During 2020, so many aspects of medical education and research changed because of the pandemic. Conferences adjusted and went virtual but still needed to continue to promote research and support continuing education. Genetic counselors with Genomic Services led and presented several projects at various meetings throughout 2020 and we would like to provide a summary of their work below.


Prenatal theoretical diagnostic yield of a rapid, targeted genetic panel designed for critically ill pediatric patients.

Danuta L Stachiw-Hietpas, Cathin R Kucera, Emily J Partack, Sarah E Witherington, Pranoot Tanpaiboon, and Thomas E Mullen

  • Presented at the National Society of Genetic Counselors 2020 virtual meeting.

Current tools fail to identify disease-causing variants in an estimated 60% to 70% of pregnancies suspected to have a genetic condition. Clinicians may also order genetic panels and/or exome sequencing (ES). ES overcomes the challenge of selecting a panel, but a broad range of detection rates, from 6% to >80%, have been reported for ES in the prenatal setting and the turnaround time can be over 2 months. Even rapid ES can take about 2 weeks for written results. Our laboratory offers a rapid (3 – 7 day turnaround time) next-generation sequencing panel that includes 1,722 genes related to congenital disorders that present in infancy, many of which can also present with ultrasound findings in pregnancy.

In this study, we estimated the theoretical diagnostic yield of this panel in the prenatal setting by comparing the genes included in the panel to results reported in 13 fetal ES studies. Our 1,722-gene panel would have theoretically detected 87% of the total disease-causing variants in these studies (181 of 209), with a range of 75% to 100% in individual studies. There was no pattern or theme to the phenotypes that our panel would not have detected. The theoretical diagnostic yield of this rapid panel suggests it may be useful in the prenatal setting.


Incidental findings involving cancer susceptibility genes detected by germline chromosomal microarray.

Elaine C Weltmer, Fatih Z Boyar, Loretta W Mahon, Domagoj Hodko, Yuri A Fesko

  • Presented at the American Society of Human Genetics 2020 virtual meeting.

Germline chromosomal microarray (CMA) is most frequently performed in childhood and is a first-line diagnostic test for patients with developmental delay, intellectual disability, autism spectrum disorders, and congenital anomalies. Copy number variants (CNVs) detected through CMA may contain genes incidental to the clinical indication, such as cancer susceptibility genes (CSG). However, few studies have been published on the frequency and types of CSG findings on CMA. This study describes the frequency and types of incidental CSG findings detected by germline CMA with the goal of adding to the discussion of the benefits and limitations of CMA testing.

Of 16,243 patients with a reportable CNV, 116 (0.7%) had a CNV containing at least 1 CSG. Among these 116 patients, 42 (36%) had a copy number loss, classified as a pathogenic or likely pathogenic finding. In 25 of the 42 (60%) patients with a copy number loss, the deleted cancer susceptibility gene was associated with a clinical syndrome that typically presents in childhood. The remaining 17 patients (40%) had a whole-gene deletion of a cancer susceptibility gene associated with an adult-onset cancer syndrome. These data suggest that a discussion of the benefits and limitations of germline CMA should include the possibility of an incidental finding of a cancer-susceptibility syndrome, including adult-onset cancer syndromes.

Frequency of 5 cancer types in families with a pathogenic or likely pathogenic variant in the ATM gene.

Diana Moglia Tully, Kelli M Conlan, Elaine C Weltmer, Natasha A Go, Charlie H Rhodes, Yuri A Fesko.

  • Presented at the National Society of Genetic Counselors 2020 virtual meeting.

The full spectrum of cancer risk associated with pathogenic or likely pathogenic variants (P/LP) in the ATM gene is unknown. While there have been clear associations established for female breast and pancreatic cancer, there is some literature to suggest an association with ovarian, colorectal, prostate, and gastric cancer. In this study, we assessed the frequencies of these 5 cancer types among carriers of P/LP ATM variants and their family members.

40 P/LP ATM carriers met inclusion criteria. Of the 40 carriers identified, 26 (65%) reported ≥1 family member with a cancer of interest (25% colorectal, 20% ovarian, 20% prostate, 17.5% gastric, 5% male breast).  Six carriers (15%) reported a family history of ≥ 1 of the 5 cancers of interest. For the remaining 50% of families, the information provided was insufficient to assess segregation.

Segregation was confirmed in one family with colorectal cancer and in another with both colorectal and ovarian cancer, further supporting a potential association with these cancer types and P/LP ATM variants. Segregation was suspected in 11 (46%) of the remaining 24 families that were evaluated for segregation, highlighting the potential associations and need for further study. Two individuals (5%) had a family history of male breast cancer which may be noteworthy since this type of cancer is particularly rare. The frequencies of all 5 cancer types in families with P/LP ATM variants suggest an association, but further research is needed.

Breast cancer in PMS2-positive patients

Kylin Boehler, Elaine Weltmer, Yuri Fesko, Felicitas L Lacbawan

  • Presented at the National Society of Genetic Counselors 2020 virtual meeting.

PMS2-associated Lynch syndrome (LS) is known to increase the risk of colorectal and endometrial cancer. Recent literature suggests that the risk of breast cancer also increases in women with a pathogenic (P) or likely pathogenic (LP) variant in PMS2, though data are conflicting. This study describes the reported personal and family histories of breast cancer (BC) in patients with P/LP variants in PMS2 at a commercial laboratory. We reviewed clinical data from 105 consecutive probands with a P/LP variant in the PMS2 gene. Of the 105 probands, 85 provided clinical information (85/105; 81%). Of these, 26 (26/85; 31%) reported a personal and/or family history of female BC: 5 reported only a personal history of BC (5/26; 19%), 18 reported only a family history of BC (18/26; 69%), and 3 reported both a personal and family history of BC (3/26; 12%). Importantly, there were no contemporaneous P/LP variants identified among the cohort of 26. The median age of first BC diagnosis among P/LP PMS2-positive individuals was younger than that among the general population (62) and older than that among BRCA1– or BRCA2-positive individuals (44 and 48, respectively).

Though larger studies are needed, these data are comparable to data reported in previous studies. Confirming an association between breast cancer and positive PMS2 variants, and understanding the age of diagnosis, may impact medical management of P/LP PMS2 carriers.

Women’s Health and Reproduction

Frequency of incidental maternal mosaic and variant turner syndrome detected by NIPT in a pregnant cohort.

Lisa M Blazejewski, Carrie J Guy, Renius Owen, Ben Anderson, Ke Zhang, Fatih Z Boyar, Felicitas L Lacbawan, Damian D Alagia

  • Presented at the American College of Genetics and Genomics 2020 virtual meeting.

Turner syndrome (TS) is a chromosomal condition most often caused by a missing X chromosome (45,X or monosomy X) or mosaic monosomy X. More rarely, “variant” TS is caused by partial monosomy X due to deletions or other rearrangements of the X chromosome. TS is characterized by short stature, a risk for congenital heart and renal anomalies, and infertility. The TS phenotype is wide-ranging, and some women (most often those with mosaic or variant TS) remain undiagnosed because they exhibit limited signs, such as isolated short stature. TS is estimated to occur in approximately 1 in 2,000 women; however, this figure is based primarily on studies of clinically ascertained individuals.

Prenatal cell-free DNA (cfDNA) screening by massively parallel shotgun sequencing (MPSS) can detect maternal sex chromosome abnormalities (SCA), such as TS, as incidental findings. Our study reviewed a dataset derived from QNatal Advanced® screening results in an apparently healthy pregnant cohort to provide insight into the frequency of mosaic/variant TS in the general obstetrical population. Results consistent with decreased representation of maternal X chromosome content were reported for 129 out of 279,658 samples tested. Follow-up testing was performed on 79 patients. A diagnosis of either mosaic or variant TS was confirmed in 62 women, while 7 others were diagnosed with X chromosome abnormalities unrelated to TS. The frequency of incidentally detected mosaic/variant TS in our cohort containing only pregnant women is 1 in 4,510. This suggests that mosaic/variant TS may be more common than previously appreciated.

Prenatal cell-free DNA screening for 22q11.2 deletion syndrome: positive predictive value estimates from a large US clinical laboratory.

Kristina F Kahl, Carrie J Guy, Nitin N Karamata, Renius Owen, Ben Anderson, Ke Zhang, Felicitas L Lacbawan, Damian P Alagia

  • Presented at the American College of Genetics and Genomics 2020 virtual meeting.

The chromosome 22q11.2 deletion syndrome is the most common microdeletion syndrome, with an estimated prevalence of 1:2,000 to 1:6,000 live births. Although prenatal cell-free DNA screening for microdeletions is offered by several laboratories, relevant professional societies have not fully endorsed its use because published research demonstrating clinical validity and utility is lacking. This study aims to assess the positive predictive value (PPV) of cell-free DNA screening for 22q11.2 deletion syndrome at a large US clinical laboratory.

From 2015 to 2018, 26 specimens had a positive result for the 22q11.2 deletion syndrome. Of the 26 positive specimens, 10 were true positives confirmed by prenatal or postnatal FISH, microarray, or MLPA, and 8 were suspected true positives based on ultrasound detection of congenital heart defects. Of the remaining specimens, 4 patients were lost to follow-up; 1 patient had a spontaneous abortion with a clinical indication of abnormal ultrasound, and 3 patients had live births. No false positives were confirmed by diagnostic testing.

Since diagnostic testing results were not obtained for all screen-positive cases, PPV was calculated as a range: 69% to 100%. These data will help clinicians understand the accuracy of cell-free DNA screening for the detection of this common microdeletion so that they can better counsel their patients.