In this report, we describe a female child with dysmorphic features and developmental delay. Chromosome microarray analysis followed by conventional karyotyping revealed a ring chromosome 9 with a 12 Mb deletion at 9pter-p23 and a 540 kb deletion at 9q34.3-qter. Four percent of the analyzed cells had monosomy 9. The patient has the features of both the Kleefstra syndrome and the chromosome 9p-syndrome, including trigonocephaly, long philtrum, hypertelorism, and retro-/micronagthia. The deletion of the patient overlaps with several of the proposed critical regions for the 9p deletion syndrome.

Ring chromosome 9 in a girl with developmental delay and dysmorphic features: case report and review of the literature.

Patients with Turner syndrome are generally characterized by having short stature with no secondary sexual characteristics. Some abnormalities, such as webbed neck, renal malformations (>50%) and cardiac defects (10%) are less common. The intelligence of these patients is considered normal. Non-mosaic monosomy X is observed in approximately 45% of postnatal patients with Turner syndrome and the rest of the patients have structural abnormalities or mosaicism involving 46,X,i(Xq), 45,X/46,XX, 45,X and other variants. The phenotype of 45,X/46,X,+mar individuals varies by the genetic continent and degree of the mosaicism. The gene content of the marker chromosome is the most important when correlating the phenotype with the genotype. Here we present an 11-year-old female who was referred for evaluation of her short stature and learning disabilities. Conventional cytogenetic investigation showed a mosaic 45,X/46,X,+mar karyotype. Fluorescence in situ hybridization showed that the marker chromosome originated from the X chromosome within the androgen receptor (AR) and X-inactive specific transcript (XIST) genes. Therefore, it is possible that aberrant activation of the marker chromosome, compromising the AR and XIST genes, may modify the Turner syndrome phenotype.

A unique mosaic Turner syndrome patient with androgen receptor gene derived marker chromosome.

Context Precise genotype-phenotype correlations in Turner syndrome (TS) have not yet been deciphered. The chromosomal basis of the clinical TS-phenotype in the absence of X chromosome aberrations on the conventional karyotyping remains more and less unexplored. Objective To elucidate the high resolution chromosomal picture and analyze the genotype -phenotype associations in girls with clinical phenotype of TS by chromosomal microarray (CMA).Design and Patients: Cross sectional observational study conducted between October 2018 to January 2020 on 47 girls presenting the clinical TS-phenotype and fulfilling the criteria for chromosomal analysis. Setting Out Patient Department at Department of Endocrinology and the Molecular research lab at tertiary care teaching institution. Results The CNV (copy number variation) polymorphs were more frequent on autosomes than X chromosomes and they were detected in 89.3%, 61.7 %, and 92.8 % of patients respectively on chromosome 14 or X or both. Total 445 and 64 CNV polymorphs were discovered on chromosome X and 14 respectively. The latter exhibiting either gain at 14q32.33 or loss at 14q11.2 or both. Karyotype was available for 27 patients; 55.6% cases displayed X chromosome abnormalities while 44.4% cases had a normal karyotype. Functional interactomes of the genes those were present in Chromosome 14 CNVs and those known to be associated with TS showed an overlap of 67% and enriched various development-related cellular pathways underlying TS-phenotype. Conclusions On high resolution karyotype analysis, clinical phenotype of TS could be found associated with CNV defects in autosomes (specifically Chr. 14,) or X chromosome or both. The syndrome of chromosome 14 CNVs defects with and without X-chromosomal defects clinically mimics TS and shares a common genomic network deserves further investigations.

Higher CNV Frequencies in Chromosome 14 of Girls With Turner Syndrome Phenotype.

Objective To identify the origin and study the morphology of small supernumerary marker chromosome (sSMC) in Turner syndrome with 45 ,X/46,X, +mar karyotype. Methods Using the conventional chromosome G-banding technique, 10 cases of Turner syndrome with 45, X/46, X,+mar chromosome karyotype were obtained, dual-color fluorescence in situ hybridization was applied to study the origin and morphology of the sSMC. Results In the 10 cases of Turner syndrome with 45, X/46,X, +mar karyotype, the sSMC of 7 cases was derived from X chromosome [sSMC(X)-], the sSMC of 2 cases was derived from Y chromosome [sSMC(Y)] and the remaining 1 case was derived from the autosome. There were 4 cases of ring(r) chromosomes and 3 of eentrie minutes (min) in the 7 sSMC (X) cases. In the 2 sSMC(Y), one case was dicentric(dic) and the other was centric minute (min) . The sSMC originated from the autosome was a centric minute (min). Conclusion The origin of sSMC of Turner syndrome with 45,X/ 46,X, +mar karyotype was almost all from sex chromosomes, and rarely from autosomes, sSMC can exist as isodicentric, ring, or centric minute. The molecular cytogenetic features of the sSMC can provide useful information for genetic counseling, prenatal diagnosis and treatment of the Turner syndrome patients with a 45 ,X/46 ,X, +mar karyotype.

Key words: 
Turner syndrome;  small supernumerary marker chromosomes;  fluorescence in situ hybridization

[Analysis of the small supernumerary marker chromosome in Turner syndrome with 45, X/46, X, + mar karyotype].

Objective To investigate the mechanism of the ring chromosome 9 formation by cytogenetic analysis of one case affected with ring chromosome 9 syndrome. Methods Routine chromosome GTG-binding analysis and dual color fluorescence in situ hybridization （FISH） with TelVision 9p and 9q probes were applied to characterize the case. Results The G-binding revealed that the patient had ring chromosome 9 with the following karyotype： 45,X,-9/46,XX, r（9）（p24q34）/46,XX, r（9;9）（p24q34; p24q34）[4/92/4]. The dual color FISH analysis with TelVision 9p and TelVision 9q probes failed to detect a hybridization signal on the ring chromosome in the case, which indicated that at least 115 kb were deleted on the terminal 9p and 95 kb were deleted on the terminal 9q. Comparing to the cases reported in the literatures, our patient shared some common features of the 9p- and 9q syndrome. Conclusion The clinical features of patients with identical r（9） breakpoints present variable phenotypes. The possible cause might be the submicroscopic variation in the deletion breakpoints, variation in the ring stability, the modification of the expression of the deleted by the individual＇s genetic background, or the effect of changes in the fetal environment. The haploinsufficieney of genes located in the deleted regions may play critical roles in the patient phenotype as well.

Key words: 
ring chromosome 9 syndrome;  dual-color fluorescence in situ hybridization;  clinical phenotypes

Zhi-chun Ye

Papers

[Analysis of the small supernumerary marker chromosome in Turner syndrome with 45, X/46, X, + mar karyotype].

Analysis of ring chromosome 9 syndrome with fluorescence in situ hybridization