Interstitial deletion 4p15.32p16.1 and complex chromoplexy in a female proband with severe neurodevelopmental delay, growth failure and dysmorphism.

Complex chromosomal rearrangements involve the restructuring of genetic material within a single chromosome or across multiple chromosomes. These events can cause serious human disease by disrupting coding DNA and gene regulatory elements via deletions, duplications, and structural rearrangements. Here we describe a 5-year-old female with severe developmental delay, dysmorphic features, multi-suture craniosynostosis, and growth failure found to have a complex series of balanced intra- and inter-chromosomal rearrangements involving chromosomes 4, 11, 13, and X. Initial clinical studies were performed by karyotype, chromosomal microarray, and FISH with research-based short-read genome sequencing coupled with sanger sequencing to precisely map her breakpoints to the base pair resolution to understand the molecular basis of her phenotype. Genome analysis revealed two pathogenic deletions at 4p16.1-p15.32 and 4q31.1, accounting for her developmental delay and dysmorphism. We identified over 60 breakpoints, many with blunt ends and limited homology, supporting a role for non-homologous end joining in restructuring and resolution of the seminal chromoplexy event. We propose that the complexity of our patient's genomic rearrangements with a high number of breakpoints causes dysregulation of gene expression by three-dimensional chromatin interactions or topologically associating domains leading to growth failure and craniosynostosis. Our work supports an important role for genome sequencing in understanding the molecular basis of complex chromosomal rearrangements in human disease.

Further supporting SMARCC2-related neurodevelopmental disorder through exome analysis and reanalysis in two patients.

BAFopathies are a heterogenous group of neurodevelopmental disorders caused by mutations in genes encoding subunits of the BAF complex, and they exhibit a broad clinical phenotypic spectrum. Pathogenic heterozygous variants in SMARCC2 have been implicated in Coffin-Siris syndrome 8 (MIM 618362) with variable neurodevelopmental presentations. We report here two relatively severely affected patients with two different SMARCC2 variants: one has de novo pathogenic variant, c.1824_1826del, p.(Leu609del), in a suspected hotspot region through reanalysis of previously negative clinical exome data, and the other has a likely pathogenic loss-of-function variant, c.1094_1097delAGAA, p.(Lys365Thrfs*12) through exome analysis in an adopted subject. Regardless of variant type, both patients have severe developmental delays, severe speech delay, short stature, hypotonia, seizures, and craniofacial dysmorphisms, blurring previously speculated genotype-phenotype correlation on missense and loss-of-function variants. This report extends our understanding of the genotypic and phenotypic spectrums of the SMARCC2-related neurodevelopmental disorder.