Abstract
BACKGROUND: The 10q26 microdeletion syndrome (OMIM #609625) is a distinct genomic disorder characterized by a spectrum of clinical features including craniofacial anomalies, developmental delay (DD)/intellectual disability (ID), hypotonia, cardiovascular, and urogenital malformations. Despite the identification of critical regions within 10q26 linked to the syndrome's phenotype, the specific genes responsible for the associated facial characteristics, microcephaly, cognitive issues, and growth deficiencies remain elusive. Interstitial deletions at 10q25.3-q26.3 are rare, and their contributions to 10q26 microdeletion syndrome remain unknown. METHODS: We conducted trio-whole-exome sequencing (WES) on a fetus presenting with ventricular septal defect (VSD), aortic span, intrauterine growth retardation (IUGR), and microcephaly. Variant classification was assessed according to the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines, and the causative gene associated with cognitive phenotype was refined by means of smallest regions of overlap (SRO). RESULTS: A homozygous variant c.1544A>G (p.Tyr515Cys) in MMP21 and a large deletion at 10q26.13-q26.2 which unmasked the homozygous mutation were identified in the proband. The maternally inherited 10q26.13q26.2 deletion was classified as likely pathogenic, while the variant c.1544A>G was of uncertain significance (VUS) based on ACMG/AMP criteria. A critical interval of approximately ~500 kb implicating the involving genes DOCK1 and INSYN2A (inhibitory synaptic factor 2A) in the cognitive phenotype of 10q26 microdeletion syndrome was refined. CONCLUSION: This study introduces a recessive MMP21 mutation unmasked by a rare 10q26.13q26.2 deletion via WES in a Chinese fetus with congenital heart disease (CHD), IUGR, and microcephaly. We further refine INSYN2A as a potential candidate gene for cognitive phenotype in 10q26.1-q26.3 region. Our study also highlights the utility of WES for its advantage in simultaneously analyzing both single nucleotide variants (SNVs) and copy number variants (CNVs) and provide a reference for prenatal diagnosis and genetic counseling in patients with similar conditions.