This study analyzed exome sequencing results from 73 fetuses with isolated increased nuchal translucency but normal chromosomal microarray analysis. Exome sequencing identified pathogenic variants in 4 cases (5.5% diagnostic rate), including 3 de novo dominant variants and 1 recessive variant. Three of the 4 cases developed structural anomalies on later ultrasound. This shows exome sequencing can detect genetic conditions in some cases with increased nuchal translucency not detected by other tests, aiding parental counseling.

1. This article has been accepted for publication and undergone full peer review but has
not been through the copyediting, typesetting, pagination and proofreading process
which may lead to differences between this version and the Version of Record. Please
cite this article as doi: 10.1002/pd.5789
Title page
Exome sequencing improves genetic diagnosis of fetal increased nuchal
translucency
Xin Yang,* Lv-Yin Huang,* Min Pan,* Li-Li Xu, Li Zhen, Jin Han, Dong-Zhi Li
Prenatal Diagnostic Center, Guangzhou Women and Children’s Medical Center affiliated to
Guangzhou Medical University, Guangzhou, Guangdong, China
* These authors contributed equally to this study.
Corresponding author at: Dong-Zhi Li, Prenatal Diagnostic Center, Guangzhou Women and
Children’s Medical Center, Guangzhou, Guangdong 510623, China. E-mail:
drlidongzhi2014@sina.com
Conflict of Interest: None.
Running head: Exome sequencing and increased nuchal translucency
Word count: 1578
Figures: 1
Tables: 3
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2. What is already known on this topic?
 Increased nuchal translucency (NT) has been associated with increased risks for aneuploidy
and structural abnormalities (particularly congenital heart disease).
 Exome sequencing (ES) improved the identification of genetic disorders in fetuses with
structural abnormalities.
What this study adds?
 In this small series we have shown that ES may identify a genetic condition in cases with an
apparently isolated increased NT and normal chromosomal microarray analysis (CMA) in
early pregnancy. The majority of these cases will have abnormalities detected later in
pregnancy.
 In occasional cases with an increased NT and normal CMA, ES can detect a genetic
condition even though no other abnormalities are detected in pregnancy.
 This information may aid early parental decision making.
Data Availability Statement:
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
This article is protected by copyright. All rights reserved.

3. Abstract
OBJECTIVE
The aim of this retrospective study is to determine the monogenic syndromes in fetuses with
isolated first-trimester increased nuchal translucency (NT) in order to provide more accurate
parental counseling.
METHOD
Medical trio exome sequencing (ES) was performed on DNA extracted from chorionic villi in 73
fetuses with isolated first-trimester increased NT (≥3.5mm) and normal chromosomal microarray
analysis (CMA). This testing targets coding exons for 4200 clinically relevant disease-causing
genes. The interpretation of variants was performed according to the American College of Medical
Genetics guidelines.
RESULTS
Pathogenic variants were detected in four cases in which phenotypes and genotypes correlate well.
Medical trio ES offered a 5.5% (4/73) increase in diagnostic rate over CMA in cases with isolated
increased NT. Three of four cases with pathogenic variants developed structural anomalies on
ultrasound at mid pregnancy, leading to the pregnancy termination. Only one case with a
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4. pathogenic variant demonstrated normal ultrasound throughout pregnancy.
CONCLUSION
Our results indicate that after a normal CMA, fetuses with isolated first-trimester increased NT
have a 1.4% (1/73) risk of significant childhood genetic syndromes caused by known
disease-causing variants, which will not be detectable on prenatal ultrasound. This information
may be useful in parental counseling.
KEYWORDS
increased nuchal translucency; prenatal diagnosis; medical trio exome sequencing; prenatal
screening
Introduction
Ultrasound measurement of nuchal translucency (NT) thickness is currently a routine
part of prenatal care during the first trimester and is recommended for all women.
Increased NT has been associated with increased risks for aneuploidy and structural
abnormalities (particularly congenital heart disease), which can result in miscarriage,
fetal demise, or neonatal death. In one study, the frequency of aneuploidy at a NT
between the 3.0 and 3.4 mm, 3.5 to 4.4 mm, 5.5 to 6.4 mm, and ≥8.5 mm was 7, 20,
50, and 75 percent, respectively.1
The overall frequency of structural anomalies is 4 to
10 percent in euploid fetuses with increased NT, with the risk of a cardiac defect
ranging from 2 to 6 percent compared to the 0.6 percent baseline risk of congenital
heart disease in the general obstetrical population.2,3
Also isolated increased NT is
associated with a high risk, approximately 4 percent, for chromosomal
microdeletions/microduplications.4
However, even where karyotype is normal, the
likelihood of adverse pregnancy outcome is greater with increasing NT. One study
reported that increased NT of 3.5 to 4.4 mm was associated with a normal outcome in
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5. 70 percent of fetuses, whereas increased NT of 5.5 to 6.4 mm was associated with a
normal outcome in only 30 percent of cases.5
One reason is that fetuses with increased
NT are also at a higher risk for a wide range of genetic disorders and syndromes.
Although such an association has been confirmed by some studies,6
the specific risk
for these rare syndromes is not well defined. In this study, we sought to determine the
monogenic syndromes in fetuses with isolated first-trimester increased NT in order to
provide more accurate parental counseling in clinical practice.
Materials and Methods
Between January 2017 and December 2018, routine early ultrasound screening was
performed in 14,053 unselected pregnant women, including NT measurement at 11-14
weeks’ gestation at our center. An enlarged NT (≥3.5mm) was detected in 139 fetuses
(1.0%). Among these fetuses, 21 (15.1%) showed additional structural abnormalities
at NT scan while 118 (84.8%) had none. During this period, a detailed first trimester
ultrasound had been conducted in fetuses with increased NT. Cases with other
structural anomalies, e.g. cardiac defects, omphalocele, abnormal limbs and
holoprosencephaly on NT scan, or cases with no postnatal outcomes were excluded
from this study. For genetic testing, the CVS samples first underwent rapid
aneuploidy testing using quantitative fluorescent polymerase chain reaction (QF-PCR).
When QF-PCR detected triploidy, trisomy 21, 18, 13 or monosomy X, no further
testing was done. Cases showing normal QF-PCR results were tested further with
chromosomal microarray analysis (CMA) (CytoScan750 K array, Affymetrix Inc,
Santa Clara, CA). At our center, parental blood was routinely sampled at the time of
invasive procedures and archived for the purpose of parental testing when the fetal
results of CMA required parental confirmation.
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6. The archived CVS DNA of cases with isolated fetal increased NT and normal CMA
were sent for medical trio exome sequencing (ES) with stored parental samples. In
this study, we used medical ES rather than whole ES because medical ES only focus
on genes (4200 clinically relevant disease-causing genes) which were associated with
Mendelian disorders recorded by OMIM with shorter period and relatively cheaper
for patient diagnosis. Furthermore, the average depth of sequencing coverage for
medical ES is about 300×, higher than that of whole ES (about 100×). The
NextSeq500 sequencer (Illumina, San Diego, CA) was used for sequencing of
enriched DNA. NextGENe v2.4.1.2 software (SoftGenetics, State College, PA) was
used for variants calling. After filtering out the synonymous and common SNPs
(MAF>0.1%), rare variants with high confidence were considered as disease-causing
candidate. Variant annotation was further confirmed through literature and population
databases, including 1000 Genomes, dbSNP, GnomAD, Clinvar, HGMD, and OMIM.
The interpretation of variants was performed according to the American College of
Medical Genetics (ACMG) guidelines.7
The study was approved by the ethics
committee of Guangzhou Women and Children’s Medical Center.
Results
During the study period, we had 118 cases with isolated first-trimester increased
NT. Among these, 10 cases were excluded because they received the prenatal
diagnosis at other clinics. The remaining 108 cases had CVS done at our center; of
these the median maternal age was 32 years (range, 24-45), the median gestational
age 12.9 weeks (range, 11.3-13.5) and median NT thickness 4.1 mm (range, 3.5-6.1).
Seventy-three cases were included for trio medical ES (Table 1).
The genetic testing results were presented in Figure 1 and Table 2. Four cases were
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7. detected to have pathogenic variants which correlate well with phenotypes. Of the
four cases, de novo disease-causing variants were identified in three cases in an
autosomal dominant manner. In Case 1, a nonsense NM_014159: c.4376C>T
(p.R1459X) variant was detected in SETD2 gene, which was reported to cause
Luscan-Lumish syndrome.8
In Case 3 and 4, two known Noonan syndrome-causing
variants, NM_002834.4:c.124A>G (p.T42A) in PTPN11 gene and NM_002880:
c.770C>T (p.S257L) in RAF1 gene were detected, separately.9,10
Compound
heterozygous variants were found in TMEM231 gene in Case 2: a paternally inherited
splice variant NM_001077416: c.525+1G>A and a maternally inherited nonsense
variant c.661C>T (p.R221X). Variants in TMEM231 in an autosomal recessive
manner are known to cause ciliopathies such as Meckel syndrome.11
As the fetus
presented with some ciliopathy phenotypes on second-trimester ultrasound, the two
variants were classified as likely pathogenic and pathogenic, separately. Although the
parents had terminated the pregnancy, the results were still reported to the families
with extensive genetic counseling. Furthermore, we also detected 12 variants of
unknown significance (VOUS) in genes with an autosomal dominant or recessive
manner in 7 cases (Table 3).
Discussion
Over 100 developmental and genetic syndromes have been reported in cases with
increased NT, although many might be an incidental association.12,13
For instance,
rasopathies and a variety of skeletal dysplasias have repeatedly been diagnosed in
patients who had increased NT in utero.14-17
These cases can be detected prenatally by
using ES testing, and some are not detectable on prenatal ultrasound if they have no
major structural abnormalities. In our clinical practice, patients with an isolated
increased NT and normal CMA result are recommended to await for a
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8. second-trimester fetal anatomy survey and echocardiogram, which are usually
conducted 6-8 weeks after the NT scan. As such, many patients must spend these
many weeks awaiting more information about the health of the fetus and often request
more detailed and in-depth examinations of the fetal health at the time of increased
NT identification. For pregnancies with increased NT, once the presence of
aneuploidy is ruled out, the risk of perinatal outcome dose not statistically increase
until the NT reaches >99th percentile.18
The 99th percentile was defined as
NT≥3.5mm for all gestational ages.19
Therefore, we attempted to determine the
pathogenic defects in cases with isolated increased NT ≥3.5mm with ES technique.
A few studies have reported the use of ES in fetuses with increased NT. Lord et al.
detected two pathogenic variants (a stop gained variant of MID1 and a missense
variant of PTPN11) in 93 fetuses with increased NT (≥4.0mm), with a diagnostic rate
of 2.2%.20
Petrovski et al. detected two pathogenic variants (a frameshift variant
of RERE and a missense variant of RIT1) in 59 fetuses with increased NT (≥3.5mm),
with a diagnostic rate of 3.4%.21
Both studies found a rasopathy variant in their
isolated NT cases (a variant of PTPN11 and a variant of RIT1, separately). Taken
together, the two studies reported a diagnostic rate of 2.6%. However, we achieved a
diagnostic rate of 5.5% in our cohort. This discrepancy in genetic diagnoses might be
driven by different sample size. Another reason might be the different NT inclusions
used. Although our study sample is relatively small, we still found that increased NT
is associated with a high risk of rasopathies compared with other rare genetic
syndromes. Two of four positive cases in our cohort had the disease-causing variants
of rasopathies. Their association has been evidenced by other studies.22,23
Three of our four cases with pathogenic variants developed structural anomalies on
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9. ultrasound at mid pregnancy, leading to the pregnancy termination. Only one case
with the SETD2 variant demonstrated normal ultrasound throughout pregnancy. The
two cases with rasopathies developed pleural effusion and cardiac defect at second
trimester, respectively, two markers commonly found in fetuses of rasopathies.22,24
Our results indicate that after a normal CMA, fetuses with isolated first-trimester
increased NT have a 1.4% (1/73) risk of significant childhood genetic syndromes
caused by a known disease-causing variant, which will not be detectable on prenatal
ultrasound. This information, although needing larger studies for confirmation, may
be useful in parental counseling.
In conclusion, in this small series we applied ES for 73 fetuses with isolated
first-trimester increased NT, and the trio medical ES yielded an additional diagnostic
rate of 5.5%, which is equivalent to that of CMA for the same cases with normal
karyotype. Thus, in the investigation of fetuses with increased NT, ES should be an
option in combination with other technologies like karyotyping or CMA in those who
require it. This test can give patients a chance of timely diagnosis of some rare genetic
syndromes before their phenotypical signs appear. However, one limitation of the use
of ES in isolated increased NT at the first trimester is that a number of variants with
uncertainty of pathogenicity would be found because of the lack of phenotypes in
early pregnancy, which might be present only in late gestation or even after birth.
Therefore, follow-up with detailed ultrasound is still warranted and may be required
for accurate interpretation of ES results.
ACKNOWLEDGEMENTS
This study was supported by National Natural Science Foundation of China (81873836),
Guangzhou Institute of Pediatrics/Guangzhou Women and Children’s Medical Center
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10. (JY-2019-006) and Science and Technology Department of Guangdong Province
(2016A020218003).
CONFLICT OF INTEREST
None declared
ETHICAL STATEMENT
The work was carried out according to the principles of the Declaration of Helsinki and approved
by the ethics committee of Guangzhou Women and Children Medical Center. Informed consent
was obtained from the patients.
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13. 2013;21(9):936-942
Figure legend
Figure 1 – Flow chart of this study.
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QF-PCR (n=108)
Normal QF-PCR (n=83)
CMA testing (n=83)
Pathogenic CNVs (n=3)
arr1q42.11q44(224,225,265-247,517,799)×1(23.29Mb)
arr22q11.21(18,631,364-21,800,471)×1(3.17Mb)
arr17p12p11.2(15,759,453-20,547,625)×1(4.79Mb)
(Likely) pathogenic variants (n=4)
No pathogenic variants (n=69)
Lost follow-up (n=5)
NT 3.5mm, CMA(-)
NT 3.6mm, CMA(-)
NT 3.6mm, CMA(-)
NT 4.0mm, CMA(-)
NT 4.1mm, CMA(-)
Common aneuploidies
(n=25)
Trisomy 21 17
Trisomy 18 5
Monosomy X 3
Trio ES (n=73)
14,053 pregnancies
receiving NT scan
Increased NT (≥3.5 mm)
(n=139)
Increased NT (≥3.5 mm),
isolated (n=118)
Increased NT (≥3.5 mm), with
other structural defects
(n=21)
PND at other clinics
(n=10)

14. Table 1. Distribution of pregnancy complications according to NT within the
study subjects (n =73).
NT n No. of cases with No. of cases with Pregnancy
(mm) second-trimester pathogenic variants outcome
structural ultrasound TOP Livebirth
3.5-3.9 24 3 0 5 19
4.0-4.4 19 3 2 7 12
4.5-4.9 15 4 0 6 9
5.0-5.4 9 3 1 5 4
≥6.0 6 3 1 5 1
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15. Table 2. Clinical and molecular information of fetuses with increased NT and pathogenic variants.
Case MA
(y)
CRL/NT
(mm)
Ultrasound findings at second
trimester
Sequencing results Inheritance Disease association(s)
[MIM #]
Outcome
1 26 59 / 4.0 Normal SETD2 (NM_014159)
c.4376C>T(p.R1459X)
Pathogenic
AD
De novo
Luscan-Lumish
syndrome (616831)
Livebirth
Intellectual disability and
autism spectrum disorder
at 24 months of age
2 32 56 /4.0 Dandy-Walker malformation
Bilateral enlarged kidneys
Oligohydramnios
TMEM231 (NM_001077416)
c.525+1G>A (pat)
Likely pathogenic
c.661C>T (p.R221X) (mat)
Pathogenic
AR
Meckel syndrome
(249000)
TOP
3 30 50 / 5.1 Bilateral pleural effusion
Increased nuchal fold
PTPN11 (NM_002834.4)
c.124A>G (p.T42A)
Pathogenic
AD
De novo
Noonan syndrome
(163950)
TOP
4 2 6 51 / 6.3 Hypertrophic cardiomyopathy
Mild shortened limbs
Polyhydramnios
RAF1(NM_002880)
c.770C>T (p.S257L)
Pathogenic
AD
De novo
Noonan syndrome
(163950)
TOP
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16. Table 3. Clinical and molecular information of fetuses with increased NT and variants of unknown significance.
Case MA
(y)
CRL/NT
(mm)
Ultrasound findings at
second trimester
Sequencing results Inheritance Disease association(s)
[MIM #]
Outcome
1 27 52 / 4.5 Normal SALL1 (NM_00 2968.2)
c.598C>T(p.L200F)
AD
De novo
Townes-Brocks
syndrome (157480)
Livebirth
Normal physical and
neurobehavioral
development at 18
months of age
2 39 55 / 5.0 Left ventricular hypoplasia SPTAN1 (NM_001130438.2)
c.3109G>A (p.E1037K)
AD
De novo
epileptic
encephalopathy, early
infantile, 5 (613477)
TOP
3 29 46 /3.9 Diaphragmatic hernia
Club feet
ATP13A2 (NM_022089)
c.2529+8C>T (pat)
c.745G>A (p.A249T) (mat)
AR
Spastic paraplegia 78
(617225) / Kufor-Rakeb
syndrome (606693)
TOP
4 30 50 / 5.1 Normal EDN1 (NM_001955)
c.106G>A (P.G36R) (pat)
c.448G>A (p.G163E) (mat)
AR
Question mark ears,
isolated (612798) /
Auriculocondylar
syndrome 3 (615706)
Livebirth
Normal physical and
neurobehavioral
development at 18
months of age
5 3 6 55 / 5.0 Transposition of the great
arteries; ventricular
septal defect
MYO18B (NM_032608)
c.442G>A (p.V148M) (pat)
c.1988G>A (p.G663D) (mat)
AR Klippel-Feil syndrome 4,
autosomal recessive, with
nemaline myopathy and
facial dysmorphism
(616549)
Livebirth
Surgical intervention for
heart defect at 1 month of
age.
Normal neurobehavioral
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17. development at 24
months of age
6 25 54 / 4.9 Fetal growth restriction,
oligohydramnios
ANK (NM_020987)
c.10152G>C (p.Q3384H) (pat)
c.14048A>G (p.S4350G)
(mat)
AR Mental retardation,
autosomal recessive 37
(615493)
TOP
7 28 52 / 5.1 Normal SMPD1 (NM_000543)
c.610C>G (p.L204V) (pat)
c.1598C>T (p.P533L) (mat)
AR Niemann–Pick disease
type A (257200) and type
B (607616)
Livebirth
Normal physical and
neurobehavioral
development at 24
months of age
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