Original Article
Prenatal diagnosis and molecular cytogenetic characterization of a de novo
pure distal 9p deletion and literature review
Chih-Ping Chen
a,b,c,d,e,f *, Yi-Ning Su
g,h, Chen-Yu Chen
a, Schu-Rern Chern
b, Peih-Shan Wu
i,
Jun-Wei Su
a,j, Chen-Chi Lee
a, Li-Feng Chen
aand Wayseen Wang
b,ka Department of Obstetrics and Gynecology, Mackay Memorial Hospital, Taipei, Taiwan
b Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan
c Department of Biotechnology, Asia University, Taichung, Taiwan
d School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
e Institute of Clinical and Community Health Nursing, National Yang-Ming University, Taipei, Taiwan
f Department of Obstetrics and Gynecology, School of Medicine, National Yang-Ming University, Taipei,
Taiwan
g Department of Obstetrics and Gynecology, School of Medicine, Taipei Medical University, Taipei, Taiwan
h Dianthus MFM Clinic, Taipei, Taiwan
i Gene Biodesign Co. Ltd, Taipei, Taiwan
j Department of Obstetrics and Gynecology, China Medical University Hospital, Taichung, Taiwan
k Department of Bioengineering, Tatung University, Taipei, Taiwan
* Correspondence to: Chih-Ping Chen, MD
Department of Obstetrics and Gynecology, Mackay Memorial Hospital 92, Section 2, Chung-Shan North Road, Taipei, Taiwan
Tel: +886-2-25433535; Fax: +886-2-25433642, +886-2-25232448 E-mail: [email protected]
Highlights
We report prenatal diagnosis of distal 9p deletion.
The detection was based on abnormal maternal serum screening.
The analysis was based on aCGH on uncultured amniocytes.
A review of distal 9p deletion is presented.
Abstract
We present rapid aneuploidy diagnosis of distal 9p deletion by array comparative genomic
hybridization using uncultured amniocytes in a pregnancy associated with an abnormal maternal
serum screening result and intrauterine growth restriction (IUGR) in the fetus. We review the
literature of prenatal diagnosis of distal 9p deletion, and add abnormal maternal serum
biochemistry and fetal IUGR in the distinctive prenatal findings in pregnancy with fetal distal 9p
deletion. We discuss the consequence of haploinsufficiency of DOCK8, KANK1, VLDLR and
DMRT1 in this case.
Keywords:
array comparative genomic hybridization; distal 9p deletion; maternal serum
screening; prenatal diagnosis
1. Introduction
Chromosome distal 9p deletion syndrome (OMIM 158170) is a clinically well-defined syndrome
characterized by major clinical features such as mental retardation, hypotonia, seizures;
craniofacial dysmorphisms of trigonocephaly, synophrys, midface hypoplasia, short nose,
depressed nasal bridge, anteverted nares, hypertelorism, up-slanting palpebral fissures, long
philtrum, microstomia, high and narrow palate, and small posteriorly rotated ears; abnormal
genitalia of hypoplastic labia majora, prominent labia minora and clitoris, cryptorchidism and
hypospadias; wide-set nipples, hernias, scoliosis, diastasis recti, short and broad distal phalanges
of fingers, square-shaped nails and foot position anomalies; and relatively rare malformations such
as congenital heart defects, microphthalmia, choanal atresia, stenostic external ear canals, cleft
palate, diaphragmatic hernia, hydronephrosis, hypoplasia of the corpus callosum, enlarged cisterna
magna and postaxial hexadactyly of the fingers [1-13].
Prenatal diagnosis of chromosome aberration associated with distal 9p deletion is very rare. The
reported cases have been associated with unbalanced translocations [14,15], inverted duplication
and deletion of distal 9p [4], mosaic ring chromosome 9 [16,17] and pure distal 9p deletion [18].
To our knowledge, only two cases of prenatally detected pure 9p deletion have been described
[18]. Here, we report prenatal diagnosis and array comparative genomic hybridization (aCGH)
characterization of a de novo pure distal 9p deletion associated with abnormal maternal serum
screening.
2. Methods and Methods
2.1. Array-CGH
Whole-genome aCGH on uncultured amniocytes derived from 10 mL amniotic fluid and on
parental bloods was performed using NimbleGen ISCA Plus Cytogenetic Array (Roche
NimbleGen, Madison, WI, USA). The NimbleGen ISCA Plus Cytogenetic Array has 630,000
probes and a median resolution of 15-20 kb across the entire genome according to the
manufacturer’s instruction.
2.2. Conventional cytogenetic analysis
20 mL amniotic fluid was collected, and the sample was subjected to in situ amniocyte culture
according to the standard cytogenetic protocol. Parental bloods and cord blood were collected for
cytogenetic analysis according to the standard protocol. Routine cytogenetic analysis by
G-banding techniques at the 550 bands of resolution was performed.
2.3. Clinical description
A 32-year-old, gravida 2, para 0, woman underwent first-trimester screening for Down syndrome
using maternal serum biochemistry and nuchal translucency (NT) thickness at 12 weeks of
gestation. Her husband was 31 years old, and there was no family history of congenital
malformations. The levels of free -human chorionic gonadotrophin (-hCG) and
pregnancy-associated plasma protein A (PAPP-A) were 1.086 multiples of the median (MoM) and 0.519
MoM, respectively. The NT thickness was measured 2.7 mm. The woman was screened positive
for a Down syndrome risk of 1/147. The woman hesitated at invasive prenatal diagnosis but was
later persuaded by the family. She consulted the hospital and requested for amniocentesis at 25
weeks of gestation. Prenatal ultrasound at 25 weeks of gestation showed a female fetus with
severe intrauterine growth restriction (IUGR). The biparietal diameter measured 5.01 cm, and the
femur length measured 3.57 cm, equivalent to 21 weeks of gestation. aCGH using uncultured
amniocytes showed a 6-Mb deletion at 9p24.3-p24.1 (Fig. 1). Amniocentesis revealed a female
fetus with del(9)(p24.1p24.3) (Fig. 2). The parental karyotypes were normal. Prenatal ultrasound
at 26 weeks of gestation revealed a fetus with fetal biometry equivalent to 24 weeks. A 586-g
female fetus was subsequently delivered with a midface hypoplasia, short nose, depressed nasal
bridge, hypertelorism, up-slanting palpebral fissures, long philtrum, microstomia and small
posteriorly rotated ears. The female external genitalia were normal. Postnatal cytogenetic analysis
of cord blood confirmed the prenatal diagnosis.
We used next-generation sequencing in order to further confirm our results from karyotyping and
aCGH shown in Fig. 1 and Fig. 2, we called single nucleotide polymorphism (SNP) variants as
well as indels (insertions and deletions), and mapped to
human genome reference sequence
(GRCh37/hg19) in chromosome 9.
3. Results
aCGH showed a 6-Mb deletion at 9p24.3-p24.1, or arr 9p24.3p24.1 (198,350-6,256,729)1 (NCBI
build 37) (Fig. 1). The deleted region encompasses the genes of DOCK8, KANK1, DMRT1,
DMRT3, DMRT2 and VLDLR. The fetal karyotype was 46,XX,del(9)(p24.1p24.3)dn (Fig. 2). The
father’s karyotype was 46,XY. The mother’s karyotype was 46,XX. We differentiated
heterozygous and homozygous variants and noted that continuous homozygous variants are scored
from position 178,806 to 6,535,975, indicates that it lacks differences at these SNPs in the region
and shows loss of heterozygosity (LOH) (Fig. 3).
4. Discussion
The present case was associated with IUGR, abnormal maternal serum biochemistry and the 9p
deletion syndrome. An abnormal maternal serum biochemistry result in the first or second
trimester may result in early prenatal detection of rare fetal chromosomal abnormalities [19-22].
The present pregnant woman was 32 years of age. She underwent amniocentesis because of a
positive Down syndrome screen risk of 1/147 calculated by first-trimester maternal serum levels of
free -hCG and PAPP-A and NT thickness. The association of fetuses with the chromosome 9p
deletion syndrome with abnormal first-trimester screening for Down syndrome in this presentation
indicates that fetal distal 9p deletion may be associated with abnormal first-trimester Down
syndrome screening.
Table 1 presents the perinatal findings and prenatal diagnosis of reported cases with the
chromosome distal 9p deletion syndrome. Abnormal maternal serum biochemistry, increased NT
thickness, ambiguous external genitalia, male-to-female sex reversal, IUGR and fetal structural
abnormalities can be distinctive prenatal findings in pregnancy with fetal distal 9p deletion. Chen
et al. [4] reported prenatal ultrasound diagnosis of ventriculomegaly in a male fetus with inv dup
del(9)(:p22.1p24.3::p24.3qter). Chen et al. [2] reported IUGR in the third trimester in a fetus
with partial monosomy 9p (9pterp22) and partial trisomy 7p (7pterp15.1). Brisset et al. [15]
reported increased NT thickness of 4.4 mm, IUGR, a single umbilical artery, partial agenesis of the
cerebellar vermis, bilateral choroid plexus cysts and facial dysmorphisms on ultrasound in a
female fetus with partial monosomy 9p (9pterp24.3) and partial trisomy 17q (17q24.3qter).
Chen et al. [16] reported abnormal second-trimester maternal serum screening with a positive risk
of 1/57 for Down syndrome and ambiguous external genitalia on prenatal ultrasound in a male
fetus with mosaic r(9)(p24q34.3). Stumm et al. [16] reported second-trimester sonographic
diagnosis of male-to-female sex reversal in a male fetus with ring chromosome 9. Witters et al.
[14] reported prenatal ultrasound diagnosis of sex reversal and multiple anomalies in a male fetus
with partial monosomy 9p (9pterp24) and partial trisomy 3p (3pterp14.2). Vialard et al. [18]
reported prenatal diagnosis of ambiguous external genitalia in a male fetus with del(9)(p22) in the
second trimester, and hypoplastic left heart and a single umbilical artery in a female fetus with
del(9)(p22). Distal 9p deletion has been associated with 46,XY gonadal dysgenesis and sex
reversal [23-27]. Therefore, prenatal diagnosing sex reversal or ambiguous external genitalia
should alert fetal 9p deletion.
The present case had haploinsufficiency of the genes of DOCK8, KANK1, DMRT1, DMRT3,
DMRT2 and VLDLR. Genetic aberrations in DOCK8, KANK1 and VLDLR may result in
neurological and/or psychiatric disorders. DOCK8 (OMIM 611432) encodes dedicator of
cytokinesis 8, which is a member of the DOCK180-related protein family [28]. Heterozygous
disruption of DOCK8 either by a deletion or by a translocation breakpoint has been associated with
autosomal dominant mental retardation 2 (MRD2; OMIM 614113) [29]. KANK1 (OMIM 607704)
encodes kidney ankyrin repeat-containing protein and is a maternally imprinted gene that is
expressed only from the paternal allele [30]. Deletion of KANK1 will cause
parent-of-origin-dependent inheritance of familial cerebral palsy (cerebral palsy spastic quadriplegic 2; OMIM
612900) with affected individuals inheriting the deletion from paternal origin [30]. VLDLR
(OMIM 192977) encodes very low-density lipoprotein receptor (VLDLR) and is involved in
Reelin signaling pathway and neuronal migration. Mutations of VLDLR can cause autosomal
recessive cerebellar ataxia, mental retardation and dysequilibrium syndrome 1 (CAMRQ1; OMIM
224050) [31-34]. Mutations in Reelin and VLDLR will result in similar abnormal gyration and
psychiatric disorders because VLDLR is a part of the Reelin signaling pathway which regulates
cortical neuronal migration, promotes maturation of dendrites and dendritic spines, and modulates
synaptic function [31,35-37]. 9p24.3 deletions have been associated with 46,XY sex reversal
(SRXY4; OMIM 154230). The DMRT cluster is located at 9p24.3, and among DMRT1, DMRT2
and DMRT3, only DMRT1 has been shown to be the strongest candidate gene for sex reversal
[38-41]. DMRT1 (OMIM 602424) encodes doublesex-and MAB3-related transcription factor 1, which
is a male-specific transcriptional regulator involved in sex determination and differentiation
[42,43]. DMRT1 suppresses female differentiation in testes, and involves inhibition of meiosis in
testes [38-40]. Haploinsufficiency of DMRT1 has been shown to be sufficient for both 46,XY
gonadal dysgenesis and 46,XY ovotesticular disorder of sexual development [41].
In summary, we present prenatal diagnosis and molecular cytogenetic characterization of de
novo pure distal 9p deletion associated with abnormal maternal serum screening and IUGR by
aCGH using uncultured amniocytes. We review the literature of prenatal diagnosis of distal 9p
deletion. We discuss the consequence of haploinsufficiency of DOCK8, KANK1, VLDLR and
DMRT1 in this case.
Acknowledgements
This work was supported by research grants NSC-99-2628-B-195-001-MY3 and NSC-101-2314-B-195-011-MY3 from the National Science Council and MMH-E-102-04 from Mackay Memorial Hospital, Taipei, Taiwan.
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