SMARCC1 is a susceptibility gene for congenital hydrocephalus with an autosomal dominant inheritance mode and incomplete penetrance

A Jewish couple of mixed origin was referred for genetic counseling following termination of pregnancy at 18 weeks of gestation due to severe ventriculomegaly with aqueduct stenosis. Trio exome sequencing revealed a loss‐of‐function heterozygous variant in the SMARCC1 gene inherited from an unaffected mother. The SMARCC1 gene is associated with embryonic neurodevelopmental processes. Recent studies have linked perturbations of the gene with autosomal dominant congenital hydrocephalus, albeit with reduced penetrance. However, these studies were not referenced in the SMARCC1 OMIM record (*601732) and the gene was not considered, at the time, an OMIM morbid gene. Following our case and appeal, SMARCC1 is now considered a susceptibility gene for hydrocephalus. This allowed us to reclassify the variant as likely pathogenic and empowered the couple to make informed reproductive choices.

Transvaginal ultrasound examination at 17 þ 3 weeks gestation revealed a male fetus with a dilated third ventricle with aqueduct stenosis, and dilated lateral ventricles (LVs) measuring 14 and 15 mm ( Figure 1). In addition, a unilateral pelvic kidney was noted. No other anomalies were detected. Due to the poor prognosis, the couple decided to terminate the pregnancy at 18 weeks of gestation. Clinical data are summarized in Table 1.

| DIAGNOSTIC METHOD
Following genetic counseling and informed consent, trio exome sequencing (ES) was performed in-house on a NovaSeq 6000 (Illumina). The bioinformatic pipeline, including variant analysis, up to final report was performed using the Franklin data analysis platform (Genoox), as previously described. 1 Table 2.

| DIAGNOSTIC RESULTS AND INTERPRETATION
The variant was initially classified as a variant of unknown significance because it was inherited from an unaffected mother ( Figure 1) and since SMARCC1 was not considered, at the time, an OMIM morbid gene. However, recent publications suggest that SMARCC1 insufficiency increases the risk of congenital hydrocephalus. 2,3 ES results of 381 children with congenital hydrocephalus demonstrated that SMARCC1 had significantly more protein-altering, de novo variants than would be expected by chance. Interestingly, all reported patients with SMARCC1 variants had congenital hydrocephalus due to aqueduct stenosis, as was seen in this study. It is noteworthy that in most cases, the loss-of-function variants were transmitted from an unaffected parent, except for two cases with de novo variants. 2,3 Thus, the suggested inheritance model is autosomal dominant with incomplete penetrance. Moreover, in a mouse model harboring a unique SMARCC1 missense variant, 20% of heterozygotes and 80% of homozygotes had exencephaly, a neural tube defect (NTD). This phenotype has been attributed to inappropriate proliferation and increased apoptosis of neural progenitor cells in the neural tube. 4 Inline with the mouse model, a single report described monozygotic twins with NTDs and a loss-of-function variant in SMARCC1. 5 Given these findings and our appeal to OMIM, the gene was upgraded to a susceptibility gene for hydrocephalus (#620241). 6 The variant was therefore, reclassified as likely pathogenic according to the American College of Medical Genetics and Genomics guidelines.
Following these results, we recommended segregation analysis and MRI. The mother reported that she had migraines since childhood but was otherwise healthy. Brain MRI showed a small arachnoid cyst. The SMARCC1 variant was found to be inherited from her mother (Figure 1), who was reportedly healthy, but her brain MRI demonstrated a hemangioma. It is currently unclear whether these findings are related to the SMARCC1 variant.

| PREGNANCY OUTCOME
The pregnancy was terminated at week 18. Post-mortem examination showed a male fetus weighing 210 g, appropriate for gestational age. Multiple congenital anomalies were noted (Figure 1

| DISCUSSION
Our report confirms the association between SMARCC1 haploinsufficiency and congenital hydrocephalus with aqueduct stenosis, in addition to other multisystem malformations, including brain (e.g. lobar holoprosencephaly) and renal (e.g. dilation of renal pelvises) as well as dysmorphic features. This appears to be inherited in an autosomal dominant pattern with incomplete penetrance. A recently published review reported two novel pathogenic SMARCC1 variants in fetuses with ventriculomegaly. One variant was associated with additional brain malformations, including gyration delay and abnormal aspect of frontal horns. In addition, abnormalities were noted in other systems, including renal and skeletal malformations. 7 Overall, our and previous reports suggest that SMARCC1 haploinsufficiency is not only associated with hydrocephalus due to aqueduct stenosis, but also with other central nervous system (CNS) and non-CNS malformations.
Further studies are needed to assess the degree of penetrance.
Our report further exemplifies that incomplete penetrance may be misleading in the interpretation and classification of variants inherited from an apparently healthy parent. This highlights the importance of a thorough analysis using updated relevant sources. This allows accurate genetic counseling regarding recurrence risks and