Utilizing Fetal MRI and Prenatal Medical Exome Sequencing for Prenatal Diagnosis of Kinked Brainstem: A Case Series

Objective Utilizing fetal MRI and prenatal Medical Exome Sequencing (pMES) for prenatal diagnosis in fetuses exhibiting a kinked or 'z-shaped' brainstem. Methods A retrospective analysis was conducted on cases of brainstem kinking identified on antenatal imaging between January 2013 and December 2022. Systematic review was performed on clinical data from these cases, encompassing maternal demographics, indications for invasive prenatal diagnosis, ultrasound findings, SNP-array results, trio-medical exome sequencing (Trio-MES) results, pregnancy outcomes and follow-ups. Results Two cases of fetuses presenting with a "kinked brainstem," along with other CNS abnormalities in fetal MRI were identified using Trio pMES. Prenatal phenotype features observed in our case series include "Z" shaped brainstem, hydrocephalus, hyperechogenic kidneys and generalized skin edema, cobblestone lissencephaly, cerebellar dysplasia, cerebral arachnoid cyst. Trio pMES identified a homozygous variant at c.815_816del (p.Leu272ArgfsTer117) in the FKRP gene for Patient 1. For Patient 2, a de novo heterozygous variant c.848A > G(p.H283R) was detected in the TUBA1A gene. Both variants were predicted to be likely pathogenic or pathogenic. Conclusion A kinked or "z-shaped" brainstem is a finding that can be more easily delineated on fetal MRI compared to fetal ultrasound, indicating an underlying dystroglycanopathy (Walker-Warburg phenotype) or tubulinopathy. Prenatal exome sequencing can aid in achieving early prenatal genetic diagnosis for cases of "kinked brainstem". Moreover, our study expands its scope by incorporating additional features such as hyperechogenic kidneys and generalized skin edema into the prenatal findings of Walker-Warburg syndrome.