RESUMEN
Emerging research has demonstrated that genomic alterations disrupting topologically associated domains (TADs) and chromatin interactions underlie the pathogenic mechanisms of specific copy number variants (CNVs) in neurodevelopmental disorders. We report two patients with a de novo deletion and a duplication in chromosome 4q31, potentially causing FBX-related neurodevelopmental syndrome by affecting the regulatory region of FBXW7. High-throughput chromosome conformation capture (Hi-C) analysis using available capture data in neural progenitor cells revealed the rewiring of the TAD boundary close to FBXW7. Both patients exhibited facial dysmorphisms, cardiac and limb abnormalities, and neurodevelopmental delays, showing significant clinical overlap with previously reported FBXW7-related features. We also included an additional 10 patients with CNVs in the 4q31 region from the literature and the DECIPHER database for Hi-C analysis, which confirmed that disruption of the regulatory region of FBXW7 likely contributes to the developmental defects observed in these patients.
Asunto(s)
Cromosomas Humanos Par 4 , Variaciones en el Número de Copia de ADN , Proteína 7 que Contiene Repeticiones F-Box-WD , Trastornos del Neurodesarrollo , Humanos , Proteína 7 que Contiene Repeticiones F-Box-WD/genética , Variaciones en el Número de Copia de ADN/genética , Masculino , Femenino , Trastornos del Neurodesarrollo/genética , Cromosomas Humanos Par 4/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Preescolar , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/patología , Predisposición Genética a la Enfermedad , Niño , LactanteRESUMEN
BACKGROUND: Interstitial deletions of chromosome band 10q11-q22 was a genomic disorder distinguished by developmental delay, congenital cleft palate and muscular hypotonia. The phenotypes involved were heterogeneous, hinge on the variable breakpoints and size. CASE PRESENTATION: Here, we presented a patient with soft palate cleft, growth and development delay. The patient was a 2 years and 5 months girl who was not able to walk unless using a children's crutches to support herself. Whole-exome sequencing (WES) and whole-genome mate-pair sequencing (WGMS) were both performed by next generation sequencing (NGS). A 20.76 Mb deletion at 10q11.23q22.1 (seq[GRCh37/hg19]del(10)(50,319,387-71,083,899) × 1) was revealed by the WGMS, which was verified as de novo by quantitative polymerase chain reaction (QPCR). CONCLUSION: Children with 10q11-q22 deletions greater than 20 MB have never been reported before, and we are the first to report and provide a detailed clinical phenotype, which brings further knowledge of 10q11-q22 deletions.