Canadian College of Medical Geneticists (CCMG) points to consider: resuming genetic services in a pandemic-a summary.

The COVID-19 pandemic has disrupted the provision of genetic care in Canada. With the public health effort to flatten the curve, many clinics have moved to virtual care for select populations of patients while triaging and postponing others. As genetic services are asked to gradually resume, a roadmap is needed to ensure clinical care decisions for at-risk patients are transparent and equitable, that postponed care is resumed and that patients with or waiting for a genetic diagnosis are not disproportionately affected or abandoned.The purpose of this document is to highlight the guiding ethical principles and stakeholder considerations in resuming genetic services to help guide the competing needs going forward of both limiting exposures while maintaining high-quality care. Considerations highlighted are (1) environment of practice, (2) nature of consult, (3) patient factors, (4) provider factors, and (5) laboratory factors. The intended users are those providing genetic care in a Canadian context with the recognition that there are clinic-specific and regional variations that will influence decision-making. While specific to the Canadian context, the ethical principles used to guide these decisions would be relevant for consideration in other jurisdictions.

A novel DNAH11 variant segregating in a sibship with heterotaxy and implications for genetic counseling.

BACKGROUND: Isomerism or heterotaxy syndrome is the loss of normal asymmetry of the internal thoraco-abdominal organs in the left-right axis and is associated with cardiovascular malformations. Mutations within DNAH11 can be associated with primary ciliary dyskinesia and heterotaxy syndromes. METHODS: We report a family of healthy, nonconsanguinous parents with subsequent pregnancies demonstrating a novel likely pathogenic variant in DNAH11 segregating in a sibship with varied presentations. RESULT: The first affected pregnancy presented with right atrial isomerism. Further DNA testing identified three variants in DNAH11 related to primary ciliary dyskinesia: a maternally inherited heterozygous variant of unknown significance (VUS) c.2772G>A (p.Met924Ile), a maternally inherited novel likely pathogenic variant c.11662C>T (p.Arg3888Cys) as well as a paternally inherited pathogenic c.1648delA variant (p.Arg550GlyfsX16). The second pregnancy inherited the same variants including the pathogenic and likely pathogenic DNAH11 variants and presented with left isomerism and extracardiac abnormalities. CONCLUSION: We present a novel likely pathogenic variant (c.11662C>T) in DNAH11 that has manifested in heterotaxy with variability in phenotypes for subsequent pregnancies of common parents. This report demonstrates that sibship illustrates potential variability in phenotypes associated with the same pathogenic variants within a family and highlights the difficulty in genetic counseling due to the variation in clinical presentation.

Noninvasive Prenatal Testing for Trisomies 21, 18, and 13, Sex Chromosome Aneuploidies, and Microdeletions in Average-Risk Pregnancies: A Cost-Effectiveness Analysis.

OBJECTIVE: The cost effectiveness of noninvasive prenatal testing (NIPT) has been established for high-risk pregnancies but remains unclear for pregnancies at other risk levels. The aim was to assess the cost effectiveness of NIPT in average-risk pregnancies from the perspective of a provincial public payer in Canada. METHODS: A model was developed to compare traditional prenatal screening (TPS), NIPT as a second-tier test (performed only after a positive TPS result), and NIPT as a first-tier test (performed instead of TPS) for trisomies 21, 18, and 13; sex chromosome aneuploidies; and microdeletions in a hypothetical annual population cohort of average-risk pregnancies (142 000 to 148,000) in Ontario, Canada. A probabilistic analysis was conducted with 5000 repetitions. RESULTS: Compared with TPS, NIPT as a second-tier test detected more affected fetuses with trisomies 21, 18, and 13 (188 vs. 158), substantially reduced the number of diagnostic tests (i.e., chorionic villus sampling and amniocentesis) performed (660 vs. 3107), and reduced the cost of prenatal screening ($26.7 million vs. $27.6 million) annually. Compared with second-tier NIPT, first-tier NIPT detected an additional 80 cases of trisomies 21, 18, and 13 at an additional cost of $33 million. The incremental cost per additional affected fetus detected was $412 411. Extending first-tier NIPT to include testing for sex chromosome aneuploidies and 22q11.2 deletion would increase the total screening cost. CONCLUSIONS: NIPT as a second-tier test is cost-saving compared with TPS alone. Compared with second-tier NIPT, first-tier NIPT detects more cases of chromosomal anomalies but at a substantially higher cost.

Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome.

Aberrant signaling through pathways controlling cell response to extracellular stimuli constitutes a central theme in disorders affecting development. Signaling through RAS and the MAPK cascade controls a variety of cell decisions in response to cytokines, hormones, and growth factors, and its upregulation causes Noonan syndrome (NS), a developmental disorder whose major features include a distinctive facies, a wide spectrum of cardiac defects, short stature, variable cognitive impairment, and predisposition to malignancies. NS is genetically heterogeneous, and mutations in more than ten genes have been reported to underlie this disorder. Despite the large number of genes implicated, about 10%-20% of affected individuals with a clinical diagnosis of NS do not have mutations in known RASopathy-associated genes, indicating that additional unidentified genes contribute to the disease, when mutated. By using a mixed strategy of functional candidacy and exome sequencing, we identify RRAS2 as a gene implicated in NS in six unrelated subjects/families. We show that the NS-causing RRAS2 variants affect highly conserved residues localized around the nucleotide binding pocket of the GTPase and are predicted to variably affect diverse aspects of RRAS2 biochemical behavior, including nucleotide binding, GTP hydrolysis, and interaction with effectors. Additionally, all pathogenic variants increase activation of the MAPK cascade and variably impact cell morphology and cytoskeletal rearrangement. Finally, we provide a characterization of the clinical phenotype associated with RRAS2 mutations.

Genetic counselors' preferences for coverage of preimplantation genetic diagnosis: A discrete choice experiment.

Preimplantation genetic diagnosis (PGD) allows couples to test for a genetically affected embryo prior to implantation. Patient access to this ethically complex and expensive technology differs markedly across jurisdictions, with differences in private/public insurance coverage and variations in patient inclusion and diagnostic criteria. The objective of the study was to identify trade-offs regarding PGD coverage decisions amongst genetic counselors. To quantify stated preferences for PGD coverage, we conducted a discrete choice experiment with Canadian genetic counselors (GC) considering attributes regarding the scope of testing (PGD indication, risk of the condition and number of cycles covered) and patient inclusion criteria (fertility status and family history). Multinomial logit regression was used to estimate trade-offs amongst attributes using part-worth utilities and importance scores. The completed response rate was 41% with 126 GC completing the survey. Risk of the genetic condition was the most important attribute. Overall, GC were more responsive to the scope of testing criteria including the condition's risk (importance score of 42%) and PGD indication (31%) rather than family history (11%) and fertility status (8%). Based on this study's attributes and levels, condition characteristics are prioritized even above patient characteristics for PGD coverage.

Mosaic microdeletion of 17p11.2-p12 and duplication of 17q22-q24 in a girl with Smith-Magenis phenotype and peripheral neuropathy.

We report on a girl with a de novo mosaic derivative chromosome 17 involving a 7.4 Mb deletion of chromosome region 17p11.2 to 17p12 and a duplication of a 12.35 Mb region at 17q22 to 17q24. She was ascertained because of developmental delay, peripheral neuropathy, brachydactyly and minor anomalies. The derivative chromosome was present in approximately 12% of lymphocytes based on FISH studies, and was detected by array comparative genomic hybridization. To our knowledge, this is the third case of mosaicism involving deletion of the 17p11.2 region and the lowest level of mosaicism reported in a patient with Smith-Magenis syndrome (SMS).

Definition of a critical genetic interval related to kidney abnormalities in the Potocki-Lupski syndrome.

Potocki-Lupski syndrome is a genomic disorder caused by duplication of 17p11.2. It is characterized by failure to thrive, intellectual disability, hypotonia, and behavioral difficulties. Structural renal anomalies have been observed in <10% of affected individuals. We present detailed clinical and molecular data on six patients with Potocki-Lupski syndrome, two of whom had renal abnormalities, and investigate the prevalence of kidney abnormalities in the mouse model for the syndrome. In contrast to affected humans, the mouse model does not demonstrate a renal phenotype. Comparison of the duplicated segment in patients with Potocki-Lupski syndrome and the renal phenotype and the syntenic duplicated region in the mouse model allowed us to suggest a 0.285 Mb critical region, including the FLCN gene that may be important for development of renal abnormalities in patients with this duplication.

The Roberts syndrome/SC phocomelia spectrum--a case report of an adult with review of the literature.

Roberts syndrome (RBS) (OMIM #268300) is a rare autosomal recessive disorder characterized by tetraphocomelia (symmetrical limb reduction), craniofacial anomalies, growth retardation, mental retardation, cardiac and renal abnormalities. The syndrome is caused by mutations in the ESCO2 (establishment of cohesion 1 homolog 2) (Entrez 609353) gene, which is located at 8p21.1, and encodes a protein essential in establishing sister chromatid cohesion during S phase. SC phocomelia (SC) (OMIM #269000), has less severe symmetric limb reduction, flexion contractures of various joints, minor facial anomalies, growth retardation and occasionally, mental retardation. These two syndromes can be considered part of a spectrum, with RBS at the most severe range in which severely affected infants may be stillborn or die in the post-natal period, while individuals with SC phocomelia represent the milder end of the spectrum and typically survive to adulthood. In both presentations, karyotype investigations characteristically reveal premature centromere separation (PCS), otherwise known as heterochromatin repulsion or puffing. There is little literature about the follow-up of adults with the spectrum of RBS/SC phocomelia or their recommended management. We report on an adult presentation of RBS/SC phocomelia spectrum disorder with a history of major cardiac malformation in childhood, normal limbs on physical examination, mild facial anomalies, mild learning difficulties, and PCS. Molecular studies of ESCO2 have confirmed the diagnosis. A literature review, focussing on adult manifestations of this condition and a discussion of follow-up guidelines are presented.