Next generation sequencing in prenatal diagnosis

Abstract

Background: Despite WES being extensively used in the clinical diagnosis of pediatric genetic disorders, routine application of the technology in pregnancies with SCAs is yet to be widely accepted. We aim to identify the genetic causes underlying SCAs in fetuses without a definitive diagnosis after conventional genetic testing. Methods: Couples with SCAs of the fetus detected during pregnancy were recruited from the prenatal diagnostic service, Tsan Yuk Hospital. Their antenatal histories were reviewed and those with a known cause of SCA, including aneuploidy or clinically significant chromosomal abnormalities on karyotyping and microarray, were excluded. WES was performed as trios if possible. Results: Thus far from 25 fetuses (23 trios, 2 singleton) analyzed, we identified 3 plausible disease-causing mutations. One fetus with small cerebellum and flexed elbows carried a de novo mutation in EEF1A2. Pathogenic alternation in EEF1A2 leads to an autosomal dominant neurodevelopmental disorder with infantile epileptic encephalopathy. Two inherited compound heterozygous mutations, in DIS3L2 and NPHP4 are known to cause Perlman syndrome and Senior-Loken syndrome respectively. They were plausible explanations for the phenotypes of agenesis of corpus callosum and dandy-walker malformation identified from prenatal ultrasound of these fetuses. Our analysis also identified mutations in a novel gene that may cause a fetal cerebellar malformation syndrome that will require further functional work to characterize. Conclusion: WES aids the identification of genetic causes of prenatal SCA in ~10% families with negative clinical testing. Hence we suggest that the use of WES for prenatal diagnosis is practically feasible in Hong Kong. The findings could make a major impact in genetic counselling and lead to novel genes discovery, or phenotypic expansion of known genetic syndromes. Acknowledgement: We would like to thanks the Health and Medical Research Fund (ref# 02131816) offered by the Government of HKSAR.