostic yield.ResultsThe majority (79.9%) of PARs received a favorable outcome. PARs submitted to public payers were more likely to receive a favorable outcome compared with private payers (85.5% vs. 70.3%, respectively; p < 0.001). No diagnostic codes were associated with higher likelihood of PAR approval for exome sequencing. Among the 2,685 tests approved and completed, 522 (19.4%) resulted in a diagnosis.ConclusionThough there was a high PAR approval rate, our findings suggest that insurance coverage remains one barrier to genetic testing. When completed, genetic testing had a high yield in our sample. Further evidence of clinical utility and development of clinical practice guidelines may inform payer medical policy development and improve access to testing in the future.     

Clinical utility of genetic testing in 201 preschool children with inherited eye disorders

PurposeA key property to consider in all genetic tests is clinical utility, the ability of the test to influence patient management and health outcomes. Here we assess the current clinical utility of genetic testing in diverse pediatric inherited eye disorders (IEDs).MethodsTwo hundred one unrelated children (0–5 years old) with IEDs were ascertained through the database of the North West Genomic Laboratory Hub, Manchester, UK. The cohort was collected over a 7-year period (2011–2018) and included 74 children with bilateral cataracts, 8 with bilateral ectopia lentis, 28 with bilateral anterior segment dysgenesis, 32 with albinism, and 59 with inherited retinal disorders. All participants underwent panel-based genetic testing.ResultsThe diagnostic yield of genetic testing for the cohort was 64% (ranging from 39% to 91% depending on the condition). The test result led to altered management (including preventing additional investigations or resulting in the introduction of personalized surveillance measures) in 33% of probands (75% for ectopia lentis, 50% for cataracts, 33% for inherited retinal disorders, 7% for anterior segment dysgenesis, 3% for albinism).ConclusionGenetic testing helped identify an etiological diagnosis in the majority of preschool children with IEDs. This prevented additional unnecessary testing and provided the opportunity for anticipatory guidance in significant subsets of patients.     

A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology

PurposeImplementation of novel genetic diagnostic tests is generally driven by technological advances because they promise shorter turnaround times and/or higher diagnostic yields. Other aspects, including impact on clinical management or cost-effectiveness, are often not assessed in detail prior to implementation.MethodsWe studied the clinical utility of whole-exome sequencing (WES) in complex pediatric neurology in terms of diagnostic yield and costs. We analyzed 150 patients (and their parents) presenting with complex neurological disorders of suspected genetic origin. In a parallel study, all patients received both the standard diagnostic workup (e.g., cerebral imaging, muscle biopsies or lumbar punctures, and sequential gene-by-gene–based testing) and WES simultaneously.ResultsOur unique study design allowed direct comparison of diagnostic yield of both trajectories and provided insight into the economic implications of implementing WES in this diagnostic trajectory. We showed that WES identified significantly more conclusive diagnoses (29.3%) than the standard care pathway (7.3%) without incurring higher costs. Exploratory analysis of WES as a first-tier diagnostic test indicates that WES may even be cost-saving, depending on the extent of other tests being omitted.ConclusionOur data support such a use of WES in pediatric neurology for disorders of presumed genetic origin.Genet Med advance online publication 23 March 2017     

Diagnosing,discarding, or de-VUSsing: A practical guide to (un)targeted metabolomics as variant-transcending functional tests

PurposeFor patients with inherited metabolic disorders (IMDs), any diagnostic delay should be avoided because early initiation of personalized treatment could prevent irreversible health damage. To improve diagnostic interpretation of genetic data, gene function tests can be valuable assets. For IMDs, variant-transcending functional tests are readily available through (un)targeted metabolomics assays. To support the application of metabolomics for this purpose, we developed a gene-based guide to select functional tests to either confirm or exclude an IMD diagnosis.MethodsUsing information from a diagnostic IMD exome panel, Kyoto Encyclopedia of Genes and Genomes, and Inborn Errors of Metabolism Knowledgebase, we compiled a guide for metabolomics-based gene function tests. From our practical experience with this guide, we retrospectively selected illustrative cases for whom combined metabolomic/genomic testing improved diagnostic success and evaluated the effect hereof on clinical management.ResultsThe guide contains 2047 metabolism-associated genes for which a validated or putative variant-transcending gene function test is available. We present 16 patients for whom metabolomic testing either confirmed or ruled out the presence of a second pathogenic variant, validated or ruled out pathogenicity of variants of uncertain significance, or identified a diagnosis initially missed by genetic analysis.ConclusionMetabolomics-based gene function tests provide additional value in the diagnostic trajectory of patients with suspected IMD by enhancing and accelerating diagnostic success.     

Grading quality of evidence and strength of recommendations in clinical practice guidelines: Part 2 of 3. The GRADE approach to grading quality of evidence about diagnostic tests and strategies

The GRADE approach to grading the quality of evidence and strength of recommendations provides a comprehensive and transparent approach for developing clinical recommendations about using diagnostic tests or diagnostic strategies. Although grading the quality of evidence and strength of recommendations about using tests shares the logic of grading recommendations for treatment, it presents unique challenges. Guideline panels and clinicians should be alert to these special challenges when using the evidence about the accuracy of tests as the basis for clinical decisions. In the GRADE system, valid diagnostic accuracy studies can provide high quality evidence of test accuracy. However, such studies often provide only low quality evidence for the development of recommendations about diagnostic testing, as test accuracy is a surrogate for patient-important outcomes at best. Inferring from data on accuracy that using a test improves outcomes that are important to patients requires availability of an effective treatment, improved patients' wellbeing through prognostic information, or – by excluding an ominous diagnosis – reduction of anxiety and the opportunity for earlier search for an alternative diagnosis for which beneficial treatment can be available. Assessing the directness of evidence supporting the use of a diagnostic test requires judgments about the relationship between test results and patient-important consequences. Well-designed and conducted studies of allergy tests in parallel with efforts to evaluate allergy treatments critically will encourage improved guideline development for allergic diseases.     

Differential use of available genetic tests among primary care physicians in the United States: results of a national survey

PurposeThis study assesses primary care physicians' experience ordering and referring patients for genetic testing, and whether minority-serving physicians are less likely than those serving fewer minorities to offer such services.MethodsSurvey of a random sample of 2000 primary care physicians in the United States (n = 1120, 62.3% response rate based on eligible respondents) conducted in 2002 to assess what proportion have (1) ever ordered a genetic test in general or for select conditions; (2) ever referred a patient for genetic testing to a genetics center or counselor, a specialist, a clinical research trial, or to any site of care.ResultsNationally, 60% of primary care physicians have ordered a genetic test and 74% have referred a patient for genetic testing. Approximately 62% of physicians have referred a patient for genetic testing to a genetics center/counselor or to a specialist, and 17% to a clinical trial. Minority-serving physicians were significantly less likely to have ever ordered a genetic test for breast cancer, colorectal cancer, or Huntington disease, or to have ever referred a patient for genetic testing relative to those serving fewer minorities.ConclusionsReduced utilization of genetic tests/referrals among minority-serving physicians emphasizes the importance of tracking the diffusion of genomic medicine and assessing the potential impact on health disparities.     

Proband-only medical exome sequencing as a cost-effective first-tier genetic diagnostic test for patients without prior molecular tests and clinical diagnosis in a developing country: the China experience

PurposeTo evaluate the performance of proband-only medical exome sequencing (POMES) as a cost-effective first-tier diagnostic test for pediatric patients with unselected conditions.MethodsA total of 1,323 patients were tested by POMES, which targeted 2,742 known disease-causing genes. Clinical relevant variants were Sanger-confirmed in probands and parents. We assessed the diagnostic validity and clinical utility of POMES by means of a survey questionnaire.ResultsPOMES, ordered by 136 physicians, identified 512 pathogenic or likely pathogenic variants associated with over 200 conditions. The overall diagnostic rate was 28.8%, ranging from 10% in neonatal intensive care unit patients to over 35% in pediatric intensive care unit patients. The test results had an impact on the management of the 45.1% of patients for whom there were positive findings. The average turnaround time was 57 days; the cost was $360/case.ConclusionWe adopted a relatively efficient and cost-effective approach in China for the molecular diagnosis of pediatric patients with suspected genetic conditions. While training for clinical geneticists and other specialists is lagging behind in China POMES is serving as a diagnostic equalizer for patients who do not normally receive extensive clinical evaluation and clinical diagnosis prior to testing. This Chinese experience should be applicable to other developing countries that are lacking clinical, financial, and personnel resources.     

Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives

Summary of RecommendationsThe Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found sufficient evidence to recommend offering genetic testing for Lynch syndrome to individuals with newly diagnosed colorectal cancer to reduce morbidity and mortality in relatives. We found insufficient evidence to recommend a specific genetic testing strategy among the several examined.RationaleGenetic testing to detect Lynch syndrome in individuals with newly diagnosed colorectal cancer (CRC) is proposed as a strategy to reduce CRC morbidity and mortality in their relatives (see Clinical Considerations section for definition of Lynch syndrome). The EGAPP Working Group (EWG) constructed a chain of evidence that linked genetic testing for Lynch syndrome in patients with newly diagnosed CRC with improved health outcomes in their relatives. We found that assessing patients who have newly diagnosed CRC with a series of genetic tests could lead to the identification of Lynch syndrome. Relatives of patients with Lynch syndrome could then be offered genetic testing, and, where indicated, colorectal, and possibly endometrial, cancer surveillance, with the expectation of improved health outcome. The EWG concluded that there is moderate certainty that such a testing strategy would provide moderate population benefit.Analytic ValidityThe EWG found adequate evidence to conclude that the analytic sensitivity and specificity for preliminary and diagnostic tests were high.Clinical ValidityAfter accounting for the specific technologies and numbers of markers used, the EWG found at least adequate evidence to describe the clinical sensitivity and specificity for three preliminary tests, and for four selected testing strategies. These measures of clinical validity varied with each test and each strategy (see Clinical Considerations section).Clinical UtilityThe EWG found adequate evidence for testing uptake rates, adherence to recommended surveillance activities, number of relatives approachable, harms associated with additional follow-up, and effectiveness of routine colonoscopy. This chain of evidence supported the use of genetic testing strategies to reduce morbidity/mortality in relatives with Lynch syndrome. Several genetic testing strategies were potentially effective, but none was clearly superior. The evidence for or against effectiveness of identifying mismatch repair (MMR) gene mutations in reducing endometrial cancer morbidity or mortality was inadequate.Contextual IssuesCRC is a common disease responsible for an estimated 52,000 deaths in the United States in 2007. In about 3% of newly diagnosed CRC, the underlying cause is a mutation in a MMR gene (Lynch syndrome) that can be reliably identified with existing laboratory tests. Relatives inheriting the mutation have a high (about 45% by age 70) risk of developing CRC. Evidence suggests these relatives will often accept testing and increased surveillance.     

Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene,gene panel,or exome/genome sequencing

Next-generation sequencing is changing the paradigm of clinical genetic testing. Today there are numerous molecular tests available, including single-gene tests, gene panels, and exome sequencing or genome sequencing. As a result, ordering physicians face the conundrum of selecting the best diagnostic tool for their patients with genetic conditions. Single-gene testing is often most appropriate for conditions with distinctive clinical features and minimal locus heterogeneity. Next-generation sequencing–based gene panel testing, which can be complemented with array comparative genomic hybridization and other ancillary methods, provides a comprehensive and feasible approach for heterogeneous disorders. Exome sequencing and genome sequencing have the advantage of being unbiased regarding what set of genes is analyzed, enabling parallel interrogation of most of the genes in the human genome. However, current limitations of next-generation sequencing technology and our variant interpretation capabilities caution us against offering exome sequencing or genome sequencing as either stand-alone or first-choice diagnostic approaches. A growing interest in personalized medicine calls for the application of genome sequencing in clinical diagnostics, but major challenges must be addressed before its full potential can be realized. Here, we propose a testing algorithm to help clinicians opt for the most appropriate molecular diagnostic tool for each scenario.Genet Med17 6, 444–451.     

Insurance denials and diagnostic rates in a pediatric genomic research cohort

PurposeThis 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.MethodsAnalysis 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.ResultsOf 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).ConclusionMany 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.     

US physicians' attitudes toward genetic testing for cancer susceptibility

Genetic testing for an inherited susceptibility to cancer is an emerging technology in medical practice. Little information is currently available about physicians' attitudes toward these tests. To assess US physicians' opinions on unresolved issues surrounding genetic testing, a 15-min survey was administered to a stratified random sample of 1,251 physicians from 8 specialties, selected from a file of all licensed physicians in the US (response rate = 71.0%). Dependent measures included physicians' attitudes toward genetic counseling and testing qualifications, availability of guidelines, patient confidentiality and insurance discrimination issues, and clinical utility of genetic tests. More than 89% of physicians reported a need for physician guidelines, 81% thought that patients with positive genetic test results are at risk for insurance discrimination, and more than 53% thought that it was difficult to ensure the confidentiality of test results. Almost 25% indicated that genetic tests for cancer susceptibility have too many inaccurate or ambiguous results; nearly 75% thought that clear guidelines are not available for managing patients with positive test results. Only 29% of physicians reported feeling qualified to provide genetic counseling to their patients. More than 84% of oncologists considered themselves qualified to recommend genetic testing to their patients compared with 40% of primary care physicians (PCPs), and 57% of tertiary care physicians (TCPs). US physicians expressed great uncertainty about issues surrounding genetic testing for cancer susceptibility. Results of this national survey underscore the need to provide physicians with clear guidelines on the use of genetic cancer susceptibility tests and effective medical training on their appropriate implementation.     

Ambiguous genitalia: what prenatal genetic testing is practical?

Concern for ambiguous genitalia or chromosome-phenotype discordance detected in a prenatal setting has increased over the last two decades. Practitioners faced with this prenatal finding have a variety of genetic tests available to them; however, it is unclear to what extent prenatal testing for disorders of sex development (DSD) is useful or practical. We undertook a retrospective review of the medical records of 140 individuals evaluated through the DSD clinic at Seattle Children's Hospital with birthdates from 01/01/1994 through 08/16/2011 to determine the rate of prenatal detection of ambiguous genitalia in individuals with DSD, what prenatal diagnostic workup was undertaken, and the postnatal outcome, including whether a postnatal genetic diagnosis was confirmed. Of all 140 subjects, 34 (24%) were identified prenatally. The most common postnatal diagnoses were penoscrotal hypospadias with transposition of the scrotum with no known genetic cause (24/140; 17%) and 21-hydroxylase deficiency (20/140; 14%). Apart from these, no single diagnosis comprised more than a few cases. Prenatal diagnostic testing varied widely, from no tests to multiple molecular tests with amniotic fluid hormone concentrations. In the absence of other fetal anomalies or growth retardation on ultrasound, prenatal karyotype with fluorescence in situ hybridization for the SRY gene is the most useful test when ambiguous genitalia is suspected. Further prenatal testing for Smith-Lemli-Opitz syndrome in 46,XY individuals and congenital adrenal hyperplasia in 46,XX individuals may be considered. However, targeted molecular testing for rare DSD conditions in the absence of a family history of DSD has a low yield.     

Predictive,pre-natal and diagnostic genetic testing for Huntington's disease: the experience in Canada from 1987 to 2000

Predictive and pre-natal testing for Huntington's Disease (HD) has been available since 1987. Initially this was offered by linkage analysis, which was surpassed by the advent of the direct mutation test for HD in 1993. Direct mutation analysis provided an accurate test that not only enhanced predictive and pre-natal testing, but also permitted the diagnostic testing of symptomatic individuals. The objective of this study was to investigate the uptake, utilization, and outcome of predictive, pre-natal and diagnostic testing in Canada from 1987 to April 1, 2000. A retrospective design was used; all Canadian medical genetics centres and their affiliated laboratories offering genetic testing for HD were invited to participate. A total of 15 of 22 centres (68.2%), currently offering or ever having offered genetic testing for HD, responded, providing data on test results, demographics, and clinical history. A total of 1061 predictive tests, 15 pre-natal tests, and 626 diagnostic tests were performed. The uptake for predictive testing was approximately 18% of the estimated at-risk Canadian population, ranging from 12.5% in the Maritimes to 20.7% in British Columbia. There appears to have been a decline in the rate of testing in recent years. Of the predictive tests, 45.0% of individuals were found to have an increased risk, and a preponderance of females (60.2%) sought testing. A greater proportion of those at < or = 25% risk sought predictive testing once direct CAG mutation analysis had become available (10.9% after mutation analysis vs 4.7% before mutation analysis, p = 0.0077). Very few pre-natal tests were requested. Of the 15 pre-natal tests, 12 had an increased risk, resulting in termination of pregnancy in all but one. Diagnostic testing identified 68.5% of individuals to be positive by mutation analysis, while 31.5% of those with HD-like symptoms were not found to have the HD mutation. The positive diagnostic tests included 24.5% of individuals with no known prior family history of HD.     

Patients’ understanding of and responses to multiplex genetic susceptibility test results

PurposeExamination of patients’ responses to direct-to-consumer genetic susceptibility tests is needed to inform clinical practice. This study examined patients’ recall and interpretation of, and responses to, genetic susceptibility test results provided directly by mail.MethodsThis observational study had three prospective assessments (before testing, 10 days after receiving results, and 3 months later). Participants were 199 patients aged 25–40 years who received free genetic susceptibility testing for eight common health conditions.ResultsMore than 80% of the patients correctly recalled their results for the eight health conditions. Patients were unlikely to interpret genetic results as deterministic of health outcomes (mean = 6.0, s.d. = 0.8 on a scale of 1–7, 1 indicating strongly deterministic). In multivariate analysis, patients with the least deterministic interpretations were white (P = 0.0098), more educated (P = 0.0093), and least confused by results (P = 0.001). Only 1% talked about their results with a provider.ConclusionFindings suggest that most patients will correctly recall their results and will not interpret genetics as the sole cause of diseases. The subset of those confused by results could benefit from consultation with a health-care provider, which could emphasize that health habits currently are the best predictors of risk. Providers could leverage patients’ interest in genetic tests to encourage behavior changes to reduce disease risk.Genet Med advance online publication 5 April 2012     

Improved diagnostic yield of neuromuscular disorders applying clinical exome sequencing in patients arising from a consanguineous population

Neuromuscular diseases (NMDs) include a broad range of disorders affecting muscles, nerves and neuromuscular junctions. Their overlapping phenotypes and heterogeneous genetic nature have created challenges in diagnosis which calls for the implementation of massive parallel sequencing as a candidate strategy to increase the diagnostic yield. In this study, total of 45 patients, mostly offspring of consanguineous marriages were examined using whole exome sequencing. Data analysis was performed to identify the most probable pathogenic rare variants in known NMD genes which led to identification of causal variants for 33 out of 45 patients (73.3%) in the following known genes: CAPN3, Col6A1, Col6A3, DMD, DYSF, FHL1, GJB1, ISPD, LAMA2, LMNA, PLEC1, RYR1, SGCA, SGCB, SYNE1, TNNT1 and 22 novel pathogenic variants were detected. Today, the advantage of whole exome sequencing in clinical diagnostic strategies of heterogeneous disorders is clear. In this cohort, a diagnostic yield of 73.3% was achieved which is quite high compared to the overall reported diagnostic yield of 25% to 50%. This could be explained by the consanguineous background of these patients and is another strong advantage of offering clinical exome sequencing in diagnostic laboratories, especially in populations with high rate of consanguinity.     

Chromosomal microarray impacts clinical management

Chromosomal microarray analysis (CMA) is standard of care, first‐tier clinical testing for detection of genomic copy number variation among patients with developmental disabilities. Although diagnostic yield is higher than traditional cytogenetic testing, management impact has not been well studied. We surveyed genetic services providers regarding CMA ordering practices and perceptions about reimbursement. Lack of insurance coverage because of perceived lack of clinical utility was cited among the most frequent reasons why CMA was not ordered when warranted. We compiled a list of genomic regions where haploinsufficiency or triplosensitivity cause genetic conditions with documented management recommendations, estimating that at least 146 conditions potentially diagnosable by CMA testing have published literature supporting specific clinical management implications. Comparison with an existing clinical CMA database to determine the proportion of cases involving these regions showed that CMA diagnoses associated with such recommendations are found in approximately 7% of all cases (n = 28,526). We conclude that CMA impacts clinical management at a rate similar to other genetic tests for which insurance coverage is more readily approved. The information presented here can be used to address barriers that continue to contribute to inequities in patient access and care in regard to CMA testing.