Rapid prenatal diagnosis of skeletal dysplasia using medical trio exome sequencing: Benefit for prenatal counseling and pregnancy management

Prenat Diagn. 2020 Apr;40(5):577-584. doi: 10.1002/pd.5653. Epub 2020 Feb 10.

Abstract

Objective: The aim of this study is to explore the utility of rapid medical trio exome sequencing (ES) for prenatal diagnosis using the skeletal dysplasia as an exemplar.

Method: Pregnant women who were referred for genetic testing because of ultrasound detection of fetal abnormalities suggestive of a skeletal dysplasia were identified prospectively. Fetal samples (amniocytes or cord blood), along with parental blood, were send for rapid copy number variations testing and medical trio ES in parallel.

Results: Definitive molecular diagnosis was made in 24/27 (88.9%) cases. Chromosomal abnormality (partial trisomy 18) was detected in one case. Sequencing results had explained the prenatal phenotype enabling definitive diagnoses to be made in 23 cases. There were 16 de novo dominant pathogenic variants, four dominant pathogenic variants inherited maternally or paternally, two recessive conditions with pathogenic variants inherited from unaffected parents, and one X-linked condition. The turnaround time from receipt of samples in the laboratory to reporting sequencing results was within 2 weeks.

Conclusion: Medical trio ES can yield very timely and high diagnostic rates in fetuses presenting with suspected skeletal dysplasia. These definite diagnoses aided parental counseling and decision making in most of cases.

MeSH terms

  • Abnormalities, Multiple / diagnosis
  • Abnormalities, Multiple / genetics
  • Achondroplasia / diagnosis
  • Achondroplasia / genetics
  • Adult
  • Brain Diseases / diagnosis
  • Brain Diseases / genetics
  • Campomelic Dysplasia / diagnosis
  • Campomelic Dysplasia / genetics
  • Carbohydrate Metabolism, Inborn Errors / diagnosis
  • Carbohydrate Metabolism, Inborn Errors / genetics
  • Congenital Disorders of Glycosylation / diagnosis
  • Congenital Disorders of Glycosylation / genetics
  • Exome Sequencing / methods*
  • Female
  • Fetal Growth Retardation / diagnosis
  • Fetal Growth Retardation / genetics
  • Genetic Counseling / methods
  • Genetic Testing / methods
  • Humans
  • Ichthyosis / diagnosis
  • Ichthyosis / genetics
  • Limb Deformities, Congenital / diagnosis
  • Limb Deformities, Congenital / genetics
  • Male
  • Microcephaly / diagnosis
  • Microcephaly / genetics
  • Osteochondrodysplasias / diagnosis*
  • Osteochondrodysplasias / genetics
  • Osteogenesis Imperfecta / diagnosis
  • Osteogenesis Imperfecta / genetics
  • Parents*
  • Pathology, Molecular
  • Phosphoglycerate Dehydrogenase / deficiency
  • Phosphoglycerate Dehydrogenase / genetics
  • Pregnancy
  • Prenatal Care / methods*
  • Prenatal Diagnosis
  • Psychomotor Disorders / diagnosis
  • Psychomotor Disorders / genetics
  • Receptor, Fibroblast Growth Factor, Type 3 / deficiency
  • Receptor, Fibroblast Growth Factor, Type 3 / genetics
  • Seizures / diagnosis
  • Seizures / genetics
  • Thanatophoric Dysplasia / diagnosis
  • Thanatophoric Dysplasia / genetics
  • Time Factors
  • Trisomy 18 Syndrome / diagnosis
  • Ultrasonography, Prenatal
  • Young Adult

Substances

  • Phosphoglycerate Dehydrogenase
  • Receptor, Fibroblast Growth Factor, Type 3

Supplementary concepts

  • Neu Laxova syndrome
  • Phosphoglycerate Dehydrogenase Deficiency
  • Thanatophoric Dysplasia, Type I