As early diagnosis and management of inborn errors of metabolism (IEM) improves, more individuals with these conditions are pursuing pregnancy. There is limited data and available subspecialists to guide the complex aspects that may impact such pregnancies, such as partner carrier screening, preconception counseling, metabolic management of mother and fetus during pregnancy and postpartum, pre- and postnatal diagnosis of the fetus, and labor and delivery care. Here, we provide a description of the unique clinical setup of our adult reprogenetics/genomics clinic in collaboration with pediatric genetics and metabolism (PGM) on management of the complex mother/child dyad when an inborn error of metabolism is present.

Despite recent calls to action and a heavy emphasis on timeliness of care in guidelines for common inborn errors of metabolism, there is a dearth of specific measurable quality metrics for these conditions and little to no electronic decision support for their management. We have developed a novel set of process-oriented metrics based on the aforementioned guidelines that can be calculated from data already contained in most major EHRs, which we believe are responsive to the needs of the metabolism community.

PURPOSE:To better understand health care utilization and develop decision support tools, methods for identifying patients with suspected genetic diseases (GDs) are needed. Previous studies had identified inpatient-relevant International Classification of Diseases (ICD) codes that were possibly, probably, or definitely indicative of GDs. We assessed whether these codes identified GD-related inpatient, outpatient, and emergency department encounters among pediatric patients with suspected GDs from a previous study (the North Carolina Clinical Genomic Evaluation by Next-Generation Exome Sequencing [NCGENES] study).METHODS:Using the electronic medical records of 140 pediatric patients from the NCGENES study, we characterized the presence of ICD codes representing possible, probable, or definite GD-related diagnoses across encounter types. In addition, we examined codes from encounters for which initially no GD-related codes had been found and determined whether these codes were indicative of a GD.RESULTS:Among NCGENES patients with visits between 2014 and 2017, 92% of inpatient, 75% of emergency department, and 63% of outpatient encounters included ≥1 GD-related code. Encounters with highly specific (ie, definite) GD codes had fewer low-specificity GD codes than encounters with only low-specificity GD codes. We identified an additional 32 ICD-9 and 56 ICD-10 codes possibly indicative of a GD.CONCLUSION:Code-based strategies can be refined to assess health care utilization among pediatric patients and may contribute to a systematic approach to identify patients with suspected GDs.

About 95% of patients with Spinal Muscular Atrophy (SMA) have a homozygous deletion of exon 7 of SMN1. About 2-5% of patients with SMA may be compound heterozygous for a deleterious single nucleotide variant (SNV) affecting one allele and a deletion affecting the other allele. Here, we present a rare case of an infant with SMA Type 0 with a single homozygous, previously reported, likely pathogenic NM_000344.4(SMN1):c.796T>C variant affecting both copies of SMN1. A term African-American male born at 38 weeks via spontaneous vaginal delivery was transferred from an outside hospital at 11 weeks of life for diffuse hypotonia and ventilator dependence. APGARs after birth were 5 and 6, and he required positive pressure in the delivery room. He continued to receive continuous positive pressure, eventually requiring intubation at 2 weeks of life for poor respiratory effort. MRI imaging showed T2 hyperintense signal within the dorsolateral aspects of the upper cervical spinal cord, and electrodiagnostic testing was notable for a severe, generalized, sensory-motor polyneuropathy. Extensive genetic workup was performed, including karyotype, microarray, acylcarnitine profile, Angelman/Prader-Willi methylation analysis, DPMK repeat expansion analysis, a next-generation sequencing-based hypotonia panel, exome sequencing, and SMN1 copy number testing. All testing was non-diagnostic. On transfer to UNC, genetics was consulted, and a muscle biopsy was performed which showed denervation atrophy. Given the physical exam findings, muscle biopsy results, and the knowledge that SMN1 copy number testing may miss 5% of cases, copy number and gene sequencing of SMN1 was sent. This showed 2 copies of SMN1, 1 copy of SMN2, and a NM_000344.4(SMN1):c.796T>Cvariant of uncertain significance which was unable to be localized to SMN1 or SMN2. Thus, additional testing was sent to Mayo Clinic, which performed SMN1-specific amplification using PCR. This demonstrated that the NM_000344.4(SMN1):c.796T>Cvariant was present in both copies of SMN1, and was deemed Likely Pathogenic. In addition, a NM_000344.3(SMN1):c.*3+80T>G ) single nucleotide polymorphism (SNP) was identified, which is associated with SMN1 [2+0] carrier status. Parental testing subsequently demonstrated that his mother had 3 copies of SMN1, a single copy of SMN2, and heterozygosity for the NM_000344.4(SMN1):c.796T>Cvariant. No NM_000344.3(SMN1):c.*3+80T>G SNP was identified. The father had 2 copies of SMN1, 1 copy of SMN2, and no sequence variants detected. Given all of this information, we suspect that our patient has 2 copies of SMN1 on one allele, both affected by a likely pathogenic missense variant, and likely has a deletion of the other allele (occurring either de-novo or inherited). There are other possible mechanisms that could explain the child's genotype as well, including a gene conversion event. Given the absence of NM_000344.3(SMN1):c.*3+80T>G in both parents, exome data was re-visited which supported the parentage assignment. At this time we do not have a confirmed explanation for the absence of NM_000344.3(SMN1):c.*3+80T>G in both parents. We present an infant with a rare form of SMA Type 0 caused by a homozygous NM_000344.4(SMN1):c.796T>Clikely pathogenic variant affecting both copies of SMN1, likely in a [2+0] configuration. This case highlights the importance of pursuing additional SMN1 gene sequencing when the physical exam unequivocally supports the diagnosis of SMA, as well as the importance of SMN1 specific amplification testing to localize variants identified. This also highlights the limitations of exome sequencing for SMA diagnosis.

OBJECTIVE:To evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs).METHODS:We performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup.RESULTS:The overall diagnostic yield of exome sequencing in our cohort was 12.9%, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. Targeted gene lists had the same diagnostic yield as a broad NMD gene list in patients with clear neuropathy or myopathy phenotypes, but evaluation of a broader set of disease genes was needed for patients with complex NMD phenotypes. Most patients with NMD had undergone prior testing, but only 10/16 (63%) of these procedures, such as muscle biopsy, were informative in pointing to a final molecular diagnosis.CONCLUSIONS:Genome-scale sequencing or analysis of a panel of relevant genes used early in the evaluation of patients with NMDs can provide or clarify a diagnosis and minimize invasive testing in many cases.

Background: The emerging dual imperatives of personalized medicine and technologic advances make population screening for preventable conditions resulting from genetic alterations a realistic possibility. Lynch syndrome is a potential screening target due to its prevalence, penetrance, and the availability of well-established, preventive interventions. However, while population screening may lower incidence of preventable conditions, implementation without evidence may lead to unintentional harms. We examined the literature to determine whether evidence exists that screening for Lynch-associated mismatch repair (MMR) gene mutations leads to improved overall survival, cancer-specific survival, or quality of life. Documenting evidence and gaps is critical to implementing genomic approaches in public health and guiding future research. Materials and methods: Our 2014–2015 systematic review identified studies comparing screening with no screening in the general population, and controlled studies assessing analytic validity of targeted next-generation sequencing, and benefits or harms of interventions or screening. We conducted meta-analyses for the association between early or more frequent colonoscopies and health outcomes. Results: Twelve studies met our eligibility criteria. No adequate evidence directly addressed the main question or the harms of screening in the general population. Meta-analyses found relative reductions of 68% for colorectal cancer incidence (relative risk: 0.32, 95% confidence interval: 0.23–0.43, three cohort studies, 590 participants) and 78% for all-cause mortality (relative risk: 0.22, 95% confidence interval: 0.09–0.56, three cohort studies, 590 participants) for early or more frequent colonoscopies among family members of people with cancer who also had an associated MMR gene mutation. Conclusion: Inadequate evidence exists examining harms and benefits of population-based screening for Lynch syndrome. Lack of evidence highlights the need for data that directly compare benefits and harms. Keywords: Lynch syndrome, systematic review, targeted next-generation sequencing, genetic screening, general population

BACKGROUND:The emerging dual imperatives of personalized medicine and technologic advances make population screening for preventable conditions resulting from genetic alterations a realistic possibility. Lynch syndrome is a potential screening target due to its prevalence, penetrance, and the availability of well-established, preventive interventions. However, while population screening may lower incidence of preventable conditions, implementation without evidence may lead to unintentional harms. We examined the literature to determine whether evidence exists that screening for Lynch-associated mismatch repair (MMR) gene mutations leads to improved overall survival, cancer-specific survival, or quality of life. Documenting evidence and gaps is critical to implementing genomic approaches in public health and guiding future research. MATERIALS AND METHODS:Our 2014-2015 systematic review identified studies comparing screening with no screening in the general population, and controlled studies assessing analytic validity of targeted next-generation sequencing, and benefits or harms of interventions or screening. We conducted meta-analyses for the association between early or more frequent colonoscopies and health outcomes. RESULTS:Twelve studies met our eligibility criteria. No adequate evidence directly addressed the main question or the harms of screening in the general population. Meta-analyses found relative reductions of 68% for colorectal cancer incidence (relative risk: 0.32, 95% confidence interval: 0.23-0.43, three cohort studies, 590 participants) and 78% for all-cause mortality (relative risk: 0.22, 95% confidence interval: 0.09-0.56, three cohort studies, 590 participants) for early or more frequent colonoscopies among family members of people with cancer who also had an associated MMR gene mutation. CONCLUSION:Inadequate evidence exists examining harms and benefits of population-based screening for Lynch syndrome. Lack of evidence highlights the need for data that directly compare benefits and harms.

There are a number of new genetic tests and a variety of recommendations for obstetrician-gynecologists. In recent years, screening of low-risk pregnant women with noninvasive prenatal testing has been proposed as well as universal BRCA1 and BRCA2 screening of all women regardless of risk status. Both proposed genetic screening tests raise complicated issues relating to predictive value, cost, and consequences after screening to both the health care system as a whole as well as serious potential adverse consequences for the patient. In addition, there are significant barriers relating to clinician education in proper use of these genetic tests as well as logistic issues of performing adequate genetic counseling in a busy general practice. We recommend that pregnant women offered noninvasive prenatal testing be informed of its advantages and disadvantages compared with standard screening with the caveat that positive noninvasive prenatal tests must be confirmed with further, invasive testing. We recommend against population genetic screening of all women for BRCA1 and BRCA2 mutations until there are comprehensive data regarding harms and benefits as well as cost-effectiveness. Finally, we recommend that new educational models for genetics be developed for obstetrics and gynecology residency training so that future health care providers will be prepared for the opportunities and challenges that genetic testing creates.

Purpose: Utilization of sequencing to screen the general population for preventable monogenic conditions is receiving substantial attention because of its potential to decrease morbidity and mortality. However, the selection of which variants to return is a serious implementation challenge. Procedures must be investigated to ensure optimal test characteristics and avoidance of harm from false-positive test results.Methods: We scanned exome sequences from 478 well-phenotyped individuals for potentially pathogenic variants in 17 genes representing 11 conditions that are among the most medically actionable Mendelian disorders in adults. We developed five variant selection algorithms with increasing sensitivity and measured their specificity in these 17 genes.Results: Variant selection algorithms with increasing sensitivity exhibited decreased specificity, and performance was highly dependent on the genes analyzed. The most sensitive algorithm ranged from 88.8 to 99.6% specificity among the 17 genes.Conclusion: For conditions with very low prevalence, small reductions in specificity greatly increase false positives. This inescapable test characteristic governs the predictive value of genomic sequencing in the general population. To address this issue, test performance must be evaluated systematically for each condition so that the false negatives and false positives can be tailored for optimal outcomes, depending on the downstream clinical consequences.

Purpose: Next-generation sequencing has transformed genetic research and is poised to revolutionize clinical diagnosis. However, the vast amount of data and inevitable discovery of incidental findings require novel analytic approaches. We therefore implemented for the first time a strategy that utilizes an a priori structured framework and a conservative threshold for selecting clinically relevant incidental findings. Methods: We categorized 2,016 genes linked with Mendelian diseases into “bins” based on clinical utility and validity, and used a computational algorithm to analyze 80 whole-genome sequences in order to explore the use of such an approach in a simulated real-world setting. Results: The algorithm effectively reduced the number of variants requiring human review and identified incidental variants with likely clinical relevance. Incorporation of the Human Gene Mutation Database improved the yield for missense mutations but also revealed that a substantial proportion of purported disease-causing mutations were misleading. Conclusion: This approach is adaptable to any clinically relevant bin structure, scalable to the demands of a clinical laboratory workflow, and flexible with respect to advances in genomics. We anticipate that application of this strategy will facilitate pretest informed consent, laboratory analysis, and posttest return of results in a clinical context. Genet Med 2013:15(1):36–44

OBJECTIVE. There is growing interest in using PET/CT for evaluating early response to therapy in cancer treatment. Although widely available and convenient to use, standardized uptake value (SUV) measurements can be influenced by a variety of biologic and technologic factors. Many of these factors can be addressed with close attention to detail and appropriate quality control. This article will review factors potentially affecting SUV measurements and provide recommendations on ways to minimize when using serial PET to assess early response to therapy.CONCLUSION. Scanner and reconstruction parameters can significantly affect SUV measurements. When using serial SUV measurements to assess early response to therapy, imaging should be performed on the same scanner using the same image acquisition and reconstruction protocols. In addition, attention to detail is required for accurate determination of the administered radiopharmaceutical dose.

DOI: 10.1097/AOG.0000000000000871 Recent advances in genomics have led to a number of new genetic tests and a variety of recommendations for providers. The American College of Obstetricians and Gynecologists (the College) released prenatal cystic fibrosis screening recommendations in 2001 followed by recommendations for hemoglobinopathy screening in 2007, BRCA1 and BRCA2 testing in 2009, carrier screening of individuals of Ashkenazi Jewish descent in 2009, screening for Fragile X in 2010, and noninvasive prenatal testing recommendations for high-risk women in 2012. In the past year, universal BRCA1 and BRCA2 screening of all women regardless of risk status has been proposed. New data regarding noninvasive prenatal testing have also been published. Because so many of these recommendations affect the practices of obstetrician–gynecologists (ob-gyns), we believe that ob-gyns should have a firm understanding of the implications of genomics and genetic testing, including the potential benefits, limitations, and costs. The proposed noninvasive prenatal testing and BRCA1 and BRCA2 screening programs would affect millions of patients. However, are ob-gyns adequately prepared to guide and counsel patients on the use of such testing? A survey of 250 ob-gyns found that 62% had ordered BRCA1 and BRCA2 testing in the past year. However, only 19% of physicians overall correctly distinguished between low-risk and high-risk scenarios for familial breast and ovarian cancer. A lack of effective genetics training in residency and beyond as well as the inherent logistic issues of performing adequate genetic counseling in a busy general practice creates challenges for the practicing ob-gyn and could create misunderstandings about the limitations of genetic screening that adversely affect patient welfare. BRCA1 and BRCA2 mutations are estimated to account for between 5% and 15% of all breast and ovarian cancers. The original data for BRCA1 and BRCA2 were derived from high-risk populations based on family history of breast and ovarian cancer, From the Department of Genetics and the Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and the Department of Obstetrics, Gynecology, and Surgery, University of Michigan, Ann Arbor, Michigan.