Exome sequencing in fetuses with short long bones detected by ultrasonography: A retrospective cohort study

Abstract

Background: Prenatal diagnosis of fetal short long bones (SLBs) was reported to be associated with skeletal dysplasias, chromosomal abnormalities, and genetic syndromes. This study aims to identify the genetic causes for fetal short long bones, and retrospectively evaluate the additional diagnostic yield of exome sequencing (ES) for short long bones following the use of conventional genetic testing.Methods: A cohort of ninety-four fetuses with sonographically identified short long bones was analyzed by trio-exome sequencing between January 2016 and June 2021. Fetuses with abnormal results of karyotype or chromosomal microarray analysis were excluded. Variants were interpreted based on ACMG/AMP guidelines. All diagnostic de novo variants were validated by Sanger sequencing.Results: Of the 94 fetuses, 38 (40.4%) were found to carry causal genetic variants (pathogenic or likely pathogenic) in sixteen genes with 38 variants. Five fetuses (5.3%) had variant(s) of uncertain significance. Thirty-five cases (37.2%) were diagnosed as genetic skeletal dysplasias including 14 different diseases that were classified into 10 groups according to the Nosology and Classification of Genetic Skeletal Disorders. The most common disease in the cohort was achondroplasia (28.9%), followed by osteogenesis imperfecta (18.4%), thanatophoric dysplasia (10.5%), chondrogenesis (7.9%), and 3-M syndrome (5.3%). The diagnostic yield in fetuses with isolated short long bones was lower than the fetuses with non-isolated short long bones, but not reached statistical significance (27.3% vs. 44.4%; p = 0.151). Whereas, the rate in the fetuses with other skeletal abnormalities was significantly higher than those with non-skeletal abnormalities (59.4% vs. 32.5%, p = 0.023), and the diagnostic rate was significantly higher in femur length (FL) below -4SDs group compared with FL 2-4SDs below GA group (72.5% vs. 16.7%; p < 0.001). A long-term follow-up showed that outcomes for fetuses with FL 2-4SDs below GA were significantly better than those with FL below -4SDs. Additionally, fourteen (36.8%) novel short long bones-related variants were identified in the present study.Conclusion: The findings suggest that in fetuses with short long bones routine genetic tests failed to determine the underlying causes, exome sequencing could add clinically relevant information that could assist the clinical management of pregnancies. Novel pathogenic variants identified may broaden the mutation spectrum for the disorders and contributes to clinical consultation and subsequent pregnancy examination.

Prenatal ultrasound findings and prenatal diagnosis of fetal skeletal dysplasia

“…Here, the overall mean GA at initial diagnosis was 22 weeks, with signs of fetal SF in ACH patients often first observed in the third trimester, aligning with previous research. 5,8 This study additionally revealed that TD can be detected earlier by ultrasound compared to OI. (B) Result of whole exome sequencing.…”

Prenatal diagnosis and preimplantation genetics testing of 3M syndrome in a Chinese family with novel biallelic variants of CUL7

“…A hypoplastic thorax should be distinguished from short‐rib thoracic dysplasia. As fetal exome sequencing has been applied for prenatal diagnosis, studies have shown that skeletal anomalies yield approximately 40% of diagnostic results, among which achondroplasia (28.9%) and osteogenesis imperfecta (18.4%) are the most common finding (Huang et al., 2023). In our study, the fetus exhibited shortening of the long bones and nasal bones and lateral temporal bone depression.…”

“…Prenatally, the presence of shortened long bones may suggest conditions such as osteogenic imperfecta or achondroplasia, which are not specific to 3M syndrome. Eight cases of 3M syndrome in fetuses have been diagnosed, and additional features have been reported in seven cases (Chincoli et al., 2014; Guo et al., 2020; Hu et al., 2017; Huang et al., 2023; Huber et al., 2009; Meo et al., 2000; Smogavec et al., 2022): two fetuses exhibited increased nuchal translucency (NT; Guo et al., 2020; Huang et al., 2023); two fetuses had a hypoplastic thorax; one had short nasal bones (Meo et al., 2000; Smogavec et al., 2022); one fetus had head frontal bossing and bilateral temporal bone depression (Hu et al., 2017); and one had characteristic facial features, prominent heels, and slender long bones (Huber et al., 2009). The increased NT should be distinguished from RASopathies, and most RASopathies do not exhibit severely short long bones during pregnancy.…”

Diagnostic Yield of Exome Sequencing in Fetuses with Sonographic Features of Skeletal Dysplasias but Normal Karyotype or Chromosomal Microarray Analysis: A Systematic Review

“…At the time of drafting this study, another cohort study had been published from China, showing an additional diagnostic rate of 40.4% (38 out of 94 fetuses) with exome sequencing [ 26 ]. Similar to our study, it had shown that the diagnostic yield in fetuses with isolated short long bones was lower than in the fetuses with nonisolated short long bones but did not reach statistical significance.…”