UNASSIGNED: The objective of this study was to investigate the attitudes of healthcare professionals (HPs) working in the prenatal setting toward uncertain results (UR) from prenatal exome sequencing (pES) in China.
UNASSIGNED: We conducted a national survey among HPs working in the prenatal setting. UR in our study include variants of uncertain significance (VUS), variants with variable penetrance/expressivity (VVPE), and secondary findings unrelated to the indication for testing (SFs). A total of 285 questionnaires that met the inclusion criteria were collected. Data were analyzed using IBM SPSS Statistics 26.
UNASSIGNED: When performing the pre-test counseling, only 7.4% of HPs mentioned the possibility of VUS, 6.3% discussed the possibility of VVPE, and 7.4% introduced the SFs with parents with the option to not report these variants. In post-test counseling, 73.0-82.8% HPs discussed with the parents but did not make any recommendations for managing the pregnancy after reporting UR (73.0% for VUS, 82.8% for VVPE, 74.7% for SFs, respectively).
UNASSIGNED: Most parents did not have the option of opting out of reporting UR from pES in pre-test counseling. UR did not influence the pregnancy recommendation made by most HPs. Establishing national guidelines for reporting UR from pES and developing strategies to improve counseling skills may help HPs manage UR.

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BACKGROUND: Congenital talipes equinovarus (CTEV) is a rotational foot deformity that affects muscles, bones, connective tissue, and vascular or neurological tissues. The etiology of CTEV is complex and unclear, involving genetic and environmental factors. Nail-patella syndrome is an autosomal dominant disorder caused by variants of the LIM homeobox transcription factor 1 beta gene (LMX1B, OMIM:602575). LMX1B plays a key role in the development of dorsal limb structures, the kidneys, and the eyes, and variants in this gene may manifest as hypoplastic or absent patella, dystrophic nails, and elbow and iliac horn dysplasia; glomerulopathy; and adult-onset glaucoma, respectively. This study aimed to identify pathogenic variants in a fetus with isolated talipes equinovarus diagnosed by ultrasound in the second trimester, whose father exhibited dysplastic nails and congenital absence of bilateral patella.
METHODS: Prenatal whole-exome sequencing (WES) of the fetus and parents was performed to identify the genetic variant responsible for the fetal ultrasound abnormality, followed by validation using Sanger sequencing.
RESULTS: A novel heterozygous nonsense variant in exon 6 of LMX1B (c.844C>T, p.Gln282*) was identified in the fetus and the affected father but was not detected in any unaffected family members. This nonsense variant resulted in a premature termination codon at position 282, which may be responsible for the clinical phenotype through the loss of function of the gene product.
CONCLUSIONS: Our study indicating that a fetus carrying a novel nonsense variant of LMX1B (c.844C>T, p.Gln282*) can exhibit isolated talipes equinovarus, which expands the LMX1B genotypic spectrum and is advantageous for genetic counseling.

To evaluate the utility of prenatal exome sequencing (pES) in fetuses with central nervous system (CNS) abnormalities.
This was a retrospective cohort study of fetuses identified to have CNS abnormality on prenatal ultrasound and/or magnetic resonance imaging. All fetuses were first analyzed by chromosomal microarray analysis (CMA). Fetuses with a confirmed aneuploidy or causal pathogenic copy-number variant (CNV) on CMA did not undergo pES analysis and were excluded, while those with a negative CMA result were offered pES testing.
Of the 167 pregnancies included in the study, 42 (25.1%) were identified to have a pathogenic or likely pathogenic (P/LP) variant. The diagnostic rate was significantly higher in fetuses with a non-isolated CNS abnormality than in those with a single CNS abnormality (35.7% (20/56) vs 14.5% (8/55); P = 0.010). Moreover, when a fetus had three or more CNS abnormalities, the positive diagnostic rate increased to 42.9%. A total of 25/42 (59.5%) cases had de-novo mutations, while, in the remaining cases, mutations were inherited and carried a significant risk of recurrence. Families whose fetus carried a P/LP mutation were more likely to choose advanced pregnancy termination than those with a variant of uncertain significance, secondary/incidental finding or negative pES result (83.3% (25/30) vs 41.3% (38/92); P < 0.001).
pES improved the identification of genetic disorders in fetuses with CNS anomalies without a chromosomal abnormality or CNV identified on CMA, regardless of the number of CNS anomalies and presence of extracranial abnormality. We also demonstrated that pES findings can significantly impact parental decision-making. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

To evaluate the utility of trio-based prenatal exome sequencing (pES), incorporating splice-site and mitochondrial genome assessment, in the prenatal diagnosis of fetuses with ultrasound anomalies and normal copy-number variant sequencing (CNV-seq) results.
This was a prospective study of 90 ongoing pregnancies with ultrasound anomalies that underwent trio-based pES after receiving normal CNV-seq results, from September 2020 to November 2021, in a single center in China. By using pES with a panel encompassing exome coding and splicing regions as well as mitochondrial genome for fetuses and parents, we identified the underlying genetic causes of fetal anomalies, incidental fetal findings and parental carrier status. Information on pregnancy outcome and the impact of pES findings on parental decision-making was collected.
Of the 90 pregnancies included, 28 (31.1%) received a diagnostic result that could explain the fetal ultrasound anomalies. The highest diagnostic yield was noted for brain abnormalities (3/6 (50.0%)), followed by hydrops (4/9 (44.4%)) and skeletal abnormalities (13/34 (38.2%)). Collectively, 34 variants of 20 genes were detected in the 28 diagnosed cases, with 55.9% (19/34) occurring de novo. Variants of uncertain significance (VUS) associated with fetal phenotypes were detected in six (6.7%) fetuses. Interestingly, fetal (n = 4) and parental (n = 3) incidental findings (IFs) were detected in seven (7.8%) cases. These included two fetuses carrying a de-novo likely pathogenic (LP) variant of the CIC and FBXO11 genes, respectively, associated with neurodevelopmental disorders, and one fetus with a LP variant in a mitochondrial gene. The remaining fetus presented with unilateral renal dysplasia and was incidentally found to carry a pathogenic PKD1 gene variant resulting in adult-onset polycystic kidney, which was later confirmed to be inherited from the mother. In addition, parental heterozygous variants associated with autosomal recessive diseases were detected in three families, including one with additional fetal diagnostic findings. Diagnostic results or fetal IFs contributed to parental decision-making about termination of the pregnancy in 26 families (26/72 (36.1%)), while negative pES results or identification of VUS encouraged 40 families (40/72 (55.6%)) to continue their pregnancy, which ended in a live birth in all cases.
Trio-based pES can provide additional genetic information for pregnancies with fetal ultrasound anomalies without a CNV-seq diagnosis. The incidental findings and parental carrier status reported by trio-based pES with splice-site and mitochondrial genome analysis extend its clinical application, but careful genetic counseling is warranted. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.