Unique Female Patient with de novo 6q22.31q27 Duplication and Xq28 Deletion: Case Report and Brief Literature Review

Lamiae Afif ^1,2,*, Zhour El Amrani ^1,2, Aziza Sbiti ², Ilham Ratbi ¹, Imane Cherkaoui Jaouad ¹, Youssef El Kadiri ^1,2, Thomas Liehr ³, Abdelaziz Sefiani ^1,2, Abdelhafid Natiq ^1,*

1. Research team in genomics and molecular epidemiology of genetic diseases, Genomics Center of Human Pathologies, Faculty of Medicine and Pharmacy, University Mohammed V in Rabat, Morocco

2. Department of Medical Genetics, National Institute of Health in Rabat, 27 Avenue Ibn Batouta, B.P 769,11400 Rabat, Morocco

3. Jena University Hospital, Friedrich Schiller University, Institute of Human Genetics, Am Klinikum 1, D-07747 Jena, Germany

* Correspondences: Lamiae Afif and Abdelhafid Natiq

Academic Editor: Fabrizio Stasolla

Received: April 02, 2024 | Accepted: August 20, 2024 | Published: August 30, 2024

OBM Genetics 2024, Volume 8, Issue 3, doi:10.21926/obm.genet.2403259

Recommended citation: Afif L, El Amrani Z, Sbiti A, Ratbi I, Jaouad IC, El Kadiri Y, Liehr T, Sefiani A, Natiq A. Unique Female Patient with de novo 6q22.31q27 Duplication and Xq28 Deletion: Case Report and Brief Literature Review. OBM Genetics 2024; 8(3): 259; doi:10.21926/obm.genet.2403259.

© 2024 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

1. Introduction

Partial trisomy of the long arm of chromosome 6 and Xq28 deletion are two rare specific chromosomal disorders.

Most patients with unbalanced translocations have partial trisomy 6q and partial monosomy of another chromosome. The co-existence of these two types of chromosomal anomalies, especially the monosomy of another chromosome, would usually make it complicated to clearly interpret the genotype-phenotype correlation of pure 6q duplication [1,2].

This report describes a 10-year-old girl with a de novo 6q22.31q27 duplication and Xq28 deletion. To characterize the phenotype, the patient’s clinical findings are compared with those of other reported patients with similar duplication of 6q and deletion of Xq28.

2. Case Report

2.1 Patient’s Medical History

The patient was referred to the Department of Medical Genetics in Rabat for development delay and facial dysmorphism. The patient, a 10-year-old girl of a young and nonconsanguineous Moroccan couple (mother 28y, father 32y), was the family's second child. There were no health problems in the family or a history of miscarriages. She was delivered at 38 weeks of gestation, and the ultrasound scan in the third trimester showed intrauterine growth retardation.

Clinical manifestations included psychomotor delay, intellectual disability, joint contractures of both ankles, and generalized stiffness at articulations and facial dysmorphism with the following dysmorphic stigmata: carp-shaped mouth, micrognathia, frontal bossing, prominent eyes with hypertelorism, microcephaly, down slanting palpebral fissures and short neck.

The pre-analytic and post-analytic steps described in this work were performed for patients by the Department of Medical Genetics of the National Institute of Health as medical services in agreement with the tenets of the Declaration of Helsinki.

All ethical issues of the National Institute of Health in Rabat, Morocco, where the Department of Medical Genetics are in charge of an Intramural Advisory Committee.

Written informed consent was obtained from the patient's parents.

2.2 Classical Cytogenetics and Chromosomal Microarray Analysis

The patient’s parents gave informed consent for this study. Venous blood (3 to 5 ml) acquired in a heparinized tube was taken from the patient and his parents for cytogenetic and molecular cytogenetic studies.

Further routine investigations included a brain MRI, abdominal ultrasound and an electroencephalogram.

Chromosome analyses from cultivated peripheral blood lymphocytes of proband and parents were done.

Chromosomal microarray (CMA) analyses by microarray Cyto Array (180K, GRCh37/hg19 – Agilent) were performed and evaluated by Agilent Cyto Genomics 5.1.2.1 software and tamper detection algorithm ADM-2 threshold value of 6.0.

2.3 Molecular Cytogenetics Analysis

Fluorescence in situ hybridization (FISH) according to standard procedures using a whole chromosome 6 probe (wcp 6), the locus-specific probe RP11-100A16 in 6q22.31 (hg19: 121,028,121-121,205,654) and a partial chromosome probe (pcpc) for short and long arm of X-chromosome as well a subtelomeric probe for Xqter.

3. Result

Chromosome analyses revealed normal karyotypes in both parents, but a karyotype: 46,X, der(X) of their daughter(Figure 1A).

Figure 1 Techniques for Chromosomal Aberration Analysis (Karyotyping, FISH, and CGH). A) Karyotype of the patient-showing der(X). B) FISH was used to detect der(X) and 6. Using probes WCP (Whole chromosome painting) of chromosomes 6; locus-specific probe RP11-100A16, and a partial chromosome probe (pcpc) for the short and long arm of X-chromosome and subtelomeric probe for Xqter Results of FISH revealed the presence of a der(6)t(X;6)(q28;q22.31). C) Chromosomal aberration of the imbalances seen in CMA.

A 50.04 Mb heterozygote terminal duplication in 6q22.31q27(chr6:120,870,936_170,911,240) and a 3.338 Mb heterozygote terminal deletion in Xq28 (chrX:151,895,062_155,232,907) were detected (shown in Figure 1C).

FISH experiments further confirmed the presence of a der(6), classifying it as der(6)t(X;6)(q28;q22.31) as underlying chromosomal aberration of the imbalances seen in CMA (shown in Figure 1B).

4. Discussion and Conclusion

Various phenotypes have been described, and variable clinical signs exist for each chromosomal aberration. To our knowledge, the case reported here is the first in the literature involving the duplication of 6q22.31q27 and deletion of the Xq28 chromosomal region. An increased number of studies can help to identify chromosomal aberration causes and clinical effects more clearly.

The partial duplication of the long arm of chromosome 6 was described first by [De Grouchy et al., 1969], and since this time, other additional cases have been reported [3].

The phenotype's severity depends on the duplication's size and gene content.

In this study, we identified and selected all genes reported in the Online Mendelian Inheritance in Man (OMIM) database (https://www.omim.org/) and located in the deleted region (chrX:151895062_155232907) in Xq28 (see Table 1) and in the large 50.04 Mb duplication region 6q22.31-q27 (see Table 2) using UCSC genome browser tool (https://genome.ucsc.edu/) with pseudogene filtration. Here, we were able to select 73 genes in Xq28 deletion. Searching the ClinGen database (https://clinicalgenome.org/) for these genes revealed that, out of these 73 genes, 18 have been reported to have gene-disease validity (Table 1), with definitive, moderate, and/or limited classifications.

Table 1 Gene list in deletion region in Xq28 shown in UCSC and gene-disease validity from CLinGen database.

Table 2 Gene list in duplication region in 6q22.31q27 (chr6:120870936_170911240) with OMIM numbers.

The considerable size of the duplication makes it difficult to establish a straightforward genotype-phenotype correlation.

The phenotype of the duplication 6q syndrome is distinctive enough to be clinically recognizable. Full trisomy 6 is incompatible with fetal survival. However, it has been found in spontaneous abortions [4].

Very few patients have pure 6q duplication. Most patients carry partial monosomy of another chromosome, which would usually interpret the genotype-phenotype correlation of this duplication as challenging to make [1,2].

Duplicated regions of the long arm of chromosome 6 display many common anomalies but define a clinically specific syndrome.

A review of the literature of similar patients with chromosomal rearrangements involving chromosome 6 is summarized in Table 3.

Table 3 Comparative features of patients with partial trisomy of the long arm of chromosome 6 in our case and published literature.

Of particular note is the similarity of the phenotype and the breakpoint duplication 6q22 to 6qter in our case with that presented by [5,6,7].

The duplicated segment in [8,9] is slightly larger than the other cases [8,9,10,11,12]. The common duplicated segment is 6q23->q27. However, it has been suggested that the critical band involved in the expression of the phenotype of 6q duplication is located in this segment.

Almost all patients have in common microcephaly, frontal bossing, micrognathia, prominent eyes with hypertelorism, down-slanting palpebral fissures, short necks, and a carp-shaped mouth. Thus, the facial appearance allows the identification of the underlying chromosome abnormality.

Individuals with Partial Trisomy 6q may also have various internal organ malformations, such as cardiac or renal anomalies. Regarding cardiac anomaly, it has not been detected in our case but seen in 7 other compared patients [6,7,8,9,10,11,12]. Cardiac anomalies range from atrial septal defects to complex malformations. Therefore, children with partial duplication of 6q deserve a cardiac evaluation. The cases reported by [7,8,9,10,11] have also renal abnormalities.

All patients show psychomotor retardation. Motor development may be severely impaired due to multiple contractures and skeletal anomalies. They are seen in 7 of 8 patients reviewed. In our patients, they contribute to gross motor difficulties.

Duplications of 6q are the result of either an abnormal segregation of a balanced translocation or inversion carried by a parent or of a de novo unbalanced rearrangement, as in our case. Often, the duplication is combined with a deletion of the other chromosomal segment involved in the rearrangement.

The monosomic segment in our patient is Xq28; the phenotype of girls with X chromosome deletions has ranged from completely normal to severe phenotype. Characteristics of patients carrying chromosomal Xq28 rearrangements are summarized in Table 4.

Table 4 Features of patients with Xq deletion.

Observations were made in the patients about features such as developmental delay and primary/secondary amenorrhoea. Still, these two last traits are variable due to age, so it is difficult to make firm conclusions about this. For some patients, the deletion did not appear severe due to the young age and the region's size deleted.

Individuals with terminal deletions at Xq28 show perturbations of ovarian function. Several studies have been proposed to explain the deletion that occurred on Xq. It has been suggested that there is a critical region for premature ovarian failure between Xq26.2 and Xq28 [4].

The long arm of the X chromosome (Xq) appears prone to structural rearrangements and is capable of translocating with other chromosomes. Petkovic et al. (2003) reported a case of a girl with a derivative X chromosome resulting from a translocation between chromosomes X and 6. Due to the age of this patient, the phenotypic features present in Xq deletions could not be fully evaluated, similar to our case [20].

The most common finding in girls with Xqter deletions has been premature ovarian failure (POF) and secondary amenorrhea [18]. It is related to deletion and other factors. X chromosome inactivation could be one of them. It is not well known when it takes place; slight differences in the time of skewing of X inactivation in germ cells or granulosa cells may alter the number of ovarian follicles and determine the age of onset of premature ovarian failure [21].

Our analysis of the clinical features of this case in comparison with existing literature demonstrates significant similarities with the phenotype observed in partial trisomy 6q. The 6q duplication observed in this patient is likely responsible for the abnormal clinical manifestations. This case study documents a rare chromosomal configuration and explores the complexities of genotype-phenotype correlation in the context of large-scale genomic alterations. Our findings provide a foundation for future research into similar chromosomal abnormalities and their clinical manifestations.

Acknowledgments

We thank the patient and his family.

Author Contributions

LA, ZE: Investigation, Writing–original draft, Methodology. ASb: Writing–review, editing and Validation. YE: Writing–original draft and editing. IR, ICJ performed the clinical evaluation. TL, ASe: Formal Analysis, Writing–review. AN: Validation, Writing–review and editing.

Funding

This study had no funding source.

Competing Interests

The authors have no conflicts of interest to declare.

Data Availability Statement

All data generated or analyzed during this study are included in this article [and/or] its supplementary material files.