Management of individuals with heterozygous germline pathogenic variants in ATM: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).

Purpose: ATM germline pathogenic variants (GPVs) are associated with a moderately increased risk of female breast cancer, pancreatic cancer, and prostate cancer. Resources for managing ATM heterozygotes in clinical practice are limited.

Methods: An international workgroup developed a clinical practice resource to guide management of ATM heterozygotes using peer-reviewed publications and expert opinion.

Genetic disease risks of under-represented founder populations in New York City.

The detection of founder pathogenic variants, those observed in high frequency only in a group of individuals with increased inter-relatedness, can help improve delivery of health care for that community. We identified 16 groups with shared ancestry, based on genomic segments that are shared through identity by descent (IBD), in New York City using the genomic data of 25,366 residents from the All Of Us Research Program and the Mount Sinai Bio biobank. From these groups we defined 8 as founder populations, mostly communities currently under-represented in medical genomics research, such as Puerto Rican, Garifuna and Filipino/Pacific Islanders.

Noninvasive Prenatal Screening for Single-Gene Disorders.

Single-gene disorders (SGDs), also known as monogenic disorders, are caused by pathogenic variants at individual loci. Prenatal cell-free DNA screening for SGDs has been investigated for decades. Detecting paternal and de novo variants may be somewhat straightforward, whereas detecting maternally inherited variants poses a significant challenge.

Management of individuals with germline pathogenic/likely pathogenic variants in CHEK2: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).

Purpose: Although the role of CHEK2 germline pathogenic variants in cancer predisposition is well known, resources for managing CHEK2 heterozygotes in clinical practice are limited.

Methods: An international workgroup developed guidance on clinical management of CHEK2 heterozygotes informed by peer-reviewed publications from PubMed.

Results: Although CHEK2 is considered a moderate penetrance gene, cancer risks may be considered as a continuous variable, which are influenced by family history and other modifiers.

Cancer Risk C (CR-C), a functional genomics test is a sensitive and rapid test for germline mismatch repair deficiency.

Purpose: Heritable pathogenic variants in the DNA mismatch repair (MMR) pathway cause Lynch syndrome, a condition that significantly increases risk of colorectal and other cancers. At least half of individuals tested using gene panel sequencing have a variant of uncertain significance or no variant identified leading to no diagnosis. To fill this diagnostic gap, we developed Cancer Risk C (CR-C), a flow variant assay test.

Prediction of breast cancer risk based on flow variant analysis of circulating peripheral blood mononuclear cells.

Identifying women at high risk for developing breast cancer is potentially lifesaving. Patients with pathogenic genetic variants can embark on a program of surveillance for early detection, chemoprevention, and/or prophylactic surgery. Newly diagnosed cancer patients can also use the results of gene panel sequencing to make decisions about surgery; therefore, rapid turnaround time for results is critical.

Cell-free DNA screening for trisomies 21, 18, and 13 in pregnancies at low and high risk for aneuploidy with genetic confirmation.

Background: Cell-free DNA noninvasive prenatal screening for trisomies 21, 18, and 13 has been rapidly adopted into clinical practice. However, previous studies are limited by a lack of follow-up genetic testing to confirm the outcomes and accurately assess test performance, particularly in women at a low risk for aneuploidy.

Objective: To measure and compare the performance of cell-free DNA screening for trisomies 21, 18, and 13 between women at a low and high risk for aneuploidy in a large, prospective cohort with genetic confirmation of results STUDY DESIGN: This was a multicenter prospective observational study at 21 centers in 6 countries.

Single-cell analysis of somatic mutation burden in mammary epithelial cells of pathogenic BRCA1/2 mutation carriers.

Inherited germline mutations in the breast cancer gene 1 (BRCA1) or BRCA2 genes (herein BRCA1/2) greatly increase the risk of breast and ovarian cancer, presumably by elevating somatic mutational errors as a consequence of deficient DNA repair. However, this has never been directly demonstrated by a comprehensive analysis of the somatic mutational landscape of primary, noncancer, mammary epithelial cells of women diagnosed with pathogenic BRCA1/2 germline mutations. Here, we used an accurate, single-cell whole-genome sequencing approach to first show that telomerized primary mammary epithelial cells heterozygous for a highly penetrant BRCA1 variant displayed a robustly elevated mutation frequency as compared with their isogenic control cells.

Impact of introducing cell-free DNA screening into clinical care on first trimester ultrasound.

Objective: First-trimester ultrasound is an important component of prenatal care. We investigated the impact of introducing cell-free DNA (cfDNA) aneuploidy screening into routine care, on performance of first-trimester ultrasound.

Methods: Retrospective study of patients who had prenatal care at a tertiary referral center.

The training of future clinical geneticists: Evaluation and reflection on the ACMG Foundation for Genetic and Genomic Medicine Summer Genetics Scholars Program.

Purpose: The purpose of the Summer Genetics Scholars Program of the ACMG Foundation for Genetic and Genomic Medicine is to expose medical students to medical genetics and genomics early during school with the aim of increasing the number of physicians pursuing a career in this field. This survey study evaluated the Summer Genetics Scholars Program on the achievement of its goals.

Methods: Former Summer Genetics Scholars who had completed medical school were sent a 13-question survey aimed at evaluating the program and obtaining feedback about their experiences.

Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG).

Carrier screening began 50 years ago with screening for conditions that have a high prevalence in defined racial/ethnic groups (e.g., Tay-Sachs disease in the Ashkenazi Jewish population; sickle cell disease in Black individuals).

Patient attitudes toward prenatal diagnostic testing during antenatal care in an urban population.

Objective: Investigate factors that influence the decision to accept or decline diagnostic testing for pregnant women referred for genetic counseling.

Methods: Cross sectional anonymous survey of pregnant women undergoing genetic counseling at a tertiary care referral center. Subjects' perceived risk of procedure related loss and fetal chromosomal problem were obtained via survey where patients rated risk from 0 (no risk) to 10 (highest risk).

Gain-of-function pathogenic variants in SMAD4 are associated with neoplasia in Myhre syndrome.

Myhre syndrome is an increasingly diagnosed rare syndrome that is caused by one of two specific heterozygous gain-of-function pathogenic variants in SMAD4. The phenotype includes short stature, characteristic facial appearance, hearing loss, laryngotracheal stenosis, arthritis, skeletal abnormalities, learning and social challenges, distinctive cardiovascular defects, and a striking fibroproliferative response in the ear canals, airways, and serosal cavities (peritoneum, pleura, pericardium). Confirmation of the clinical diagnosis is usually prompted by the characteristic appearance with developmental delay and autistic-like behavior using targeted gene sequencing or by whole exome sequencing.