A SYSTEMATIC CLINICAL REVIEW OF PRENATALLY DIAGNOSED TETRASOMY 9p
Vinkšel M, Volk M, Peterlin B, Lovrecic L*
*Corresponding Author: Luca Lovrecic, M.D., Ph.D., Assistant Professor, Clinical Institute of Medical Genetics, University Medical Centre Ljubljana, Zaloska cesta 002, SI-1000 Ljubljana, Slovenia. Tel: +386-1-522-6057. Fax: +386-1-540-1137. E-mail: luca.lovrecic@kclj.si
page: 11

DISCUSSION

Herein we reviewed all previously published prenatal cases of tetrasomy 9p available in the PubMed database, and included our unpublished case. To the best of our knowledge, our case is the first prenatal case where the tetrasomy 9p presented with an increased NT of 4.1 mm as the only phenotypic finding during the first trimester ultrasound scan. Our case was detected early in pregnancy and therefore other abnormalities, commonly associated with tetrasomy 9p, might not have been detected. Nevertheless, properly oriented counselling and early specific diagnosis provided sufficient information and support for the parents during their decision-making process. Altogether, the most common prenatally detected features of tetrasomy 9p are CNS abnormalities (59%), limb/ skeletal malformations (50.0%), IUGR (45.0%), cleft lip and/or palate (45.0%). Additionally, facial dysmorphism, abnormality of the genitourinary system, abnormality of the amniotic fluid, and heart defects have also been described. This wide variability of clinical features in fetuses with tetrasomy 9p (Tables 2 and 3) might be explained by the difference of a mosaic vs. nonmosaic forms, the level of mosaicism, a limitation of chromosomal anomaly to certain tissues, and the size of the isochromosome 9p and Hsa9 genes presented in four copies [5,7,34,36,44]. The tissue-specific mosaicism was fully investigated in 5/7 prenatal mosaic cases [4,5,33,34,52], and it was suggested that this chromosomal rearrangement is better tolerated in lymphocytes compared to fibroblasts, amniocytes or chorionic villi (4,57), where the isochromosome was present with a lower frequency or not at all. Supporting this, there are considerably fewer cases of a mosaic form of tetrasomy 9p reported prenatally in comparison to full tetrasomy 9p. One might speculate that the loss of tetrasomy 9p cells in the long-term culture of mosaic cases is the main reason. This is supported with a report of false-negative prenatal cases [4,7,22,25,42]. With the application of microarray technology uncultured cells are analyzed, providing significant advantage over classical cytogenetic techniques (faster turn-around time, no need for culturing and losing mosaic tetrasomy 9p). Another plausible explanation for lower detection rate ultrasound presentation of these cases during pregnancy [7,22,25,42]. Interestingly, while comparing the trisomy 9p and tetrasomy 9p, we found that both syndromes have similar phenotype features but the clinical characteristics are much milder in trisomy 9p compared to tetrasomy 9p. This might be due to additional copy number of the whole 9p region in the tetrasomy 9p cases, but further cases of prenatal trisomy 9p need to be analyzed to make a conclusion. Newer case reports of the tetrasomy 9p used high throughput techniques such as a comparative genomic hybridization, which has the ability to define the break points more accurately, thus improving the understanding of the genotype-phenotype correlation. The severity of the tetrasomy 9p phenotype increases with the involvement of the q arm; it was suggested that the presence of the 9q arm in the tetrasomic cases is related to the severity of cardiac malformations, intellectual disability and death, but the review was based on a small number of cases and/or the use of cytogenetic techniques without precise mapping of the breakpoint in earlier cases (5). We identified only three non-mosaic tetrasomy 9p prenatal cases that have been molecularly characterized by aCGH [4,5,7], and involved the 9q arm [5,7]. Of the three, only one case had an additional gene involved within the amplified region of the q arm [5], i.e., CNTNAP3 gene (contactin associated protein-like 3, OMIM610517). The protein encoded by this gene belongs to the family of cell-recognition molecules. The family represents a subgroup of the neurexins. Neurexins have a role in the CNS as cell-surface receptors and their presence is important in neurotransmission and synapse formation. The exact function of CNTNAP3 remains to be determined [58]. There are still many factors to be elucidated that might play a role in the tetrasomy 9p phenotype; the contribution of each gene, a determination of the dosage-sensitive genes in 9p and/or 9q regions, the presence of presumably imprinted genes, a possible effect of the breakpoint on the disruption of gene regulation, and the unknown effect of involved non-coding regions. More cases discovered and characterized using genomic techniques and additional knowledge on the function of proteins involved will improve our understanding of the etiopathogenesis of the tetrasomy 9p disorder and offer the development of new therapeutic approaches. Fetuses with increased NT measurements are at risk of having atypical chromosomal abnormalities in addition to the risk of common aneuploidies. Currently, noninvasive prenatal testing (NITP) is clinically validated for common aneuploidies only; these rare chromosomal abnormalities, such as tetrasomy 9p, are not optimally detectable by NIPT. A recent population study in Denmark revealed that among 193 638 pregnancies that underwent invasive testing, 11% of foetuses had abnormal karyotype [59]. Of these, 23.4% phenotypically significant atypical chromosomal aberrations would be missed by currently available NIPT [59]. Therefore, the invasive diagnostic testing with high throughput techniques such as aCGH is still the gold standard for fetuses with ultrasound anomalies enabling rapid and definite diagnosis. In conclusion, an accurate and fast delivered genetic diagnosis in the prenatal setting allows the parents informed decision making. A pre-testing genetic counseling with the parents undergoing invasive procedure and genetic testing should also include rare, but clinically no less important, genomic findings, in addition to the common chromosome aberrations. The ultrasound measurement of NT remains an important marker for chromosome abnormalities even in the non-invasive prenatal screening era. However, neither ultrasound assessment nor first trimester screening can propose a definite diagnosis of tetrasomy 9p. The congenital anomalies of tetrasomy 9p show a considerable clinical variation, and the same anomalies are common in fetuses with a broad range of chromosome abnormalities, including trisomy 13, 18 and 21. An invasive genetic test is still needed for accurate diagnosis of chromosomal anomalies, including tetrasomy 9p. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.



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