Abstract - Text

Abstract-Text

Hemizygous mutations in BCORL1 (BCL6 corepressor-like 1), a transcriptional co-repressor, are associated with Shukla-Vernon syndrome, an extremely rare X-linked recessive neurodevelopmental disorder characterized by developmental delay, intellectual disability, behavioral abnormalities and dysmorphic features. Some patients present with seizures and cerebellar hypoplasia. Female carriers are mostly unaffected but may have learning difficulties. So far, only few cases of Shukla-Vernon syndrome with BCORL1 pathogenic variants haven been reported. Recently, novel variants of unknown significance (VUS) of BCORL1 in male patients with more severe clinical manifestations like neonatal intractable epilepsy, profound global developmental delay and major brain malformations, inherited from healthy mothers, were reported. All these reported mutations in BCORL1 are missense alterations. Here, we report a novel hemizygous frameshift alteration c.960dupT, p.(V321Cfs*99) in BCORL1 in two deceased male fetuses with multiple ultrasonographic abnormalities in two consecutive pregnancies of the same mother.

The first fetus presented with oligohydramnios, ventricular septal defect, horseshoe kidney, dolichocephaly and Dandy-Walker malformation and fetal growth being in the lower percentile range. The other one had a congenital heart defect (small left heart structures), ventriculomegaly, omphalocele, single umbilical artery, accelerated fetal heart rate, suspicion of renal agenesis and markedly reduced amniotic fluid. The couple has no further children and a prior early miscarriage. The phenotypically unaffected mother was a heterozygous carrier of a de novo BCORL1 variant.

This frameshift mutation in the fourth of 13 exons of BCORL1 leads to a premature stop codon and most likely to a loss of function. In the general population (dbSNP) this alteration is not listed, indicating that it is very rare. So far, no disease associated loss-of-function (LOF) variants in BCORL1 have been described in the literature. Anyhow, the probability of loss-of-function intolerance (pLI)-score of 1 might suggest that hemizygous mutations are not compatible with life. The fact that the variant occurred de novo in the mother is indicative for pathogenicity. The loss-of-function might explain the more severe phenotype of the fetuses, compared to phenotypes associated with BCORL1 missense variants. On the other hand, eight hemizygous loss-of-function mutations (frameshift and stop mutations) in BCORL1 are listed in gnomAD. In addition, in male mouse models with BCORL1 knockout, only spermatogenesis was affected. Further, BCORL1 loss is described to be associated with infertility, which might explain the underrepresentation of BCORL1 LOF variants in the general population. In summary, the current data are insufficient to assess whether this variant is associated with the malformations of the two deceased fetuses. Thus, we currently classify the sequence change as a VUS.