Clinical Utility of Whole Exome Sequencing in the Diagnosis of Fetal Short Femur
10.11714/jsysu.med.YX20250170
- VernacularTitle:家系全外显子组检测在胎儿股骨短小中的诊断应用
- Author:
Manqi CHEN
1
;
Zewei HUANG
2
;
Qi XU
1
;
Shuning ZHANG
1
;
Xiaojun CHEN
2
;
Haiyan YAN
1
;
Xiang LI
2
;
Shuai FU
1
Author Information
1. Department of Obstetrics， Sun Yat-sen Memorial Hospital， Sun Yat-sen University， Guangzhou 510120， China
2. Prenatal Diagnosis and Medical Genetics Center， Shenshan Medical Center， Memorial Hospital of Sun Yat-sen University，Shanwei 516600， China
- Publication Type:Journal Article
- Keywords:
whole exome sequencing;
copy number variation;
short femur;
prenatal diagnosis;
genetic pathology
- From:
Journal of Sun Yat-sen University(Medical Sciences)
2026;47(2):368-378
- CountryChina
- Language:Chinese
-
Abstract:
ObjectiveTo enhance the genetic diagnostic yield for fetal short femur length （FL） and to evaluate the integration of whole exome sequencing （WES） with chromosomal abnormality detection in prenatal diagnosis. MethodsA total of 27 mid-to-late trimester fetuses diagnosed with short FL ［FL < 5th percentile for gestational age or < -2 SD （Standard Deviation）］ at the Prenatal Diagnosis And Medical Genetics Center，Shenshan Medical Center，Memorial Hospital of Sun Yat-Sen University between November 2023 and May 2025 were included. Amniotic fluid or umbilical cord blood samples were collected and subjected to chromosomal karyotyping （19cases）， chromosomal microarray analysis （CMA） or low-coverage whole genome copy number variation（CNV-Seq） （27 cases）， and trio-based whole exome sequencing （trio-WES） （27 cases）. The pathogenicity of genetic variants were interpreted according to the American College of Medical Genetics and Genomics （ACMG） guidelines. ResultsTwenty-six genomic variants were detected in 17 of the 26 fetuses， including numerical chromosomal abnormalities （mosaic type）， copy number variations （CNVs）， single nucleotide variants （SNVs） and insertions-deletions （INDELs）. Genomic variants detected in 11 cases could explain the short femur phenotype.The overall diagnostic rate was 11/27， with pathogenic/likely pathogenic variants explaining 9 cases and variants of uncertain significance （VUS） accounting for 1 cases. In addition Chromosomal karyotype analysis revealed chromosome mosaicism explaining 1 case. The diagnostic rate of CNV detection （CMA/CNV-seq） was 2/27， while WES achieved a diagnostic rate of 10/27， with an incremental yield of 8/27 in cases with negative or inconclusive CNV results. Pathogenic mutations involved genes such as FGFR3， SHOX， DUOX2， CLCN5， and HBA1/HBA2. ConclusionTrio-WES significantly improves the genetic diagnostic rate for fetal short femur length， particularly in cases where chromosomal analysis fails to identify a cause. Karyotyping remains valuable for detecting low-level mosaicism in large-scale chromosomal abnormalities， thereby complementing WES and CNV detection. A stepwise or parallel genetic testing strategy is recommended in prenatal diagnosis to optimize diagnostic efficiency and support clinical decision-making.
