A Family With a 1.17Mb Deletion of 12q12:
Refining Genotype–Phenotype Correlation
Margaret P. Adam,1* Ami Mehta,2Linda Knight,2David E. Hall,3and Michael R. Rossi2
1Department of Pediatrics, University of Washington, Seattle, Washington
2Department of Human Genetics, Emory University, Atlanta, Georgia
3Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio
Received 6 April 2010; Accepted 29 May 2010
TO THE EDITOR:
Proximal deletions of chromosome 12q are rare, with only nine
previously reported individuals [Meinecke and Meinecke, 1987;
Watson etal.,1989; Tonoki etal., 1998; Gallegoet al., 2000;Rapley
et al., 2001; Miyake et al., 2004; Perez-Sanchez et al., 2004; Failla
et al., 2008; Schluth et al., 2008; Yamanishi et al., 2008]. However,
only four of these reports are of individuals whose deletion en-
compassed 12q12 [Tonoki et al., 1998; Gallego et al., 2000; Rapley
et al., 2001; Miyake et al., 2004; Failla et al., 2008] (of note, the two
individuals reported by Miyake et al.  were those originally
reported by Tonoki et al.  and Gallego et al. ).
Genotype–phenotype correlation was originally attempted by
Miyake et al.  and refined by Failla et al.  based on
three individuals had in common psychomotor and growth retar-
dation, disturbance in extraocular motility, palatal anomalies,
downturned corners of the mouth, lowset ears, widely spaced
nipples, small feet, and 5th finger clinodactyly. Here we report on
a father and son who have a 1.17Mb deletion of 12q12. Both
individuals had growth retardation in infancy, mild dysmorphic
features, small hands with proximally placed thumbs, and mild
learning issues. This is the smallest deletion of chromosome 12q12
reported to date, and lends further support to the hypothesis that
YAF2 may contribute to growth retardation and that PRICKLE1
may play a role in learning disabilities, as originally proposed by
Failla et al. .
The patient is a 14-month-old former 34-week male born to a
Caucasian and consanguinity was denied. There were no prenatal
complications and ultrasounds were unremarkable, without intra-
uterine growth retardation. The patient was born at 34 weeks by
normal spontaneous vaginal delivery. Birth weight was 1.76kg
(10th to 25th centile corrected for gestational age). Other birth
unit for 2 weeks due to feeding issues, but he had no respiratory
After discharge the patient had progressive growth issues. His
weight at 4 months was 50th centile corrected for gestational age
(5.76kg) but fell to <5th centile corrected for gestational age
(7.5kg) by 12 months. Similarly his length at 6 months was
10th centile corrected for gestational age (61.6cm), but fell to
<5th centile corrected for gestational age (66cm) by 12 months.
His head circumference was 25th to 50th centile corrected for
gestational age (40cm) at 4 months but <5th centile corrected for
gestational age (43.2cm) by 12 months. He was admitted to the
hospital at 12 months of age to determine the cause of his
growth retardation. He was found to have an oral aversion;
however, because his growth retardation was symmetric and
his weight for length was at the 50th centile, it was felt that this
could not fully explain his growth problems. Wrist radiographs to
evaluate for rickets were normal, with no evidence of epiphyseal
The patient was also noted to have mild dysmorphic features
(Fig. 1A–D), including upslanting palpebral fissures, large and
lowset ears, a broad nasal bridge (with anteverted nares in infancy),
small hands (total hand length of 7.5cm, which is <3rd centile
corrected for gestational age), proximally placed thumbs, and a
crease on the right hand. His development was questionably
delayed. He rolled at 5–6 months uncorrected age, sat between
4 and 6 months uncorrected age, and had just begun pulling to a
stand at 14 months uncorrected age. He was not yet cruising or
NE, PO Box 5371/A7937, Seattle, WA 98105-0371.
Published online 3 August 2010 in Wiley Online Library
How to Cite this Article:
12q12: Refining genotype–phenotype
Am J Med Genet Part A 152A:2394–2398.
? 2010 Wiley-Liss, Inc.
walking independently. He babbled but had no specific words.
He did use a pincher grasp.
A chromosomal oligonucelotide array [EmArray Cyto6000
Baldwin et al., 2008] was sent and demonstrated a 1.17Mb inter-
stitial deletion of chromosome 12q12. The gene content of this
region is presented in Figure 2. The patient’s father was found to
have this same deletion. Upon further questioning of the father,
from childhood. He stated that he also had difficulties in school,
which had been attributed to motivational/attention problems.
He states that he completed secondary school and is a musician.
He has some mild learning disabilities, particularly in math,
but no other known health problems. He currently is 175.9cm
(25th to 50th centile) tall with a head circumference of 55.9cm
(50th centile). He was also noted to have a broad nasal bridge and
FIG. 1. A,B:Ourpatientasaninfantandat14monthsofage,respectively.C,D:Picturesofthepatient’shandsat14monthsofage.E,F:Patient’sfather
in early childhood and as an adult, respectively. G,H: Patient’s father’s hands. Note the stubby fingers and proximally placed thumbs.
FIG. 2. Gene content of the deleted 12q12 region (modified from the UCSC Genome Browser; https://genome.ucsc.edu) in our patient and in three
previously reported patients by Failla et al. .
ADAM ET AL.
TABLE I. Summary of Clinical Findings in Our Family and Four Previously Reported Individuals With 12q12 Deletions
Tonoki et al. 
Gallego et al. 
Rapley et al. 
Failla et al. 
Our patient’s father
Age at evaluation
Normal to mild
þ (as a child)
Broad forehead, prominent
Strabismus, myopia, CFEOM
Broad nasal bridge;
Broad nasal bridge
Small with downturned
Small with downturned
narrow vermilion border
Cleft or high-arched palate
Sensorineural hearing loss
Widely spaced nipples
Proximally placed thumbs
pictures appear þ)
Single palmar crease
Fifth finger clinodactyly
2nd and 3rd toe anomalies
SD, standard deviation; þ, present; ?, absent; CFEOM, congenital fibrosis of the extraocular muscles; NR, not reported; N/A, not assessed.
2396 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
mildly upslanting palpebral fissures. He had proximally placed
thumbs andhisfingersappearedstubbywith atotal handlengthof
18.4cm (50th centile for a 15-year-old male) (Fig. 1E–H). The
remainder of the family history was unremarkable.
A comparison of features present in our patient, his father, and
the four previously reported individuals with similar deletions is
presented in Table I. Common features (reported in at least 5/6
individuals) include a history of growth retardation, a broad nasal
bridge, large/lowset ears, small hands, and psychomotor retarda-
tion, to varying degrees. The patient and his father also had
proximally placed thumbs, which were present in the patient from
from Gallego et al. . Notably missing in our patient and his
father are eye mobility abnormalities, small mouth with down-
turned corners, palatal anomalies, widely spaced nipples, and fifth
finger clinodactyly, which may be caused by deletions of genes
outside of the 1.17Mb region seen in our patients.
The deleted segment reported here encompasses five known
depletion of the Yaf2 protein in zebrafish leads to excessive apo-
[Stanton et al., 2006]. Therefore, both Miyake et al.  and
Failla et al.  proposed that this gene may be involved in the
utero. The father of our patient reports growth problems in
childhood but currently has normal growth parameters. It is
in infancy that is overcome by other growth factors working
throughout childhood and adolescence. Previously reported indi-
viduals were 10 years or younger at the time of the reports, and it
may be that their growth will improve as they reach adulthood.
Alternatively, since the previously reported individuals all had
larger deletions, it is possible that YAF2 contributes to growth
genes in the region.
GLT8D3 encodes an enzyme which belongs to the human
glycosyltransferase 8 family. These enzymes play a role in adding
the first xylose to O-glucose-modified residues of proteins such as
for a similar type of enzyme (protein-O-fucosyltransferase 1 in-
volved in the addition of O-linked fructose to Notch1) has no
phenotype [Shi and Stanley, 2003]. Homozygous knockout mice
signaling is involved in skeletal patterning, among many other
developmental processes. The majority of patients with 12q12
deletions had small hands with proximally placed thumbs. It is
theoretically possible that alterations in NOTCH1 signaling due
haploinsufficiency of GLT8D3 could lead to hand anomalies,
although one might expect more severe limb anomalies or other
major malformations, which have not been present in those
with 12q12 deletions. Interestingly, the patient reported by Failla
et al.  had multiple epiphyseal dysplasia, which was not
seen in our patient and has not been reported in other individuals
with this deletion. Therefore, that finding may be unrelated to the
and Hersh, 2006]. Recently, homozygous mutations in PRICKLE1
have been found to cause autosomal-recessive progressive myoc-
mutations appear to disrupt PRICKLE1 and REST interaction,
thus altering the normal function of PRICKLE1, as opposed to
haploinsufficiency of PRICKLE1. However, this finding underlies
the importance of PRICKLE1 in normal neural development. Of
growth retardation or learning issues [personal communication].
Our two patients had evidence of mild learning issues, whereas the
previously reported individuals had more severe developmental
issues. Again, this may be related to the sheer number of genes
deleted in the previously reported individuals, as generally the
larger the deletion, the more severe the learning problems.
PPHLN1 encodes a protein called PERIPHILIN1, which is
involved in epithelial differentiation and contributes to epidermal
integrity/barrier formation [Kazerounian and Aho, 2003]. Given
that dermatologic abnormalities have not been described in those
this gene has a significant phenotypic effect.
act as a member of splicesomes and has been proposed to be a
hepatocarcinoma candidate oncogene [Wang et al., 2007]. The
thought to be a tumor suppressor gene.
The deletion reported here represents the smallest deletion of
chromosome 12q12 reported to date and thus helps to refine
genotype–phenotype correlation for this region. Further studies
relates to the phenotypes described above.
Baldwin EL, Lee JY, Blake DM, Bunke BP, Alexander CR, Kogan AL,
microarray. Genet Med 10:415–429.
Chen S, Gonzalez-Alegre P, Griesbach HL, Wu S, Nashelsky M,
Vladar EK, Antic D, Ferguson PJ, Cirak S, Voit T, Scott MP, Axelrod
JD,Gurnett C,Daoud AS, KivityS,Neufeld MY, Mazarib A, Straussberg
R, Walid S, Korczyn AD, Slusarski DC, Berkovic SF, El-Shanti HI. 2008.
A homozygous mutation in human PRICKLE1 causes an autosomal-
recessive progressive myoclonus epilepsy-ataxia syndrome. Am J Hum
Failla P, Romano C, Reitano S, Di Benedetto D, Grillo L, Fichera M,
-phenotype correlation. Am J Med Genet Part A 146A:1354–1357.
interstitial 12q deletion. Int Pediatr 15:37–40.
Kazerounian S, Aho S. 2003. Characterization of periphilin, a widespread,
highly insoluble nuclear protein and potential constituent of the kera-
tinocyte cornified envelope. J Biol Chem 278:36707–36717.
ADAM ET AL.
Meinecke P, Meinecke R. 1987. Multiple malformation syndrome includ- Download full-text
ing cleft lip and palate and cardiac abnormalities due to an interstitial
deletion of chromosome 12q. J Med Genet 24:187.
Miyake N, Tonoki H, Gallego M, Harada N, Shimokawa O, Yoshiura K,
correlationin twopatientswith 12qproximal deletion.JHum Genet49:
Okamura Y, Saga Y. 2008. Pofut1 is required for the proper localization
of the Notch receptor during mouse development. Mech Dev 125:
Perez-Sanchez C, Ayensa F, Lloveras E, Zamora L, Cirigliano V, Perez E,
Plaja A. 2004. Prenatal diagnosis of an interstitial 12q chromosome
deletion. Ann Genet 47:177–179.
Rapley EA, Hargrave D, Persinguhe N, Barfoot R, Moore I, Radford M,
deletion association with Wilms tumor. Am J Med Genet 104:246–249.
Schluth C, Gesny R, Borck G, Redon R, Abadie V, Kleinfinger P,
12(q15-q21.2)inagirlwith facialdysmorphism andmental retardation.
Am J Med Genet Part A 146A:93–96.
Sethi MK, Buettner FFR, Krylov VB, Takeuchi H, Nifantiev NE,
Haltiwanger RS, Gerardy-Schahn R, Bakker H. 2010. Identification
of glycosyltransferase 8 family members as xylosyltransferases acting
on O-glycosylated Notch epidermal growth factor repeats. J Biol Chem
Shi S, Stanley P. 2003. Protein O-fucosyltransferase 1 is an essential
component of Notch signaling pathways. Proc Natl Acad Sci USA
Shimojo M, Hersh LB. 2006. Characterization of the REST/NRSF-interac-
tion LIM domain protein (RILP): Localization and interaction with
REST/NRSF. J Neurochem 96:1130–1138.
embryogenesis. J Biol Chem 281:28782–28793.
Tonoki H, Saitoh S, Kobayashi K. 1998. Patient with del(12)(q12q13.12)
manifesting abnormalities compatible with Noonan syndrome. Am J
Med Genet 75:416–418.
Wang H, Gao MX, Li L, Wang B, Hori N, Sato K. 2007. Isolation,
expression, and characterization of the human ZCRB1 gene mapped to
12q12. Genomics 89:59–69.
Watson MS, McAllister-Barton L, Mahoney MJ, Breg WR. 1989. Deletion
(12)(q15q21. 2). J Med Genet 26:343–344.
T, Kobayashi C. 2008. 12q interstitial deletion with bilateral cleft lip
and palate: Case report and literature review. Cleft Palate Craniofac J
2398 AMERICAN JOURNAL OF MEDICAL GENETICS PART A