Clinical characterization of individuals with the distal 1q21.1 microdeletion.

Distal 1q21.1 microdeletions have shown highly variable clinical expressivity and incomplete penetrance, with affected individuals manifesting a broad spectrum of nonspecific features. The goals of this study were to better describe the phenotypic spectrum of patients with distal 1q21.1 microdeletions and to compare the clinical features among affected individuals. We performed a retrospective chart review of 47 individuals with distal 1q21.1 microdeletions tested at a large clinical genetic testing laboratory, with most patients being clinically evaluated in the same children's hospital. Health information such as growth charts, results of imaging studies, developmental history, and progress notes were collected. Statistical analysis was performed using Fisher's exact test to compare clinical features among study subjects. Common features in our cohort include microcephaly (51.2%), seizures (29.8%), developmental delay (74.5%), failure to thrive (FTT) (68.1%), dysmorphic features (63.8%), and a variety of congenital anomalies such as cardiac abnormalities (23.4%) and genitourinary abnormalities (19.1%). Compared to prior literature, we found that seizures, brain anomalies, and FTT were more prevalent among our study cohort. Females were more likely than males to have microcephaly (p = 0.0199) and cardiac abnormalities (p = 0.0018). Based on existing genome-wide clinical testing results, at least a quarter of the cohort had additional genetic findings that may impact the phenotype of the individual. Our study represents the largest cohort of distal 1q21.1 microdeletion carriers available in the literature thus far, and it further illustrates the wide spectrum of clinical manifestations among symptomatic individuals. These results may allow for improved genetic counseling and management of affected individuals. Future studies may help to elucidate the underlying molecular mechanisms impacting the phenotypic variability observed with this microdeletion.

Prenatal testing in pregnancies conceived by in vitro fertilization with pre-implantation genetic testing.

OBJECTIVE: Women with pregnancies resulting from in vitro fertilization (IVF) with normal pre-implantation genetic testing for aneuploidy (PGT-A) are advised to undergo prenatal screening and testing during pregnancy. It is not well known how many follow these recommendations. Our objective was to study prenatal testing decisions made by women with pregnancies conceived through IVF with PGT-A. METHODS: We performed a retrospective review of women who received genetic counseling during pregnancies conceived through IVF with normal PGT-A. We excluded those who received genetic counseling preconceptionally prior to IVF. Statistical analysis included descriptive statistics and after testing for normality by the Kolmogorov-Smirnov test, independent t test, Mann-Whitney U test, or Chi-square/Fisher's exact test. RESULTS: Data from 83 women were included. Of these, 53 (63.9%) had at least one of the following prenatal tests: first trimester combined screening (16.9%), non-invasive prenatal screening (NIPS) (45.8%), second trimester serum screening (6%), and invasive diagnostic testing (6%). 10.8% had more than one of the above tests and 36.1% declined all tests. CONCLUSION: Almost two-thirds of women who were pregnant after IVF with normal PGT-A had prenatal aneuploidy screening or testing. Future prospective studies with larger cohorts are needed to further ascertain decision making in this population.

Clinical exome sequencing for fetuses with ultrasound abnormalities and a suspected Mendelian disorder.

BACKGROUND: Exome sequencing is now being incorporated into clinical care for pediatric and adult populations, but its integration into prenatal diagnosis has been more limited. One reason for this is the paucity of information about the clinical utility of exome sequencing in the prenatal setting. METHODS: We retrospectively reviewed indications, results, time to results (turnaround time, TAT), and impact of exome results for 146 consecutive "fetal exomes" performed in a clinical diagnostic laboratory between March 2012 and November 2017. We define a fetal exome as one performed on a sample obtained from a fetus or a product of conception with at least one structural anomaly detected by prenatal imaging or autopsy. Statistical comparisons were performed using Fisher's exact test. RESULTS: Prenatal exome yielded an overall molecular diagnostic rate of 32% (n = 46/146). Of the 46 molecular diagnoses, 50% were autosomal dominant disorders (n = 23/46), 41% were autosomal recessive disorders (n = 19/46), and 9% were X-linked disorders (n = 4/46). The molecular diagnostic rate was highest for fetuses with anomalies affecting multiple organ systems and for fetuses with craniofacial anomalies. Out of 146 cases, a prenatal trio exome option designed for ongoing pregnancies was performed on 62 fetal specimens, resulting in a diagnostic yield of 35% with an average TAT of 14 days for initial reporting (excluding tissue culture time). The molecular diagnoses led to refined recurrence risk estimates, altered medical management, and informed reproductive planning for families. CONCLUSION: Exome sequencing is a useful diagnostic tool when fetal structural anomalies suggest a genetic etiology, but other standard prenatal genetic tests did not provide a diagnosis.

Reproductive genetic counseling challenges associated with diagnostic exome sequencing in a large academic private reproductive genetic counseling practice.

OBJECTIVE: Diagnostic whole exome sequencing (WES) is rapidly entering clinical genetics, but experience with reproductive genetic counseling aspects is limited. The purpose of this study was to retrospectively review and report on our experience with preconception and prenatal genetic counseling for diagnostic WES. METHOD: We performed a retrospective chart review over 34 months in a large private prenatal genetic counseling practice and analyzed data for referral indications, findings, and results of genetic counseling related to diagnostic WES. RESULTS: Ten of 14 patients counseled about diagnostic WES for ongoing pregnancies pursued the test, resulting in identification of three pathogenic variants (30%). Five of 15 patients seeking counseling about familial WES results in an affected proband pursued prenatal diagnosis, resulting in identification of one affected fetus and five unaffected fetuses. We experienced challenges related to complexity and uncertainty of results, turnaround time, cost and insurance overage, and multidisciplinary fetal care coordination. CONCLUSION: Despite having experienced complexity and identified challenges of the reproductive genetic counseling, availability of diagnostic WES contributed important information that aided in prenatal care planning and decision-making. Future enhanced provider education and larger studies to systematically study the integration of WES in reproductive genetic counseling and prenatal care will be important.