Alternate Title: Prenatal De Novo Duplication 10q22.3-10q23.2 and Unexpected Deletion Xp21.1 in
the Dystrophin Locus detected by Microarray
Sub-microscopic duplication resulting in prenatal ultrasound findings seen in partial trisomy 10q
syndrome
Paul C. Browne, M.D.1
Janice G. Edwards, M.S.2
Robert Best, PhD.2
Courtney Riley Brooks, M.D.1
Peggy Walker, M.S.2
Anthony R. Gregg, M.D.1,2
Department of Obstetrics and Gynecology
Division of Maternal-Fetal Medicine1
Division of Clinical Genetics and Molecular Medicine2
University of South Carolina School of Medicine
2 Medical Park, Suite 208, Columbia, S.C. 29203
Introduction
Partial trisomy of the 10q region was originally reported in 19791. For 25 years, the diagnosis
was made cytogenetically based on large (by today’s standards), visible insertions in the region identified
by karyotype analysis. Previous case reports have included unbalanced translocations and large
duplications/insertions in the 10q region. Probands with partial trisomy 10q syndrome have
developmental delay, cranio-facial abnormalities, talipes and congenital heart disease. Prenatal diagnoses
by karyotype have been reported following diagnosis of sacrococcygeal teratoma, renal pyelectasis and
other fetal abnormalities. We report the prenatal ultrasound and MRI findings associated with diagnosis
of partial trisomy 10q with normal karyotype and abnormal microarray. .
Case Report
The patient was a 36 year old Caucasian female Gravida 3, Para 0-0-2-0 referred at 13 weeks gestation for
first trimester screening.
The past obstetrical history was significant for 2 elective first-trimester pregnancy terminations.
The patient’s past medical history was remarkable for anxiety/depression disorder. The patient’s prenatal
course was complicated by medication exposure to Xanax and Buspar, which were discontinued by the
patient in the first trimester when she became aware of the pregnancy. The patient’s prescription
medications included prenatal vitamins. The patient completed genetic counseling wherein age-related
risks for aneuploidy and options for first trimester screening versus invasive prenatal diagnosis were
considered. First trimester screening for aneuploidy rather than diagnostic testing or neither was
preferred. The patient’s nuchal translucency measurement and first trimester screening study were within
normal limits. The nuchal translucency measured 1.2 mm at 13weeks 3 days weeks (crown rump length
76.3mm).
The patient returned for second-trimester targeted ultrasound at 17 weeks’ gestation. Widening
of the palatal shelf with hypertelorism and unilateral talipes were demonstrated. The lateral ventricles
were asymmetric with a more forward projection noted on the ZZ side. The differential diagnosis
included abnormal palatal development and an encephalocoele. Follow-up genetic counseling session
included discussion of diagnostic procedures including amniocentesis with standard karyotyping and
possible follow-up microarray analysis. The patient requested amniocentesis and the karyotype was a
normal 46,XX at the 500 band level (see Figure 1).Amniotic fluid alphafetoprotein analysis was within
normal range at 0.85 MoM.. Cultured amniotic fluid cells were then forwarded to Signature Genomics
(Spokane, Washington) for microarray analysis with the Signature Chip OStm.
Follow-up ultrasound at 21 weeks’ gestation noted microcephaly. The ultrasound images
suggested widening of the paranasal sinsuses as the cause of the hypertelorism and broad nasal bridge
(see Figure2). The differential diagnoses included occult anterior encephalocele or cleft palate as the
cause of the hypertelorism. Fetal magnetic resonance imaging (MRI) was performed to further
characterize the mid-face defect (see Figure 3). The MRI confirmed the widening of the paranasal sinuses
and nasal bridge as the primary abnormality.
Further counseling included discussion of the potential outcome for a child with severe
hypertelorism and talipes . It was anticipated that binocular vision would not be possible and that craniofacial surgeries to normalize orbital position in addition to probable surgical treatment for clubfoot could
be expected. The patient opted for pregnancy termination at 21 weeks gestation by dilatation and
evacuation. Given the termination method, fetal autopsy was not possible.
Microarray analysis completed after pregnancy termination and revealed two abnormalities. The
first abnormality (see Figure 4) was a duplication of 7.1 Mb, corresponding to 10q22.3-10q23.2. FISH
studies on both parents were normal in relation to this duplication, thus the duplication was considered de
novo based on the lack of a similar gain or rearrangement in either parent. (Insert Table with gene gains
noted associated with this region).
The second finding was a deletion of 87.9 Kb in the Xp21.1 region (Figure XX) and included
exon sequence{Janice clarify}(molecular results pending) within the dystrophin gene. Neither parent
demonstrated clinical features of muscular dystrophy. Both parents were studied using fluorescence in
situ hybridization (FISH) and the same deletion Xp21.1 was identified in the father. The unexpected
deletion in the dystrophin locus was further evaluated by molecular genetic analysis in the father who had
no clinical symptomatology of muscular dystrophy at age 32 with the following finding : results pending.
Discussion
I suggest the discussion is be reworked in the following order:
1. Case result with 10q duplication as likely cause of anomalies
Reference medication exposures as unlikely cause
Comment on gene gains in duplication as likely cause of developmental abnormality
2. Mention 10q duplication from literature but point out (or leave out) those that do not share the
same duplicated material as this case. Highlight/Make specific comparison to Erdogan microarray
result case.
3. Utility of prenatal microarray and ACOG committee opinion
4. Unexpected deletion in dystrophin gene with comparison to Catrell et al
5. Conclusion
Only 4 prior cases of prenatal diagnosis of partial trisomy 10q have been reported. {Not sure if
prenatal is correct since the results were returned after the termination – nuance difference, however
management did not follow the microarray, rather the MRI confirmation and subsequent counseling. A
reviewer might not pick this up – we’ll see} All prior cases involved identification of microscopic
karyotype abnormalities. The current case represents the first prenatal diagnosis of a 10q22-10q23
duplication syndrome with a normal karyotype. This case highlights the importance of prenatal
microarray in patients with abnormal prenatal ultrasound findings with and normal routine karyotype. The
American College of Obstetricians and Gynecologists currently acknowledges the utility of microarray
studies after normal karyotype in some cases where significant birth defects are identified (Paul we
should read carefully ACOG wording).
The combination of microcephaly, craniofacial abnormalities and talipes (clubfoot) encompasses
a broad differential diagnosis. A normal karyotype is considered reassuring, and can eliminate
aneuploidy. However, a normal karyotype does not eliminate smaller genomic changes duplications or
deletions. In our case both were identified.
Many clinicians mistakenly equate a normal karyotype to a “normal” genotype. With the advent
of microarray analysis, geneticists can now identify many previously described genetic conditions
wherein genomic abnormalities are sub-microscopic. Karyotype analysis can no longer be considered
adequate genetic evaluation after a “normal” result, especially in the presence of fetal abnormalities
identified by high-resolution ultrasound studies.
The fetal abnormalities identified in the current case have not been reported to be associated with
prenatal exposure to Buspar. Midface abnormalities such as cleft lip/cleft palate have been associated
with prenatal exposure to benzodiazepines such as Valium, but have not been reported with exposure to
Xanax. (need reference for this statement)Duplication in the 10q22-10q23 region is associated with a
well-defined syndrome of abnormalities including a broad nasal bridge, microcephaly, congenital heart
disease, talipes (clubfoot) and developmental delay. (note references)Although the duplication was
smaller than many reported in the literature, the prenatal ultrasound findings closely resemble the
syndrome of partial trisomy 10q.
Summary
An apparent de novo interstitial duplication in 10q was demonstrated by microarray technology in a fetus
with significant microcephaly, severe hypertelorism and talipes The genomic imbalance was not
demonstrated on conventional karyotype at the 470 Mb resolution given the small size of the duplication
(7.1 Mb pairs). Clinicians should advise patients with suspected fetal abnormalities and a normal
karyotype to consider microarray analysis to detect sub-microscopic duplications and deletions. Despite
unexpected information and results where clinical significance is uncertain, microarray analysis can aid
physicians, genetic professionals and their patients in navigating pregnancy management decisions and
importantly, provide parents with information not otherwise available with conventional cytogenetics.
Bibliography
1. Kep-de-Pater JM, Bijlsma JB, de France HF, Leschot NJ, Duijndam-Van den Berge M, Van Hernel
JO. Partial trisomy 10q. A recognizable syndrome. Hum Genet 1979;46:29-40
2. Erdogan F, Belloso JM, Gabau E, Ajbro KD, Guitart M, Ropers HH, Tommerup N, Ullmann R, Tümer
Z, Larsen LA. Fine mapping of a de novo interstitial 10q22-q23 duplication in a patient with congenital
heart disease and microcephaly. Eur J Med Genet 2008;51-81-86.
3. Han JY, Kim KH, Jun HJ, Je GH, Glotzbach CD, Shaffer LG. Partial trisomy of chromosomal
10(q22-q24) due to maternal insertional translocation. Am J Med Genet Part A 2004;131(2);190-3.
4. Goss PW, Voullaire L, Gardner RJ. Duplication 10q22.1-q25.1 due to intrachromosomal insertion: a
second case. Ann Genet 1998;41(3):161-3.
5. Dufke A, Singer S, Borrell-Kost S, Stooter M, Pflumm DA, Mau-Holzmann UA, Starke H, Mrasek K,
Enders H. De novo structural chromosomal imbalances: molecular cytogenetic characterization of partial
trisomies. Cytogenet Genome res 2006;114(3-4):342-50.
6. Chen CP, Chern SR, Chang TY, Lee CC, Chen WL, Wang W. Prenatal diagnosis of partial trisomy
10q (10q25.3qter) and partial monosomy 18q (18q23qter). Prenat Diagn 2005;25(11);1069-71.
7. Batukan C, Ozgun MT, Basbug M, Caglayan O, Dundar M, Murat N. Sacrococcygeal teratoma in a
fetus with prenatally diagnosed partial trisomy 10q (10q24.3qter) and partial monosomy 17p
(17p13.3pter). Prenat Diagn 2007;27:365-8
8. Chen CP, Chen YJ, Tsai FJ, Chern SR, Wang W. NfkappaB2 gene duplication is associated with fetal
pyelectasis in partial trisomy 10q(10q24.1qter). Prenat Diagn 2008;28(4):364-5.
9. Chen CP, ChenYJ, Chern SR, Tsai FJ, Chang TY, Lee CC, Town DD, Lee MS, Wang W. Prenatal
diagnosis of concomitant Wolf-Hirschhorn syndrome and split hand-foot malformation associated with
partial monosomy 4p (4p16.1pter) and partial trisomy 10q (10q25.1qter). Prenat Diagn
2008;28(5):450-3.
Need to incorporate the following references into discussion:
Cottrell CE, et al. 2010. Unexpected Detection of Dystrophin Gene Deletions by Array Comparative
Genomic Hybridization. Am J Med Genet Part A 152A:2301-2307.
10. Array Comparative Genomic Hybridization in Prenatal Diagnosis. American College of Obstetricians
and Gynecologists Committee Opinion Number 446, November 2009.