Work

A novel LARP7 variant expands the phenotypic spectrum of Alazami syndrome and reveals transcriptomic dysregulation of developmental and extracellular matrix pathways

Year: 2026

Type: article

Abstract: Background LARP7 encodes a critical scaffold protein of the 7SK small nuclear ribonucleoprotein (7SK snRNP) complex that regulates RNA polymerase II transcriptional elongation. Biallelic loss-of-function variants in LARP7 cause Alazami syndrome, a rare neurodevelopmental disorder characterized by intellectual disability, growth restriction, and distinctive craniofacial features. However, the transcriptomic consequences of LARP7 deficiency in human cells remain poorly understood, and the phenotypic spectrum of the disorder is incompletely defined. Methods We investigated a 6-year-old boy with clinically diagnosed Alazami syndrome who carried a novel homozygous LARP7 frameshift variant. Clinical evaluation and exome sequencing of blood-derived genomic DNA were performed, while quantitative PCR, Western blotting, and transcriptomic analysis were conducted using patient-derived dermal fibroblasts. Transcriptomic consequences of LARP7 deficiency were assessed by RNA sequencing, followed by single-subject differential expression, pathway enrichment, and network analyses. Results The patient presented with classical features of Alazami syndrome and tetralogy of Fallot, a cardiac manifestation not previously reported in the disorder. The novel homozygous LARP7 frameshift variant resulted in marked depletion of LARP7 transcripts and complete loss of full-length protein. Transcriptome-wide analysis identified 1,224 dysregulated genes involved in extracellular matrix organization, developmental remodeling, cell-cycle regulation, and immune signaling. Pathway and network analyses highlighted dysregulation of STAT3-associated signaling together with SMAD3-linked extracellular matrix and developmental programs, identifying candidate developmental and tissue-remodeling pathways that warrant further investigation in disease-relevant models. Conclusion This study provides the first comprehensive transcriptomic characterization of genetically confirmed LARP7 deficiency in primary human cells and potentially expands the phenotypic spectrum of Alazami syndrome. The findings reveal widespread dysregulation of developmental and extracellular matrix pathways, offering new insight into the molecular basis of the multisystem manifestations of Alazami syndrome and providing a framework for future functional and genotype–phenotype studies.

Source: Frontiers in Cell and Developmental Biology

DOI: 10.3389/fcell.2026.1904805