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
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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and included our unpublished case.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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