Clinical value of genetic analysis in prenatal diagnosis of short femur

Abstract

BackgroundFetal femur length (FL) is an important biometric index in prenatal screening. The etiology of short femur is diverse, with some pathogenic causes leading to adverse outcomes. To improve the accuracy and practicability of diagnosis, we investigated the value of genetic analysis in prenatal diagnosis of short femur.MethodsWe examined chromosomal microarray analysis (CMA) (64 fetuses) and karyotyping (59 fetuses) data retrospectively for short femur without fetal growth restriction (FGR). Genetic testing was conducted for 15 fetuses.ResultsKaryotyping and CMA detected chromosomal aberrations at rates of 13.6% and 27.2%, respectively. Among fetuses with other abnormalities, detection rates were 21.0% higher with CMA than karyotyping. CMA identified chromosomal abnormalities in 36.4% of cases with a FL 2–4 standard deviations (SDs) below the gestational age (GA) mean. Abnormality detection by CMA reached 38.5% in the second trimester. Duplication of 12p, 16p13.1 deletion, and uniparental disomy 16 were identified by CMA in three cases of short femur. Gene sequencing detected clinically notable mutations in 12/15 fetuses, among which 9/12 fetuses had FLs >4 SDs below the GA mean.ConclusionsCMA yielded a higher detection value than karyotyping in fetuses with other abnormalities or a FL 2–4 SDs below the GA mean during the second trimester. Gene sequencing should be performed when FL is >4 SDs below the mean.

Prenatal diagnosis of genetic aberrations in fetuses with short femur detected by ultrasound: A prospective cohort study

“…Short femur is a sonographic soft marker for Down syndrome 5,9,10,14,28 . In our study, the incidence of trisomy 21 was only 1.24% (2/161), which was much lower than Liu et al 8 . (8.5%) reported.…”

“…Fetal short femur is a diagnostic challenge for clinicians. Although in most cases, it represents a normal fetus and/or familial variation, it may be a marker of aneuploidy, be associated with skeletal dysplasia, or be a sign of IUGR 1–13 . We performed a prospective study to investigate the genetic aberrations and clinical prognoses in fetuses with short FL, and explore the relationships with respect to degree of femoral shortening and to GA at initial diagnosis.…”

“…While a short FL often represents a normal variant, it is also recognized as a marker of skeletal dysplasia or chromosomal abnormalities 7–10 . Additionally, there are multiple studies reporting on short FL as an early marker of intrauterine growth retardation (IUGR), small for gestational age (SGA) neonate, low birth weight (LBW), and preterm birth (PTB) caused by placental dysfunction 4,11–13 …”

“…With a sensitivity of 16% in prediction of Down syndrome, 14 short FL in the second trimester is considered an important ultrasound soft marker for fetal aneuploidy, particularly trisomy 21 5–10 . Molecular‐level approaches have increasingly been applied in prenatal diagnosis during the past decade.…”

“…Recently, CMA has be recommended as the first‐tier approach for the prenatal diagnostic evaluation of fetuses with structural anomalies 15 . There is, however, a paucity of studies that focus on the prevalence of submicroscopic chromosomal aberrations in fetuses with short FL 8,16 …”