Introduction
Snijders Blok- Campeau Syndrome is a rare syndrome with only 60 total cases reported. Of these reported cases, the vast majority are diagnosed post-birth following whole genome sequencing for concerns of intellectual disability, dysmorphic facial features and macrocephaly. Only two prior prenatal cases have been reported, following antenatal diagnosis of hydrocephalus (PMID: 37635562) and macrocephaly (PMID: 34000720). Snijders Blok-Campeau syndrome has been reported with anomalies of the central nervous system, but not Dandy-Walker malformation specifically (PMID: 32483341).



The severity of neurological effects of this syndrome, as well as presence of phenotypic features, is highly variable among patients.

Case Presentation
A 38 y/o G5P1031 presented at 16 weeks gestation to Maternal Fetal Medicine for asymmetric choroid plexus cyst with low-risk cell-free DNA screening. Follow up anatomy ultrasound at 19 weeks showed Dandy-Walker malformation. Fetal MRI confirmed prominent fluid collection in the posterior fossa, hypoplastic vermis and an increased tegmento-vermian angle.

Diagnostic Workup
In light of the imaging findings, the patient elected to proceed with amniocentesis with concurrent chromosome microarray and whole genome sequencing (WGS). Chromosome microarray was negative.



Whole genome sequencing identified a de novo, heterozygous, likely pathologic variant in the CHD3 gene, specifically c.1643G>A p.Arg548Gln. Pathogenic variants in this gene have previously been associated with Autosomal Dominant Snijders Blok-Campeau syndrome.

Treatment and Management
The patient and her partner underwent extensive counseling with Maternal Fetal Medicine, Clinical Genomics and Pediatric Neurology. Discussed range of potential neurologic impairment with Dandy-Walker malformation, including ataxia, cognitive impairment, seizures and increased chance of childhood mortality.

Outcome and Follow-Up
Ultimately, the patient had already elected to undergo termination based on the imaging findings, but results of the WGS were provided to the patient on the day of her induction. They were also counseled on the low recurrence risk in future pregnancies, and the small risk of gonadal mosaicism.

Discussion
The CHD3 gene encodes protein Mi-2alpha of the Nucleosome Remodeling and Deacetylase (NuRN) complex, and is overall crucial in modification of chromatin organization and dynamics. Pathogenic variants of the CHD3 gene, can affect chromatin remodeling process and subsequently disrupt regulation of gene expression for normal neurodevelopment, as seen with Snijders-Blok Campeau syndrome.



Most reported cases of Snijders-Blok Campeau syndrome are based on postnatal phenotypes and subsequent genetic testing. Few cases have detected this syndrome antenatally based on sonographic findings. Given the variability in neurologic deficit severity and phenotypic presentation, antenatal diagnosis may be challenging, but can offer patients options and education regarding pregnancy care.



Genetic testing beyond a chromosome microarray is not routinely performed for patients with Dandy-Walker malformation, but this case adds to the list of single-gene disorders which are associated with Dandy-Walker malformation, including dystroglycanopathies (PMID: 31756055), DDX3X-associated intellectual disability (PMID: 38058759), Ritscher-Schinzel syndrome, Kabuki syndrome (PMID: 33008324) and Joubert syndrome.

Conclusion
Dandy-Walker malformation has not previously been reported in cases of Snijders-Blok Campeau, so this case represents an expansion of the phenotype. Additional research will be necessary to understand the mechanism by which pathogenic variants in CHD3 can cause brain malformations, and what other factors influence the phenotype.

Dandy- Walker malformation can be attributed to chromosomal abnormality or syndrome in approximately one-third of cases (PMID: 28635420) , however a wide spectrum of single-gene disorders have also been associated, which are not detected by microarray. Thus, in the setting of normal non-invasive prenatal screening with Dandy-Walker malformation, consideration for whole genome sequencing should be undertaken, if available.



Prenatal genetic testing can significantly alter a patient’s ongoing pregnancy course, and thus should be offered to each patient with concerns of sonographic anomalies.