American Journal of Medical Genetics 77:391–394 (1998)
Constitutional del(19)(q12q13.1) in a Three-Year-Old
Girl With Severe Phenotypic Abnormalities
Affecting Multiple Organ Systems
Anita S. Kulharya,1* Ron C. Michaelis,2 Karen S. Norris,1 Harold A. Taylor,2 and
Jaime Garcia-Heras3
1
Medical College of Georgia, Department of Pediatrics, Augusta, Georgia
2
Greenwood Genetic Center, Greenwood, South Carolina
3
Texas Department of Health, Bureau of Laboratories, Genetic Testing Center, Denton, Texas
We present the clinical, cytogenetic, and
molecular studies on a constitutional dele-
tion of 19q ascertained prenatally due to de-
creased fetal activity and IUGR. Chromo-
some analysis by GTG banding on amnio-
cytes suggested a del(19)(q13.1q13.3), but
the analysis of microsatellites by PCR dem-
onstrated that the deletion involved the dis-
tal segment of q12 and the proximal segment
of q13.1 (15 cM). The severely affected
female infant born at 38 weeks has clini-
cal findings that may be related to hap-
loinsufficiency of specific genes within
19q12.1→q13.1 that control important pro-
cesses of normal development and cell func-
tion. Am. J. Med. Genet. 77:391–394, 1998.
© 1998 Wiley-Liss, Inc.
KEY WORDS: chromosome 19; long arm de-
letion; paternal origin
INTRODUCTION
Translocations, inversions, duplications, and rings of
chromosome 19 are not uncommon, but constitutional
deletions are rare [Borgaonkar, 1994]. To our knowl-
edge, there is only one reported deletion of 19p [Hur-
goiu and Suciu, 1984] and a recent case of a submicro-
scopic de novo deletion of 19q in a patient with Dia-
mond-Blackfan anemia and congenital anomalies
[Gustavsson et al., 1997].
We describe another case of a constitutional intersti-
tial deletion of the long arm of chromosome 19. The
deleted region in our case does not overlap the deletion
reported by Gustavsson et al. [1997]. The patient is a
Contract grant sponsor: Texas Department of Health.
*Correspondence to: Dr. Anita S. Kulharya, Medical College of
Georgia, Department of Pediatrics, CA1016, Augusta, GA 30912.
E-mail: akulhary@mail.mcg.edu
Received 9 October 1997; Accepted 7 February 1998
© 1998 Wiley-Liss, Inc.
3-year-old severely affected girl who has been followed
since birth. This abnormality was ascertained by am-
niocentesis at 27 weeks due to IUGR and decreased
fetal activity. Cytogenetic and microsatellite analysis
by PCR determined the deletion to be of paternal origin
with breakpoints at q12 and q13.1.
CLINICAL REPORT AND METHODS
Clinical Manifestations
The mother was a 33-year-old Caucasian woman
with 2 previous abortions, one spontaneous and the
other a product of an ectopic pregnancy. Her clinical
history was otherwise unremarkable, and results of a
triple screen test at 16 weeks of gestation were normal.
Initial ultrasound findings at 22 weeks were normal;
but at 27 weeks 3 days, another ultrasound study was
performed because of decreased fetal activity. The fetal
measurements corresponded to 24 weeks gestational
age. The head was slightly larger than the abdomen
and femora, suggesting asymmetric IUGR. The ultra-
sound study also showed multicystic kidneys and fetal
hand abnormalities. A fetal echocardiogram and color
flow Doppler ultrasound studies showed no abnormali-
ties.
A female infant with single umbilical artery was de-
livered at 38 weeks by cesarean section. The head cir-
cumference (OFC) was 27.5 cm (50th centile for 24
weeks), length 40 cm (50th centile for 29 weeks), and
weight 1,295 g (50th centile for 30 weeks). She was
extremely hypotonic. Minor facial anomalies included
micrognathia, posteriorly angulated and apparently
low-set ears, hypertelorism, and a broad nasal root. A
high arched palate and a 3 × 2 cm area of triangular
cutis aplasia in the posterior fontanelle were present.
There was clinodactyly of the fifth fingers; the 2nd toe
overlapped the 3rd toe. The infant was very thin with
very little subcutaneous fat. The cry was weak even at
the height of irritability (Fig. 1). Congenital dislocation
of the right hip was detected, and while it was not
apparent at age 4 weeks, it recurred several times dur-
ing the following few months.
The infant had very poor suck and oral motor coor-
392 Kulharya et al.
Fig. 1. The infant at age 4 months.
dination, control, and strength. Severe oral dysphagia
was noted with video fluoroscopy. There was a delayed
epiglottis reaction so she was considered a high risk for
aspiration. She was fed through a gastrostomy tube for
several months which was later converted to a gastros-
tomy button. She received occupational therapy and
physical therapy twice a week.
CT images of the brain obtained shortly after birth
were normal. Ultrasound study showed bilateral hy-
dronephrosis with a normal renal cortex. The hydrone-
phrosis resolved by age 2 months. At 11 months, weight
was below 5th centile (level of a 2 month old). Length
was <5th centile and corresponded to age 7 months.
Congenital deafness, right hip agenesis, cardiomegaly,
and a slightly thickened myocardium with right coro-
nary dilation and elevated serum liver enzyme levels
were detected. For the first 2 years of life she showed
severe failure to thrive. She was frequently hospital-
ized due to bronchospastic episodes and upper airway
obstruction with stridor, choking, coughing, and pro-
duction of large mucous plugs which became progres-
sively more severe. The choking did not occur at the
time of feedings. Bronchoscopy demonstrated an abnor-
mal subglottic space with dynamic narrowing. She had
pneumonia at age 20 months with perihilar infiltrates
throughout the right lung that resolved over time.
At 36 months she can neither sit on her own nor roll
but is able to sit when propped and has achieved lim-
ited head control. There is absence of speech. Urine and
plasma amino acid profiles were normal (Beckman
Amino Acid Analyzer with ninhydrin detection).
Cytogenetic Studies
Chromosome analysis was done on amniocytes and
blood lymphocytes in the mother using standard pro-
cedures. The father was unavailable for chromosome
analysis. Fluorescent in situ hybridization was per-
formed using the CISS technique [Pinkel et al., 1988]
with a chromosome 19 specific library [Oncor, Gai-
thersburg, MD].
Microsatellite Analysis
Lymphocyte DNA was isolated from patient and
mother by standard techniques. Microsatellite markers
were amplified by PCR following a standardized proto-
col. Primers were synthesized using the Beckman Oligo
system. Each reaction contained 19 mM Tris-HCl, pH
8.3, 50 mM KCl, 1.5 mM MgCl2, 0.67 mM of each
primer, 200 mM dATP, dGTP, and dTTP, 2.5 mM unla-
beled dCTP, 16.7 nM 32P-labeled dCTP (3000 Ci/mmol),
and 0.45 unit of AmpliTaq DNA polymerase (Perkin-
Elmer/Cetus) in a total volume of 15 ml. The samples
underwent denaturation at 94°C for 5 min, then 30
cycles of 94 °C for 30 sec, 55 °C for 45 sec, and 72 °C for
45 sec, followed by a 10 min final extension period at 72
°C. The PCR products were electrophoresed on a 6%
acrylamide/7 M urea gel and visualized by autoradiog-
raphy using XAR film (Kodak) at −80 °C.
The position of markers (Table I) represents a con-
sensus obtained by a synthesis of information from the
following maps in the Genome Data Base: Whitehead
YAC contigs WC19.1, WC19.2, and WC19.3; CHLC
chromosome 19 (G3); Généthon Chromosome 19
(March 1996); Radiation Hybrid Consortium Tran-
script Map-Chromosome 19; and CEPH/Généthon
Chromosome 19 Linkage Map. Markers D19S222,
D19S414, D19S416, D19S425, and D19S431 appeared
on between 2 and 5 maps each, allowing one to deter-
mine the degree of agreement between maps. There
were no discrepancies between any of the maps regard-
ing the order of any of these markers. In addition, the
specific cM positions of these markers were identical on
the Whitehead YAC contigs, the CHLC Chromosome
19 Recombination Minimizing Map, the Généthon
Chromosome 19 Map, and the Radiation Hybrid Con-
sortium Transcript Map. The cM positions agreed upon
by the above-mentioned group of maps were used for
Table I and discussion of results.
The only discrepancy of which we are aware regard-
ing the ordering of these markers involves the place-
ment of D19S191. The Lawrence Livermore National
 del(19)(q12q13.1) 393

TABLE I. Microsatellite Analysis of Markers in 19q12-q13*

Band Marker cM Mother Proposita Interpretation
q12 D19S566 46 2,3 1,2 Not deleted
D19S407 47 1,2 1,3 Not deleted
D19S931 48 1,2 2 Deleted
D19S222 49 1,2 2 Deleted
D19S414 53 1 1 Deleted
q13.1 D19S416 58 1,2 2 Deleted
D19S425 59 1,2 2 Deleted
D19S569 60 1,2 2 Deleted
D19S224 60 1,2 2 Deleted
D19S881 62 1,2 1 Deleted
D19S223 63 2,3 1,2 Not deleted
D19S220 64 2,3 2,3 Not deleted
D19S422 65 1,3 1,2 Not deleted
D19S191 76 1,2 1 Not deleteda Fig. 2. Partial karyotype showing the deletion 19q12→q13.3 in lym-
phocytes (550–600 bands). The deleted 19 is on the right. The arrows on
q13.2 D19S200 83 2,3 1,2 Not deleted
the normal 19 (left) and the idiogram of chromosome 19 (850 bands) in-
D19S197 84 1,2 2 Not deletedb dicate the deleted region.
q13.3 D19S246 105 1 1,2 Not deleted
*The order and cM position of the markers was determined as described in
the Methods section. DNA sample, it is possible that the deletion is smaller
a
Either homozygous or within the deletion. Please refer to the discussion of if the patient is homozygous for any of the most proxi-
the ordering of these markers in the Methods and Results sections.
b
Presumed homozygous. mal or distal markers which seem deleted.
For all 8 markers for which the patient showed only
one allele, the PCR product size matched one of the
Laboratory (LLNL) chromosome 19 map places maternal alleles. Therefore, it was concluded that the
D19S191 distal to D19S425 [Olsen et al., 1997]. This deletion occurred on the paternal chromosome 19. The
places D19S191 within the region of chromosome 19 patient showed a single PCR product for markers
that is deleted in our patient. The discrepancy between D19S191 and D19S197, mapping 14 and 22 cM distal
the positioning of D19S191 on the LLNL map and the to the proposed distal breakpoint. This was interpreted
other maps has not been explained. as homozygosity for these markers because the patient
Since paternal DNA was not available, alleles were carries two alleles for each of the more proximal mark-
compared between the mother and the patient. The ers D19S223, D19S220, and D19S422. Further, as
deletion was inferred by the presence of an uninter-
rupted cluster of contiguous markers for which the pa-
tient showed only one allele that was flanked on both
sides by markers for which she showed two alleles

RESULTS
Cytogenetics
The initial karyotype demonstrated a deletion in the
proximal portion of 19q, but the breakpoints were dif-
ficult to distinguish due to a uniform euchromatic
banding pattern (Fig. 2). The deletion was confirmed
after birth in lymphocytes. The breakpoints were
thought to be at q13.1 and q13.1 in both amniocyte and
lymphocyte karyotype analysis. The FISH analysis did
not show any evidence of a cryptic rearrangement in-
volving chromosome 19 and any other chromosome.
The mother’s karyotype was normal, and the father
was unavailable for testing.
Molecular Studies
Microsatellite analysis (Table I, Fig. 3) confirmed the
deletion on 19q and helped to delineate the break-
points. A 15 cM region was deleted including the dis-
tal segment of band q12 and the proximal segment
of band q13.1. The proximal breakpoint lies in a 1 cM
region between markers D19S407 and D19S931, while
the distal breakpoint is in a 1 cM interval between
markers D19S881 and D19S223. Based on these data,
the karyotype was reinterpreted as 46,XX,del- Fig. 3. Microsatellite analysis at D19S407 (A), D19S931 (B), D19S881
(19)(q12q13.1). Given the unavailability of a paternal (C), and D19S223 (D). Left lane, patient; right lane, mother.
394 Kulharya et al.
noted in the Methods section, the chromosome 19 map
maintained by the LLNL places D19S191 slightly dis-
tal to D19S425. This places D19S191 within the region
that is deleted in our patient.
DISCUSSION
We describe a second case of a constitutional deletion
of 19q in a 3-year-old mentally retarded girl with mul-
tiple minor anomalies who was identified prenatally at
27 weeks of gestation. The cytogenetic breakpoints
were refined at the molecular level by microsatellite
analysis. The severity of the phenotype and the variety
of organ systems affected may reflect the gene density
within the deleted region of chromosome 19. The
OMIM Gene Map lists 57 genes whose loci overlap the
deletion and 15 that map within q12-q13.1. Many of
them are necessary for normal function in a variety of
cell types and therefore could have contributed to any
of the abnormalities. Examples of these include genes
encoding an RNA polymerase II subunit (POLR21,
q12), a Na+/K+ transporting ATPase (ATP1A3, q12-
q13.2), the urokinase-type plasminogen activator re-
ceptor (PLAUR, q13), two zinc finger proteins
(ZNF146, q13.1; and AFP36, q13.1), synaptotagmin-3
(SYT3, 19q), a voltage-gated sodium channel subunit
(SCN1B, q13.1), the cytoskeletal-associated protein 1
(CKAP1, q13.11-q13.12), and the ribosomal protein
S11 (RPS11, 19q).
Although a complete genotype–phenotype correla-
tion cannot be established in this patient, several genes
in this region are good candidates for specific anoma-
lies. The deletion of the DFN4 gene (q13) which is in-
volved in type IV autosomal dominant nonsyndromic
congenital deafness may contribute to the profound
congenital deafness. The hypotonia and muscle weak-
ness may be the result of a deletion of genes encoding
either ubiquinol–cytochrome c reductase (UQCRFSI,
q12) or the VIB subunit of cytochrome c oxidase
(COX6B, q13.1). USF2 and NPHS1 are genes whose
loss may account for the renal anomalies. The up-
stream transcription factor 2 gene (USF2, q13) is prob-
ably responsible for at least one case of translocation
induced bilateral multicystic dysplasia [Moerman et
al., 1994]. The hemizygous deletion of the gene for re-
cessive congenital nephrosis of the Finnish type
(NPHS1, q12-q13.1) is a possible cause of the resolving
hydronephrosis. Deletion of the CCAAT/enhancer bind-
ing protein gene (CEBPA, q13.1) could explain the low
levels of lipid storage and lack of subcutaneous fat,
since mice with targeted mutations of the mouse ho-
molog of the CEBPA gene do not accumulate lipids in
hepatocytes or adipocytes [Wang et al., 1995]. The
growth retardation may have several causes, among
them deletion of the gene encoding the transforming
growth factor b-1 (TGFB1, q13.1-q13.3). Given the pos-
sible inclusion of the maple syrup urine disease gene
(MSUD1, q13.1q13.2) in the deletion, plasma and urine
amino acids were analyzed. Both profiles were normal,
and the urine isoleucine level was lower than published
normal ranges. While heterozygous deletions of
MSUD1 would not produce the recessive disorder
MSUD, these findings suggest that the deletion did not
include the MSUD1 gene.
The paucity of previous reports of constitutional de-
letions of 19q probably reflects the lethal effects of hap-
loinsufficiency of this region, but may also reflect dif-
ficulties in identifying deletions by GTG banding. If the
latter is a significant factor, this study demonstrates
the advantages of combining cytogenetic and molecular
techniques to resolve an ambiguous diagnosis. Wheth-
er a 19q deletion syndrome can be established awaits
further reports of patients with similar rearrange-
ments.
ACKNOWLEDGMENTS
We thank Dr. David Flannery for his helpful com-
ments. We thank the family for their cooperation,
Karen Buchanan for her assistance with figures, and
the Texas Department of Health for partial financial
support.
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