The present case report demonstrated that the patient carried an unbalanced translocation inherited from the mother who was a balanced translocation carrier, which resulted in partial trisomy for 9p (spanning ~ 32.34 Mb) and partial monosomy for 7p (spanning ~ 3.30 Mb). To the best of our knowledge, the present study is the first report of an unbalanced translocation involving chromosomes 7p and 9p.
9p trisomy is often caused by heterozygous segregation of familial chromosomal translocations. Most reports include deletions of other chromosomes. Common phenotypes of trisomy 9p include growth and language intellectual disability, abnormal ear position, hypertelorism, bulbous nose, low mouth angle, and abnormal hand and foot finger development[
2]. The severity of the partial trisomy 9p phenotype was correlated with the length of the repeat in the short arm of chromosome 9 and the repeat region. Duplications in the 9p13-p21 region have less effect on mental development whereas some genes associated with mental development (
DOCK8,
FOXD4,
VLDLR, etc.) are present in the 9p22-9p24 region where the very low density lipoprotein receptor gene (
VLDLR) transduces a variety of extracellular signals across the neural cell membrane into the CNS, regulates synaptic plasticity and is important for specific learning and memory functions in the hippocampus [
7]. The duplications in p21.1-p24.3 of chromosome 9 in the patient involved“trisomy 9 syndrome, which contains 100 OMIM genes. There are multiple patients in the Decipher database carrying pathogenic or potentially pathogenic variants that partially overlap with this CNV interval. It has been reported in the literature that the main clinical manifestations of patients with 9p22-p24 duplication include short stature, microcephaly, peculiar facial features, and congenital heart disease [
8‐
10]. The clinical phenotype of this patient was generally consistent with the phenotypes reported in the literature, with the addition of other typical phenotypic features, such as a hawkish nose and presence of unilocular ptosis. This discrepancy may be due to the fact that it carries a 9p repeat fragment that is less consistent with the above literature. Another possibility may be due to its coexistence with a heterozygous deletion of approximately 3.30 Mb in the 7p22.2p22.3 region, which contains 30 OMIM genes including 11 morbidity-associated genes (
BRAT1,
FAM20C, EIP3B,
LFNG,
INTS1, etc.).
INTS1 and
BRAT1 genes are located at 7p22.3 and are associated with uniform neurodevelopmental disorders [
11]. It has been reported in the literature [
12] that the main clinical phenotype of patients with 7p22.2p22.3 deletion is a peculiar facial appearance, with developmental delay in speech, etc. Both chromosomal copy number variants in this patient have been reported frequently in patient databases, with the involvement of additional genes, and all were determined to be pathogenic CNVs according to ACMG guidelines. The reported phenotypes correlate with the patient’s phenotype, but the reported phenotypes were more variable and our patient was comparatively younger. Many phenotypes require further clinical excavation, verification and follow-up observations. Whether haploinsufficiency of any OMIM gene necessarily leads to a clinical phenotype requires further summary and follow-up of additional cases. In this case, the patient had both trisomy 9p and monosomy 7p. It is possible that abnormal alterations in these two chromosomes interact to form a specific phenotype.
Phenotypic outcomes such as recurrent spontaneous abortion, embryonic arrest and multiple neonatal malformations tend to manifest in carriers of chromosomal balanced translocation. The results of karyotype analysis suggested that the mother of the patient was a 46, XX, t (7; 9) (p22; p21) balanced translocation carrier, which was the direct cause of the microdeletion of segment 7p22.2p22.3 and the duplication of segment 9p21.1p24.3 in the patient. The reason for this is that the probability for a balanced translocation carrier to produce normal gametes is extremely low, with a theoretical probability of obtaining phenotypically normal offspring of only 1/9 [
13,
14] and an actual probability of about 1/3. The mechanism of CNV formation in this patient may be due to the instability of the parental translocation chromosome break sites. For such children, prenatal diagnosis and preimplantation genetic diagnosis (PGD) are the main ways to reduce birth defects, so that children with genetic defects and various congenital anomalies can be detected early, and intrauterine treatment can be performed at the right time for those who are eligible and can be corrected, and those who cannot be corrected can have their pregnancies terminated in time to reduce the birth of defective children. In addition, prenatal diagnosis allows the chromosomes of both parents to be known in order to obtain the karyotype, breakpoints, and mode of inheritance of the translocation, providing a basis for genetic counseling and prenatal diagnosis for the incidence of translocation chromosome carriers and pregnancy outcome as well as revealing the genetic etiology of the clinical manifestations of the affected children. During the genetic counseling process, a comprehensive analysis should be performed in conjunction with several factors such as the type of translocation in the translocation carrier, the chromosomes involved in the translocation, and the location of the breakpoint of the translocation.
In conclusion, the occurrence of concurrent partial trisomy 9q (9p21.1p24.3) and partial monosomy 7p (7p22.2p22.3) has not previously been reported up to now. This study combined the application of karyotype analysis and CNV-seq to finally confirm the diagnosis for the patient. The use of CNV-seq and karyotype may facilitate a sensitive and powerful approach towards the diagnosis of submicroscopic unbalanced genomic rearrangements. This study clarified the origin and formation mechanism of CNV in children, and analyzed the relationship between chromosomal structure abnormalities and patient phenotype. Due to the clear mechanism of its occurrence and high risk of recurrence, clinical genetic counseling was presented to the patient’s mother where she was advised to undergo prenatal examination and diagnosis in the event of future pregnancies.