Autopsy findings in EPG5‐related Vici syndrome with antenatal onset: Additional report of Focal cortical microdysgenesis in a second trimester fetus

We read with interest the report of the autopsy findings of a fetus with Vici syndrome by Touraine et al. (2017).Wewould like to report another sibpairwithVici syndrome, oneof the sibbeing a 21weeks fetus inwhich additional histopathological features were detected. These sibs were conceivedof a third degree consanguineouscouple. Theclinical details of the elder sibling were limited, as the child expired prior to complete workup. This female childwas found to have global developmental delay, failure to thrive, sensori-neural hearing loss, cortical blindness, fair complexion relative to parents with hypopigmented body hair, history of recurrent lower respiratory tract infections and no significant dysmorphism; many of these findings ascertained retrospectively following molecular diagnosis in the second sib (Figure 1a). MRI brain showed complete agenesis of corpus callosum, ventriculomegaly, and pontine hypoplasia at 2 months age, but no other significant abnormalities (Figure 1b). In the subsequent conception, ultrasound at 17 weeks depicted bilateral prominent lateral ventricles, and MRI at 20 weeks confirmed complete corpus callosum agenesis and pontine hypoplasia (Figure 1c). In view of the severe phenotype of the first sibling, a poor prognosis was anticipated and the pregnancy terminated. Postmortem examination of the baby did not reveal any obvious dysmorphism or external anomalies. Anthropometry revealed, weight at 350 gms (30th centile for 21 weeks), crown heel length of 29.5 cm (90th centile for 21 weeks) and head circumference of 18.5 cm (50th centile for 21 weeks). Visceral examinationwas unremarkable. Partial brain autolysis prevented detailed assessment of sulcation pattern. Complete corpus callosum agenesis was present, with bilateral prominent lateral ventricles, but other brain structures were unremarkable. Histopathological examination of the brain tissue indicated dilated ventricular cavities with congested meningocortical vessels, intermittent foci of aberrations in cortical layering and presence of multiple small dysgenetic clusters of undifferentiated neurons in the cortex. These featureswere indicative of focal cortical microdysgenesis (Figure 1d). In view of partial autolysis of brain tissue, detailedhistopathological characterizationof individual brain structures was not feasible. No definitive diagnosis could be concluded on basis of these findings, and whole exome sequencing on fetal DNA wasplanned.WES revealedanovel homozygoussingle basepair deletion inEPG5 (NM_020964.2:c.4665delA;p.E1555fs) causingframeshift at the 6th codon of exon 27and creating a stop codon (TAG) at 17thposition of the altered exon 27 from start (Figure 1e). The pathogenicity of the variant was tested using online program Combined Annotation Dependent Depletion (CADD) version 1.3. The variant was validated in the family using Sanger sequencing and submitted to ClinVar (SCV000494026.1). This variant was consistent with the diagnosis of Vici syndrome, and the clinical presentation of the first sibling. Clinical details were submitted to Phenomecentral (ID P0003689). Prenatal testing in subsequent pregnancy revealed a fetus with heterozygous EPG5mutation and normal neurosonography findings. This researchwas prospectively reviewed and approved by a duly constituted institutional ethics committee. The histological features of focal cortical microdysgenesis add to the previously described pathological findings from five cases of Vici syndrome, none of which report this finding (Byrne et al., 2016; Dionisi Vici et al., 1988; Miyata, Hayashi, & Itoh, 2014; Rogers, Aufmuth, & Monesson, 2011). This abnormality appears along the continuum of cortical developmental defects, which manifest variably as polymicrogyria, simplified gyration, white matter neuronal heterotopia in other reported cases of this rare disorder (Byrne et al., 2016; del Campo et al., 1999;Maillard et al., 2017). Interestingly, the elder sibling in this family did not have MRI abnormalities of sulcation-gyration, indicating that this is an inconsistent feature, and cannot always be used for supporting an antenatal suspicion of Vici syndrome. To conclude, this is a report of a novel EPG5mutation in a 21week fetus and its sibling affected with Vici syndrome. This is the second report of brain histology in Vici syndrome in the prenatal period, at earliest reported gestation till date; with previously unreported finding of focal cortical microdysgenesis, thereby expanding the spectrum of disordered cortical development in this syndrome.