(1188) Genotype-phenotype correlations in prenatal skeletal dysplasias

Objective:

While the genetic mechanisms of many skeletal dysplasias are well-established, the relationship between these mechanisms and phenotype variation is poorly understood. This retrospective case series explores whether dysplasias caused by similar biologic or genomic effects exhibit prenatal phenotypic heterogeneity.


Study Design:
A retrospective case series of prenatal skeletal dysplasias were identified over three years across five Fetal Sequencing Consortium centers and an additional center. All cases included had prenatal duo or trio genome sequencing and resulted in a live birth.  Data abstracted included fetal biometric measurements [femur length (FL), abdominal circumference (AC), thoracic circumference (TC)], additional imaging studies, and genetic results.

Results:

Eleven cases were identified and listed in descending  FL Z-scores in Table 1.  Figure 1 demonstrates the ultrasound findings based on the underlying gene function. Long bone changes (FL/AC< 0.16, bowing, fractures), often the first feature of skeletal dysplasia detected on ultrasound, were seen across all gene functions. Thoracic findings (TC/AC< 0.83, pulmonary hypoplasia, short ribs), associated with more severe disease, were seen in variants in fibroblast growth factor receptor signaling (FGFR1, FGFR3) and collagen synthesis (COL1A1, COL1A2).  Ciliary signaling pathway gene variants (ECV2, KIAA0586, DYNC2H1) were associated with more non-skeletal anomalies. All variants affecting cartilage formation (CSGALNACT1, ACAN) and DNA repair (POLE) had milder phenotypes.


Conclusion:
There is significant phenotypic variation among skeletal dysplasias when stratified by genetic mechanisms and fetal phenotype alone appears to be poorly predictive of underlying mechanisms. Exome or genome sequencing should be considered for suspected skeletal dysplasias due to the phenotypic and molecular heterogeneity of these conditions. Future studies should incorporate functional analyses to elucidate the molecular mechanisms driving severe congenital skeletal disease, especially as in-utero fetal therapies are developed.