Beyond Diagnostic Yield: Prenatal Exome Sequencing Results in Maternal, Neonatal, and Familial Clinical Management Changes

Abstract

At present, it is recommended that chromosomal microarray (CMA) be offered in cases of fetal congenital anomalies. However, 60% to 70% of these cases do not receive a genetic diagnosis following microarray, and exome sequencing is being used more frequently in these cases with a reported diagnostic yield of approximately 10% to 30%. It is unknown whether this diagnostic yield is meaningful to patients and their families, given the risks and limitations such as discovering additional findings, limited ability to interpret variants based on limited phenotypic data, and the cost of the test.In this study, chart reviews were completed retrospectively for 20 patients who had prenatal exome sequencing during pregnancy or after a fetal demise or termination of pregnancy (TOP). All patients enrolled had detailed prenatal phenotyping by ultrasound, fetal magnetic resonance imaging, and fetal echocardiogram. They also were evaluated by a multidisciplinary team consisting of a clinical geneticist, genetic counselor, maternal fetal medicine specialist, neonatologist, and others. Patients were eligible for exome sequencing if their fetus was diagnosed with congenital anomalies that were thought to be caused by underlying genetic conditions, but other genetic testing deemed appropriate was not diagnostic. All patients underwent CMA testing prior to exome, and maternal and neonatal charts were reviewed in all cases. The clinical utility of exome was defined as changes to prenatal management, delivery management, neonatal management, family planning, family medical care, and other aspects of care.Of the 20 patients enrolled, 19 were sequenced as trios (the fetus and both parents were included), and 1 was completed as a maternal-fetal duo. In 14 cases (70%), there was an ongoing pregnancy, 3 (15%) were completed after a fetal demise, and 3 (15%) after TOP. The average gestational age at exome sequencing was at 28 weeks 4 days' gestation. Overall, 8 patients (40%) received a diagnostic result, and of these, 3 were autosomal recessive disorders, and 1 was an autosomal dominant disorder. This autosomal dominant disorder was inherited from a previously undiagnosed mother. The last 4 cases were de novo autosomal dominant and somatic mosaic disorders. In 7 other patients (35%), results were inconclusive because of variants of uncertain clinical significance. In 2 cases, variants in novel genes were reported. There were 5 patients who received negative exome results, and 2 of these 5 patients received a postnatal diagnosis of a nongenetic disorder. In 8 patients who had a diagnosis and 1 who received an inconclusive result (45%), there were clinical management changes based on the exome results. In case 1, exome detected compound heterozygous likely pathogenic variants in NMNAT2 with a recurrence risk of 25%. This prompted the parents to do preimplantation genetic testing for their next pregnancy. In other cases, the exome sequencing detected Proteus syndrome, SCN4A-related congenital myopathy, Koolen-de Vries syndrome, Kabuki syndrome,...