A novel LARP7 variant expands the phenotypic spectrum of Alazami syndrome and reveals transcriptomic dysregulation of developmental and extracellular matrix pathways.
- 1Department of Genetics and Genomics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
Abstract
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. 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. 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. 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.
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BibTeX
@article{hassan2026novel,
title = {{A novel LARP7 variant expands the phenotypic spectrum of Alazami syndrome and reveals transcriptomic dysregulation of developmental and extracellular matrix pathways.}},
author = {Mozan Hassan and Manal Irshaid and Aalia Batool and Wadima Aldhaheri and Latifa Ba Qehaizel and Shamma Alzaabi and Shamma Alnuaimi and Sara Saeed and Fatma Al Jasmi and Nadia Akawi},
journal = {Frontiers in cell and developmental biology},
year = {2026},
month = oct,
doi = {10.3389/fcell.2026.1904805},
url = {https://europepmc.org/article/MED/42952713},
note = {CC BY},
}
RIS
TY - JOUR
TI - A novel LARP7 variant expands the phenotypic spectrum of Alazami syndrome and reveals transcriptomic dysregulation of developmental and extracellular matrix pathways.
AU - Mozan Hassan
AU - Manal Irshaid
AU - Aalia Batool
AU - Wadima Aldhaheri
AU - Latifa Ba Qehaizel
AU - Shamma Alzaabi
AU - Shamma Alnuaimi
AU - Sara Saeed
AU - Fatma Al Jasmi
AU - Nadia Akawi
PY - 2026
DA - 2026/10/14
JO - Frontiers in cell and developmental biology
DO - 10.3389/fcell.2026.1904805
UR - https://europepmc.org/article/MED/42952713
AB - 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. 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. 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. 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.
SN - 2296-634X
ER -