Complex Genomic Rearrangement Involving the TBX4 Promoter Manifesting With Variable Expressivity in a Five‐Generation Family

Functional noncoding variants within the TBX1 enhancer contribute to tetralogy of Fallot.

Reduced dosage of Kmt2d modifies Tbx1 haploinsufficiency toward phenotypes of 22q11.2DS

Haploinsufficiency of TBX1, which occurs in 22q11.2 deletion syndrome (22q11.2DS), leads to a heterogeneous spectrum of clinical manifestations, including craniofacial anomalies, immunodeficiency, and congenital heart defects. The variability in syndromic presentation between patients may be partially explained by variants in chromatin regulatory genes that act to further modify TBX1 function. To investigate this relationship, we selected KMT2D as a candidate gene because of its role in the etiology of Kabuki syndrome, which shares overlapping features with 22q11.2DS. We demonstrate that conditional inactivation of Kmt2d in the Tbx1 lineage in Tbx1-heterozygous mice leads to fully penetrant perinatal lethality and increased incidence of craniofacial dysmorphism, thymus and parathyroid gland hypoplasia, and aortic arch anomalies. At early stages, mutant embryos were found to have defects of the caudal pharyngeal apparatus, including abnormal patterning of the third pouch endoderm, hypoplastic fourth arches, and defective fourth arch arteries. Finally, analysis of single-cell RNA sequencing revealed dysregulation, and largely downregulation, of genes involved in basic cellular functions, suggesting that Tbx1 and Kmt2d developmentally converge upon essential biological processes. Overall, these results indicate that reduced dosage of Kmt2d perturbs the developmental landscape of the Tbx1 heterozygote, eliciting phenotypes that are shared between 22q11.2DS and Kabuki syndrome.

Expanding the Genomic Spectrum of NHLRC2-Associated FINCA Disease: Integrated Bioinformatic Characterization of a Novel Deep Intronic Variant Predicted to Activate a Pseudoexon

A male infant with a severe FINCA-like phenotype is reported, including early-onset hemolytic anemia, pulmonary involvement, neurodevelopmental impairment, growth failure, recurrent infections, and fatal progression at 8.5 months.

Position effect at the SOX3 locus by an interchromosomal insertion causes hereditary spastic paraplegia.

This work provides mechanistic evidence that a position effect at the SOX3 locus can cause hereditary spastic paraplegia and identifies a 3D regulatory rewiring of SOX3 and transcriptional dysregulation of SOX3 targets in iPSC-derived neurons.

Systematic genotype-phenotype mapping and transcriptomic analyses highlight SEMA6A as a candidate for neuronal migration defects in 5q22-q23 deletions.

Re-analysis of human fetal cortex single-cell RNA sequencing data demonstrated that SEMA6A and FLNA are significantly co-expressed in apical radial glia and newborn excitatory neurons, suggesting that SEMA6A is a candidate contributor to neuronal migration defects in 5q22.3-q23.3 deletions.

Identification of a novel and a recurrent CDC45 variant in a Chinese family with Meier-Gorlin syndrome 7 and a literature review

A Chinese patient presenting with classic hallmarks of MGORS7 alongside atypical clinical features, including hearing and visual impairments is reported, suggesting that growth hormone therapy may be beneficial for growth retardation in patients with MGORS7.