A Complex Chromosome Rearrangement Disrupting <i>SYT1</i> Supports Haploinsufficiency as a Cause of Baker–Gordon Syndrome

Baker-Gordon syndrome (BAGOS) is an autosomal dominant neurodevelopmental disorder caused by <i>de novo</i> heterozygous missense mutations in <i>SYT1</i>. The precise pathogenic mechanism of BAGOS is still unclear, with preliminary data favoring a dominant-negative effect, although a previous case presenting a reciprocal translocation disrupting <i>SYT1</i> supports haploinsufficiency as a possible mechanism. We report a child with a syndromic neurodevelopmental disorder compatible with BAGOS and carrying a t(5; 12)(q31; q21) by G-banded karyotype. Optical genome mapping (OGM) is based on ultrahigh molecular weight DNA molecules allowing the combined analyses of numerical and structural chromosome variants. The rearrangement was investigated using OGM, which revealed an additional structural variant, a paracentric inversion in the segment of Chromosome 12 translocated to der(5). The breakpoint of the paracentric inversion is mapped to Intron 9 of the <i>SYT1</i> gene, interrupting the C2B domain. This is the second BAGOS case reported in the literature caused by <i>SYT1</i> disruption, supporting that reduced amounts of functional SYT1, either by haploinsufficiency or dominant-negative effect, is responsible for <i>SYT1</i>-associated neurodevelopmental syndrome.