Genet Med Research Articles

Implementation of Population-Based Newborn Screening Reveals Low Incidence of Spinal Muscular Atrophy

(Abstracted from Genet Med 2020;22:1296–1302) Spinal muscular atrophy (SMA) is a neurodevelopmental disorder that is associated with muscle weakness and atrophy. There are several subtypes that are categorized as SMA type 1 (presenting in early infancy), where infants are unable to sit unassisted; SMA type 2 (presenting between 6 and 18 months of age), where patients are unable to walk independently; SMA type 3 (presenting after 18 months of age), where some patients were able to walk independently, but others lose this ability; and SMA type 4 (presenting in adulthood), which is rare and less severe.

Please Wait for the Host to Start This Meeting: A Push for H.R. 3235 Amid COVID-19.

Please Wait for the Host to Start This Meeting: A Push for H.R. 3235 Amid COVID-19.

COVID-19’s Impact on Genetics at One Medical Center in New York

COVID-19’s Impact on Genetics at One Medical Center in New York

Outcomes in Pregnancies With a Confined Placental Mosaicism and Implications for Prenatal Screening Using Cell-Free DNA

(Abstracted from Genet Med 2020;22:309–316) The most common type of confined placental mosaicism (CPM), the presence of a chromosomal abnormality in the placenta but not in the fetus, involves trisomy/disomy. Confined placental mosaicism occurs in 97% of rare autosomal trisomy (RAT) cases detected by chorionic villus sampling (CVS).

The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG)

The use of fetal exome sequencing in prenatal diagnosis: a points to consider document of the American College of Medical Genetics and Genomics (ACMG)

Points to consider: is there evidence to support BRCA1/2 and other inherited breast cancer genetic testing for all breast cancer patients? A statement of the American College of Medical Genetics and Genomics (ACMG)

Points to consider: is there evidence to support BRCA1/2 and other inherited breast cancer genetic testing for all breast cancer patients? A statement of the American College of Medical Genetics and Genomics (ACMG)

Chromosomal Microarray vs. NIPS: Analysis of 5541 Low-Risk Pregnancies

(Abstracted from Genet Med 2019;21:2462–2467) Prenatal genetic testing is conducted today using a variety of methods: noninvasive prenatal screening (NIPS) and invasive prenatal testing with karyotyping and/or chromosomal microarray analysis (CMA). While NIPS can detect some genetic aberrations without an invasive procedure, karyotyping and CMA require amniocentesis or chorionic villi sampling.

Increasing the Clinical Psychiatric Knowledge Base About Pathogenic Copy Number Variation.

Specific copy number variants (CNVs) have been robustly associated with intellectual disability, autism, and schizophrenia. Most of the literature focus has been on documenting the existence of these phenomena. There are few data to guide therapeutic choices for these “orphan” diseases. We call for systematic and longitudinal case reports which, if carefully conducted, may provide crucial initial knowledge to guide therapeutics. We provide a step-by-step overview, a tailored set of consensus criteria for high-quality case reports, and a specific set of learning resources.

Identifying Occult Maternal Malignancies From 1.93 Million Pregnant Women Undergoing Noninvasive Prenatal Screening Tests

(Abstracted from Genet Med 2019;21:2293–2302) Noninvasive prenatal screening for aneuploidy using cell-free DNA (cfDNA) has been used since 2011 to identify fetal genetic disorders such as trisomies 13, 18, and 21. However, these tests can give false-positive results or fail all together when other conditions, such as maternal cancer, are present.

Abstract P6-08-39: Hereditary cancer risk assessment using a chatbot in women presenting to obstetrics and gynecology practices across the U.S.

Abstract Background: Hereditary cancer risk assessment is standard of care in the obstetrics and gynecology (ob/gyn) practice. Historical data indicates 1 in 12 individuals have a family history consistent with hereditary cancer(1), however recent data from a small community practice found that 1 in 4 women met National Comprehensive Cancer Network (NCCN) criteria for genetic testing(2). The aim of this study was to assess the number of women who meet NCCN criteria for genetic testing in a diverse population across the United States (US) by using a computer program that conducts conversations with patients (a.k.a. chatbot) for risk assessment(3). Method: We partnered with Clear Genetics Inc. (San Francisco, CA) to use a HIPAA compliant chatbot for collecting personal and family history of cancer from women in 28 ob/gyn practices across the US. Patients received a text message or email asking them to complete the chatbot five days before their scheduled appointment. Reminders were sent at three days and again one day prior if not completed. After history collection was complete, an algorithm determined if the patient had a known familial variant or met NCCN guidelines for hereditary cancer testing, including BRCA-Related Breast and/or Ovarian Cancer, Lynch, and Polyposis syndromes(3). Incomplete chats, minors under age 18 or those who declined to provide information were excluded. Additionally, some ob/gyn practices elected to exclude pregnant patients. Results: Over 15,000 chatbots were sent to patients. Overall, 65% of patients completed the chatbot and 26% of these patients met NCCN criteria or had a known familial variant(3). 14.5% of completed assessments were excluded (1.2% declined, 1.4% minors and 11.9% pregnant patients). Some patients received the chatbot less than five days before their appointment due to administrative delays at the ob/gyn practice, and 15% of intended recipients did not receive the chatbot due to incorrect contact information. Patients reviewed their experience with an average rating of 4.6 out of 5. Conclusions: A novel chatbot tool was used to collect pertinent cancer history and provide NCCN criteria assessment to identify patients for inherited cancer risk. This study population was nearly four times the size of the most recent study identifying 1 in 4 women met NCCN criteria for genetic testing. In addition, this study was more diverse - examining multiple ob/gyn practices across the US compared to a single community practice. Results of this study were consistent with newly reported data indicating 1 in 4 patients meet NCCN criteria for hereditary cancer testing. There is a need for increased education and tools to help ob/gyn practices identify these patients consistent with ACOG Practice Guideline 634(4), in light of a higher number of patients who need genetic testing.

Population Genomic Screening of All Young Adults in a Health-Care System: A Cost-Effectiveness Analysis

(Abstracted from Genet Med 2019;21:1958–1968) It is generally accepted that genetic screening has the potential to prevent disease through early identification. The authors suggest that one cost-effective way to implement genetic screening into a single-payer or state-funded health care system is a combined genetic screening approach—one that tests for multiple conditions concurrently—versus individual targeted testing.

Estimating Yields of Prenatal Carrier Screening and Implications for Design of Expanded Carrier Screening Panels

(Abstracted from Genet Med 2019;21:1940–1947) Prenatal genetic carrier screening once had a limited focus on a small number of genetic variants for a handful of conditions in high-risk populations. Today, screening occurs across multiple variants in many ancestry groups.

Implementing Cancer Genomics in State Health Agencies: Mapping Activities to an Implementation Science Outcome Framework

Objective: To show how state health agencies can plan and evaluate activities to strengthen the evidence base for public health genomics, we mapped state cancer genomics activities to the Doyle et al. [Genet Med. 2018;20(9):995–1003] implementation science outcome framework. Methods: We identified state health agency activities addressing hereditary breast and ovarian cancer and Lynch syndrome by reviewing project narratives from Centers for Disease Control and Prevention Cancer Genomics Program funding recipients, leading discussions with state health agencies, and conducting an environmental scan. Results: State health agencies’ cancer genomics activities included developing or adding to state surveillance systems, developing educational materials, bidirectional reporting, promoting health plan policy change, training providers, and promoting recommendations and standards. To address health disparities, programs have tracked group differences, developed culturally appropriate educational materials, and promoted access to services for underserved populations. Conclusion: State health agencies can use the Doyle et al. [Genet Med. 2018;20(9):995–1003] performance objectives and outcome measures to evaluate proposed and ongoing activities. By demonstrating whether activities result in improved outcomes, state health agencies can build the evidence for the implementation of cancer genomics activities.

Algorithm-driven electronic health record notification enhances detection of Turner syndrome

Causes for short stature in females are numerous; Turner syndrome is among the commoner etiologies. A simple blood test, array comparative genomic hybridization (aCGH, commonly called "microarray") or karyotype, can typically identify partial or complete absence of the second sex chromosome. Chromosome analysis has been a standard recommendation in evaluating idiopathic proportional short stature in females (J Clin Endocrinol Metab 2008;93:4210–7) (Genet Med 2009;11:465–70). In this volume of The Journal, Alexandrou et al used an algorithm-driven review of electronic health records (EHRs) to identify 216 females with idiopathic short stature, of which 72 females had never received chromosome analysis. Interestingly, the females who received chromosome analysis were significantly shorter with a greater mid-parental height deflection than those who had not received either microarray or karyotype. Of the 72 patients initially identified without chromosome analysis, 32 were successfully studied with aCGH. Of these, 2 new cases of Turner syndrome were identified and 1 new patient had a chromosome copy number variant associated with short stature. This study demonstrates the power of EHRs in capturing signs and symptoms of unrecognized diseases. As the completeness of EHRs becomes widespread, the strategy of recognizing overlooked healthcare needs by searching for signs in the EHR may be more frequently used. This strategy can also identify deviation from disease-specific guidelines and help to create systematic compliance with standards of care. In this study, one-third of females with idiopathic short stature did not receive the recommended (10 years ago) chromosome analysis in their initial evaluations. EHR-driven strategies could help compliance with disease-specific guidelines and serve as a focus for quality improvement. Article page 227▸ Algorithm-Driven Electronic Health Record Notification Enhances the Detection of Turner SyndromeThe Journal of PediatricsVol. 216PreviewEarly diagnosis of Turner syndrome enhances care, but in routine practice, even within larger referral centers, diagnosis is delayed. Our study examines the utility of an electronic health record algorithm in identifying patients at high risk for Turner syndrome. Six percent of those identified had missed diagnoses of Turner syndrome. Full-Text PDF

We must now put in place an updated, comprehensive newborn screening program for deaf and hard-of-hearing infants

We must now put in place an updated, comprehensive newborn screening program for deaf and hard-of-hearing infants

Clinical Utility of Expanded Carrier Screening: Results-Guided Actionability and Outcomes

(Abstracted from Genet Med 2019;21(5):1041–1048) One in 300 pregnancies is impacted by a recessive or X-linked condition. Universal screening is recommended by guidelines for 2 of these conditions (cystic fibrosis and spinal muscular atrophy), but this misses approximately 70% of carriers of other diseases and fails to detect somewhere between 13% and 94% of pregnancies affected with severe conditions, depending on race/ethnicity.

CFTR Variants and Renal Abnormalities in Males With Congenital Unilateral Absence of the Vas Deferens (CUAVD): A Systematic Review and Meta-analysis of Observational Studies

(Abstracted from Genet Med 2019;21(4):826–836.) Congenital absence of the vas deferens (CAVD) is a urological disease classified into 3 subtypes: congenital bilateral absence of the vas deferens (CBAVD), congenital unilateral absence of the vas deferens (CUAVD), and congenital bilateral partial aplasia of the vas deferens. The most common subtype is CBAVD (prevalence of 1%–2%), but CUAVD (prevalence of 0.5%–1.0%) also may be discovered during evaluations for infertility or surgical procedures involving male genitalia.

Insurance coverage does not predict outcomes of genetic testing: The search for meaning in payer decisions for germline cancer tests.

In this work, we explore the results of germline cancer genetic tests in individuals whose insurance would not cover this testing. We enrolled 31 patients with a personal history of cancer whose health insurer denied coverage for a clinical germline cancer panel genetic test recommended by a medical genetics provider into a study providing exome sequencing and return of cancer-related results. Five participants (16%) had a pathogenic variant identified related to increased cancer risk. Three participants (10%) had a variant of uncertain significance (VUS) in a gene related to their cancer history. These rates are not significantly different than the 12% rate of pathogenic or likely pathogenic (P/LP) variants and VUS in 1,462 patients approved by insurance to have a similar clinical germline cancer test (p=.59 for P/LP variants; p=.87 for VUS; Shirts et al., Genet Med, 18:974, 2016). Health insurance guidelines may not meaningfully differentiate between patients with cancer who are likely to benefit from germline cancer genetic testing and those who will not. Failure to identify pathogenic variants in this research cohort would have led to suboptimal care. Strategic evaluation of current germline cancer genetic testing coverage policies is needed to appropriately deliver precision medicine.

The use of ACMG secondary findings recommendations for general population screening: a policy statement of the American College of Medical Genetics and Genomics (ACMG)

The American College of Medical Genetics and Genomics (ACMG) has previously published policy statements on the reporting of secondary findings in clinical exome and genome sequencing (ACMG SF v1.0 and ACMG SF v2.0), also known as the “ACMG 56” and “ACMG 59,” respectively.1.Green R.C. Berg J.S. Grody W.W. et al.ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.1:CAS:528:DC%2BC3sXhtVKku73K10.1038/gim.2013.73Genet Med. 2013; 15: 565-574Google Scholar,2.Kalia S.S. Adelman K. Bale S.J. et al.Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.10.1038/gim.2016.190Genet Med. 2017; 19: 249-255Google Scholar These recommendations specifically stated that “reporting some incidental [a.k.a. secondary] findings would likely have medical benefit for the patients and families of patients undergoing clinical sequencing” (ACMG board’s emphasis). The ACMG SF v2.0 list of genes was not validated for general population screening. The use of ACMG SF v2.0 for purposes other than reporting incidental findings after clinical sequencing is not endorsed by ACMG. Many of the ACMG SF v2.0 genes have uncertain penetrance when identified in asymptomatic individuals (e.g., SCN5A and Brugada syndrome).3.Hosseini M. Kim R. Udupa S. et al.Reappraisal of reported genes for sudden arrhythmic death: an evidence based evaluation of gene validity for Brugada syndrome.10.1161/CIRCULATIONAHA.118.035070Circulation. 2018; 138: 1195-1205Google Scholar This policy statement is meant to reduce unproven interventions based solely on genotype information. In the absence of penetrance data that can only be obtained through robust genotype–phenotype correlation, the medical ethical principle of nonmaleficence should dominate.•The ACMG strongly discourages any reference to the term ACMG SF v2.0 (or ACMG 59) outside of the reporting of incidental findings after clinical sequencing.•Further, ACMG SF™, ACMG 59™, ACMG 56™, and related words and designs incorporating ACMG™, are trademarks of the American College of Medical Genetics and Genomics and may not be used without permission.•The ACMG encourages further ascertainment of genotype–phenotype correlation and research to establish the efficacy of interventions in asymptomatic patients with pathogenic and likely pathogenic variants in known associated genes. The authors declare no conflicts of interest. Disclaimer: This statement is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this statement is completely voluntary and does not necessarily assure a successful medical outcome. This statement should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. The Board of Directors of the American College of Medical Genetics and Genomics approved this statement on 16 October 2018 Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

MON-235 Bone Morphogenic Protein Receptor Variants: A New Cause of Primary Ovarian Insufficiency

Primary ovarian insufficiency (POI) is a major cause of infertility. This disease is characterized by amenorrhea with an increase in gonadotropin levels and affects 1% of women before the age of 40. POI may be the result of a broad spectrum of disorders caused by two main mechanisms: abnormal follicular development and follicle depletion due to a defect in their formation or an aberrantly rapid depletion of the stock. Although the majority of cases are idiopathic, POI can be trigged by autoimmune disease, infectious agents, iatrogenic effects, or genetic causes. It may also be part of syndromic diseases such as Turner, Fragile-X or Blepharophimosis Ptosis Epicanthus Inversus syndrome. However, in the majority of cases, the cause of POI is unknown suggesting that new causative genes are yet to be discovered. We conducted a Whole Exome Sequencing on 69 Caucasian women with sporadic POI and performed a bioinformatics analysis on a specific subset of 420 coherent candidate genes1. We identified variations in about fifty genes potentially linked to POI, including new genes never described to be associated with the diseases aetiology, such as AuTophagy related Genes (ATG)2, KHDRBS1 gene encoding an RNA-binding protein3, NOTCH2 gene4... We also found variants in genes encoding Bone Morphogenetic Protein Receptors (BMPR1A and BMPR1B) in three patients. These receptors bind ligands of TGFβ superfamily. Mutations of members of this family (e.g. BMP15, GDF9) are known to be involved in the etiology of POI. BMPR encode transmembrane receptors with serine-threonine kinase activity expressed in the granulosa cells of growing follicles. Missense variations, located in the kinase domain of both receptors 1A and 1B, are predicted to be deleterious in silico. We studied the signaling pathway of these receptors: SMAD proteins phosphorylation, measurement of their transcriptional activity and expression of specific target genes and showed that they are deleterious. Bmpr1a -/- and Bmpr1b-/- mouse models develop infertility due to a reduced spontaneous ovulation and compromised cumulus expansion respectively, indicating that both genes play a crucial role in fertility. Altogether, our study describes the first BMPR1A and 1B mutations associated with POI and increases the number of genes formally implicated as being responsible for this condition. 1Patiño LC, Beau I, Carlosama C, Buitrago JC, González R, Suárez CF, Patarroyo MA, Delemer B, Young J, Binart N, Laissue P. Hum Reprod. 2017; 32(7):1512-1520. 2Delcour C, Amazit L, Patino L, Magnin F, Fagart J, Delemer B, Young J, Laissue P, Binart N, Beau I. Genet Med. 2018 (in press) 3Carlosama C, Patiño L, Beau I, Morel A, Delemer B, Young J, Binart N, Laissue P. Clin Endocrinol (Oxf). 2018 (in press) 4Patiño LC, Beau I, Morel A, Delemer B, Young J, Binart N, Laissue P. Hum Mutat. 2018 (in press)