Ring Chromosome 9 and Chromosome 9p Deletion Syndrome in a Patient Associated with Developmental Delay: A Case Report and Review of the Literature

Abstract

Ring chromosomes have been described for all human chromosomes and are typically associated with physical and/or mental abnormalities resulting from a deletion of the terminal ends of both chromosome arms. This report describes the presence of a ring chromosome 9 in a 2-year-old male child associated with developmental delay. The proband manifested a severe phenotype comprising facial dysmorphism, congenital heart defects, and seizures. The child also exhibited multiple cell lines with mosaic patterns of double rings, a dicentric ring and loss of the ring associated with mitotic instability and dynamic tissue-specific mosaicism. His karyotype was 46,XY,r(9)(p22q34)[89]/46,XY,dic r(9; 9)(p22q34;p22q34)[6]/45, XY,-9[4]/47,XY,r(9),+r(9)[1]. However, the karyotypes of his parents and elder brother were normal. FISH using mBAND probe and subtelomeric probes specific for p and q arms for chromosome 9 showed no deletion in any of the regions. Chromosomal microarray analysis led to the identification of a heterozygous deletion of 15.7 Mb from 9p22.3 to 9p24.3. The probable role of the deleted genes in the manifestation of the phenotype of the proband is discussed.

Ring chromosome formation by intra‐strand repairing of subtelomeric double stand breaks and clinico‐cytogenomic correlations for ring chromosome 9

“…The r(9) patients of Qin et al (2016) and Marsudi et al (2018) supported that haploinsufficiency of the DMRT1 gene could lead to 46,XY complete gonadal dysgenesis and sex reversal. The relevant manifestations of Nicolaides‐Baraitser syndrome were shown in the r(9) patients of La Cour Sibbesen et al (2013), Sivasankaran et al (2016) and Qin et al (2016) but not in the patients of Laursen et al (2015), Lyu et al (2019) and the present patient. The phenotypes of isolated metopic craniosynostosis and trigonocephaly were also seen in the r(9) studies of La Cour Sibbesen et al (2013), Sivasankaran et al (2016) and Qin et al (2016).…”

“…The relevant manifestations of Nicolaides‐Baraitser syndrome were shown in the r(9) patients of La Cour Sibbesen et al (2013), Sivasankaran et al (2016) and Qin et al (2016) but not in the patients of Laursen et al (2015), Lyu et al (2019) and the present patient. The phenotypes of isolated metopic craniosynostosis and trigonocephaly were also seen in the r(9) studies of La Cour Sibbesen et al (2013), Sivasankaran et al (2016) and Qin et al (2016). The infectious complications, which candidate genes could be CD274 and IL33 at 9p24.1, were seen in the r(9) patient of Qin et al (2016).…”

“…Review of literature found seven patients of r(9) with clinical and cytogenomic findings, including one prenatal fetus (Penacho et al, 2014) and six postnatal patients (La Cour Sibbesen, Jespersgaard, Alosi, Bisgaard, & Tümer, 2013; Laursen et al, 2015; Sivasankaran, Kanakavalli, Anuradha, Samuel, & Kandukuri, 2016; Qin et al, 2016; Marsudi et al, 2018; Lyu, Li, Li, Shang, & Ma, 2019). Ring chromosome instability index (RCII) was defined as the percentage of cells with ring chromosome variants and loss of ring chromosome.…”

From karyotypes to precision genomics in 9p deletion and duplication syndromes

“… 16 Additionally, in approximately 50% of all cases of 9p minus syndrome, the affected individual also has an associated translocation event, and these translocations have not previously been preferentially linked to any specific chromosome. 18 Beyond translocation events, even more complex variations including ring chromosomes 2 and mosaicism have also been observed for some rearrangements and CNVs involving 9p 19 as well as trisomy 9p mosaic syndrome. 20 , 21 Understanding the exact nature of the variation is essential to identify the genes affected by the variant and to link genotype to phenotype.…”

“…Despite the general genetic and phenotypic variability seen in individuals with 9p deletions and duplications, some progress has been made in associating common 9p phenotypes with genes in the region. These candidates include DMRT1 (MIM: 602424 ) and DMRT3 (MIM: 614754 ) in the DSD phenotype; 17 , 27 , 29 FREM1 (MIM: 608944 ) implicated for trigonocephaly; 19 , 34 FOXD4 (MIM: 601092 ) for speech and language deficits; 12 , 19 , 26 DOCK8 (MIM: 611432 ) for IDs and seizure disorders that are commonly seen in individuals with 9p CNVs; 12 , 15 , 19 , 29 GLDC (MIM: 238300 ), 19 VLDLR (MIM: 192977 ), 19 and ZDHHC21 (MIM: 614605 ) 10 for IDs and/or seizure disorders; 19 and CBWD1 (MIM: 611078 ), which is associated with cobalamin deficiency (feeding difficulties, failure to thrive, hypotonia, seizures, microcephaly, ID, and developmental delay 26 ). KANK1 (MIM: 607704 ) (previously known as ANKRD15 ) displays what appears to be a maternal imprinting mechanism in which inherited cerebral palsy can occur when the paternal copy of the gene is disrupted.…”