Pure Interstitial Trisomy 11q Arising from a Nonrecurrent 11q13.1q22.3 Mosaic Intrachromosomal Duplication in a Patient with Craniofacial Dysmorphism and Genital Anomalies

Abstract

<b><i>Introduction:</i></b> The pure interstitial trisomy 11q11q23.2 is an uncommon genomic disorder associated with nonrecurrent intrachromosomal duplications. The phenotype is characterized by intellectual disability and craniofacial abnormalities. Given their uncommonness, a comprehensive genotype-phenotype correlation has not fully been defined. <b><i>Case Presentation:</i></b> We report the clinical and cytogenomic characterization of a 5-year-old boy with intellectual disability, psychomotor retardation, craniofacial dysmorphism, genital anomalies, and pure interstitial trisomy 11q arising from a nonrecurrent 11q13.1q22.3 intrachromosomal duplication in a high-mosaic state (>80%). The duplicated chromosome was characterized by cytogenetics, multicolor banding FISH, and SNP array. We demonstrated the wide mosaic distribution of the 11q duplication by interphase FISH in tissues from different embryonic germ layers. The duplication involves a copy number gain of 45.3 Mb containing 22 dosage-sensitive genes. We confirmed the overexpression of dosage-sensitive genes along the duplicated region using RT-qPCR. <b><i>Discussion:</i></b> Only 8 patients have been described. Our patient shares clinical features with previous reports but differs from them by the presence of genital anomalies. We provide a detailed clinical review and an accurate genotype-phenotype correlation and propose <i>PC</i>, <i>NDUFV1</i>, <i>FGF3</i>, <i>FGF4</i>, and <i>DHCR7</i> as dosage-sensitive genes with a possible role in the clinical spectrum of our patient; however, expression changes of <i>FGF3/4</i> were not detected since they must be regulated in a spatiotemporal way. This patient contributes to the accurate description of the pure interstitial trisomy 11q. Future reports could continue to delineate the description, considering the relationship between the chromosome segment and the genes involved.

Structural perturbation of chromatin domains with multiple developmental regulators can severely impact gene regulation and development

“…Interestingly, duplication of this region in the genome of Ridgeback dogs leads to dermoid sinus and causes dysregulation of FGF genes (Salmon Hillbertz et al, 2007). In humans, duplication of the chromosomal 11q13 region, which includes FGF3 and FGF4 causes intellectual disability, craniosynostosis and microcephaly (Grillo et al, 2014;Jehee et al, 2007;Martinez Anaya et al, 2023;Ziebart et al, 2013). Furthermore, global DNA hypermethylation seen in gastrointestinal stromal tumor (GIST) patients leads to recurrent loss of CTCF binding in the boundary between ANO1 and the FGF genes, and higher levels of FGF activity (Flavahan et al, 2019).…”