PHENOTYPIC VARIABILITY
OF 17Q12 MICRODELETION SYNDROME –
THREE CASES AND REVIEW OF LITERATURE
Țuțulan-Cuniță A, Pavel AG, Dimos L, Nedelea M,
Ursuleanu A, Neacșu AT, Budișteanu M, Stambouli D
*Corresponding Author: Andreea Țuțulan-Cuniță, Cytogenomic Medical Laboratory, 35 Calea Floreasca,
Bucharest, 14453, Romania, Tel: 0040212331354, Fax: 0040212331357, E-mail: cunita@cytogenomic.ro
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DISCUSSION
While the number of reported prenatal cases of 17q12
microdeletion is increasing and its clinical description is
continuously updated, the phenotypic variability of this
syndrome and the difficulties it raises in genetic counselling
invite a broader discussion regarding the molecular
mechanisms underlying this condition and their correlation
with clinical presentations. Decramer et al. (2017) [10]
suggest that about 20% of prenatal hyperechogenic kidney
cases are caused by 17q12 deletions, though O’Donnelly et
al. (2014) [11] hypothesize it to be the second most common
genetic anomaly in fetuses with abnormal ultrasound
results and a normal karyotype, following 22q11.21 deletion,
at a similar frequency with 16p13.11 deletion. 17q12
deletion is also among the ten most common microdeletions
in children with unexplained neurodevelopmental
disorders [12].
Our report describes three cases with prenatal urinary
tract anomalies (multicystic dysplastic kidney, megabladder,
and hydronephrosis, respectively); two of the pregnancies
were subsequently terminated, while the third case had
developmental delay and ASD. All our patients carry only
one functional copy of four genes classified as pathogenic
in OMIM: PIGW, ACACA, ZNHIT3, HNF1B, as well as the
LHX1 gene. While the mechanism causing megabladder
in the fetus of patient B cannot be traced unequivocally to
17q12 deletion, the presence of urinary tract abnormalities
in the clinical phenotype of this syndrome suggests a
plausible causal relationship.
As illustrated in table 1, prenatal phenotypes associated
with 17q12 microdeletion cover a large spectrum of
ultrasound markers, from none to hyperechogenic, multicystic,
or enlarged kidneys, absent unilateral kidney, and
hydronephrosis. These markers can be detected at as early
as 15 weeks of gestation [35], along with other findings (intestinal
obstruction, congenital diaphragmatic hernia, lung
anomalies, persistent left superior vena cava, poly- or oligohydramnios
etc.). Two of our cases fall within the beginning
of this spectrum, with single urinary tract abnormalities and
with normal fetal growth. It is estimated that prenatal renal
cysts are detected in more than half of the patients with postnatal
kidney anomalies and that, regardless cyst detection
in utero, most patients develop or increase their number in
the first year of life [10]. Our reviewed cases include two
sets of twins (P30-31, P44-45) carrying identical deletions.
P30-31 twins exhibited similar prenatal phenotypes while
progressing discordantly following birth, some patients
presented prenatal kidney abnormalities which resolved
after birth, while others did not show any anomaly upon
prenatal ultrasound, but postnatal developmental delay
and neuropsychiatric symptoms (Table 1). Moreover, the
reviewed literature describes patients with mild phenotypes,
who were diagnosed with 17q12 microdeletion syndrome
only after having an affected pregnancy or due to other primary
complains such as hypomagnesemia and subsequent
investigations leading to renal disorder (e.g. P92 – Table
1). Difficulties in reviewing medical records and attaining
an accurate medical history, particularly in adult and elder
patients, make, however, statistics ultimately unreliable.
Among the reviewed patients, 42.7% had kidney anomalies,
at least 30.7% exhibited some degree of developmental
delay, and 65.3% had neuropsychiatric features such as autism,
intellectual disability of variable severity, or attention
deficit. Thus, the neuropsychiatric phenotypes appear to be
more frequent among the patients with 17q12 microdeletion
than renal disorder. Among other phenotypes described in
these patients were fetal diaphragmatic hernia (4.3%) and
amniotic fluid anomalies (polyhydramnios 12%; oligohydramnios
2.1%; anhydramnios 1.1%) in prenatal cases, and
in postnatal cases, digestive tract anomalies, particularly
related to liver and pancreas (24%), cardiovascular anomalies
(10.7%), skeletal anomalies (14.7%), facial dysmorphisms
(24%). Ocular anomalies, diabetes, and hypomagnesemia
were also described, albeit rarely. The broad spectrum of
observed phenotypes emphasizes, once more, the high variability
of this syndrome, adding to a 34.4% incomplete penetrance
estimated in the case of this deletion [36].
For 45.3% of the cases, family history included potentially
related phenotypes, though with only 37.3% being
genetically confirmed. 10 out of 92 patients inherited the
microdeletion from either a mildly affected or an affected
parent, while 4 out of 92 inherited it from an asymptomatic
parent. Although dedicated databases such as DECIPHER
and CNV Morbidity Map of Developmental Delay list
large numbers of cases with this genetic aberration, two
deletions are also found in the Control section of the last
morbidity map (Figure 1), proving, in accordance with Mefford et al. (2007) [1], that asymptomatic carriers may
not be uncommon. Differences in deletion size (or other genetic
modifiers) may also account for part of the observed
phenotypic variation, although almost identical deletions
(including in twins) may lead to variable phenotypes.
The third patient had ASD as a main feature, in association
with mild developmental delay, dysmorphic features
and prenatal hydronephrosis. ASD has been previously
reported in patients with 17q12 deletion, e.g., Vasileiou et
al. [2019] [27] described 2 cases and Loirat et al. (2010)
[23] reported 3 unrelated boys with de novo 17q12 deletion,
with ASD and kidney problems, hypothesizing that
autistic behavior may be due to HNF1B deletion. Yet, Clissold
et al. (2016) [37] found ASD as a main feature of this
syndrome, alone or in association with learning difficulties
and/or attention deficit hyperactivity disorder (ADHD).
This was not, however, found in subjects with HNF1B gene
mutation. Moreno-de-Luca et al. (2010) [12] reported on 6
boys out of 18 patients with 17q12 deletion, who presented
ASD in association with other manifestations (dysmorphic
features, kidney problems, macrocephaly, intellectual
disability). This deletion was also found in patients with
schizophrenia. The authors concluded that 17q12 deletion
is associated with a high risk for ASD and schizophrenia,
and that at least one out of the 15 genes included in this
region is important for normal brain development. It has
also been noted that the degree of severity of the neuropsychological
phenotype is lower in patients referred for
kidney anomalies, than in patients with only neurological
symptoms. Laliève et al. (2019) [38] found that 87.3% of
the 119 patients carrying a HNF1B (or larger) deletion,
attended mainstream schooling, though Laffargue et al.
(2015) [8] report that only approx. 60% of the children
enrolled in their study had a normal progression through
school. Thus, 17q12 microdeletion does not systematically
involve neuropsychological anomalies. Yet, a tendency
toward a lower IQ and a higher risk of neuropsychological
disorders for the carriers of the microdeletion, as compared
with normal population was noted.
Kaman et al. (2019) reported a 17q12 deletion patient
with atopic dermatitis and allergy; however, while
an association of these clinical manifestations with this
genetic defect is possible, the presence of a different genetic
anomaly was not excluded [26].
In conclusion, we bring further evidence for the genetic
and morpho-physiological complexity of the 17q12
deletion syndrome, and report a novel, atypical clinical
phenotype (patient B), with megabladder, single umbilical
artery and choroid plexus cyst, not yet described in fetuses
with 17q12 deletion. However, whole gene deletion of
HNF1B has been previously associated with megabladder
in a patient with prune belly phenotype [39], a disorder with a partially overlapping clinical presentation with
17q12 deletion syndrome. Our first case strongly suggests
that genetic testing should be considered for isolated or
unilateral multicystic dysplastic kidneys, though current
fetal medicine guidelines recommend invasive investigations
only in bilateral forms or when other organs are
involved (The FMF Foundation [40]). Nonetheless, 17q12
microdeletion should always be considered in patients with
ASD, especially in association with developmental delay
and kidney problems. 17q12 microdeletion syndrome is
challenging due to the wide clinical spectrum and the high
variability of this disorder even within the same family.
In addition to the uncertainty regarding long-term postnatal
outcome, more patients and more longitudinal studies
should be considered in order to reach a higher degree of
accuracy in the counselling of prospective parents.
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