7q36 deletion and 9p22 duplication: effects of a double imbalance
© Pelegrino et al.; licensee BioMed Central Ltd. 2013
Received: 27 August 2012
Accepted: 11 November 2012
Published: 15 January 2013
The etiology of mental retardation/developmental delay (MRDD) remains a challenge to geneticists and clinicians and can be correlated to environmental and genetic factors. Chromosomal aberrations are common causes of moderate to severe mental retardation and may represent 10% of these occurrences. Here we report the case of a boy with development delay, hypoplasia of corpus callosum, microcephaly, muscular hypotonia, and facial dysmorphisms. A deletion of 7q36.1 → 36.3 and duplication of 9p22.3 → 23 was detected as a result of an unbalanced translocation of paternal origin. Breakpoint delimitation was achieved with array comparative genomic hybridization assay. Additional multiplex ligation dependent probe amplification (MLPA) analyzes confirmed one copy loss of 7q36.3 region and one copy gain of 9p24.3 region. Patient resultant phenotype is consistent with the already described findings for both 7q deletion and 9p duplication syndromes.
Mental retardation/developmental delay (MRDD) is a relevant public health concern, since it may represent one of the major causes of child disability, with prevalence estimated in 1-3% . In Brazil, the Governmental Census conducted in 2010 estimated that MRDD can be found in 1.4% of population , but this number may be underestimated. Actually, there are deficiencies not only in evaluating MRDD prevalence around the world but also in methodology for screening and impairment degree stratification [3, 4]. MRDD causes are heterogeneous and may have both environmental and genetic bases. It is estimated that 65-80% of patient’s MRDD etiology remains unknown .
9p duplication syndrome is considered one of the most frequent autosomal anomalies in life born together with trisomies 13, 18 and 21 . More than 150 cases of 9p duplication are reported in literature  and common features include mental retardation, failure to thrive, hypotonia, microcephaly, low set malformed ears, upward-slanted eyes, small palpebral fissures, congenital heart disease, skeletal and genitourinary anomalies, enophthalmos or microphthalmos, broad base nose and prominent nasal tip, downward slanting mouth, among others characteristics [7, 8].
Similarly, deletion of 7q is a described syndrome  and clinical findings comprise low birth weight, mental retardation, development delay, facial dysmorphisms and genitourinary malformations [10–19]. Additionally, more severe phenotypes, as sacral agenesis and holoprosencephaly (HPE), may occur [9, 14–17, 20]. Here we report the case of a boy exhibiting 7q deletion and 9p duplication due to an unbalanced translocation t(7;9) from paternal origin.
The patient (male) is the first child of a 31-year-old mother and her unrelated 28-year-old husband. Mother was Caucasian and father Japanese descent. Ultrasonography on 33 weeks of gestation revealed intrauterine growth retardation (IUGR) and diminished vascular sport. The mother reported only vitamins ingestion during pregnancy. The proband was born by cesarean section (37 weeks), Apgar were reportedly 5-8, weight of 1950 g, length of 41 cm and occipitofrontal head circumference 29.0 cm.
The newborn presented peculiar facies, severe microcephaly, and generalized hypotonia. He also developed jaundice without ABO incompatibility and phototerapy was required. Echocardiography with 2 days of life disclosed normal heart function. At the age of 5 months the child weight (5345 g), length (58 cm) and occipitofrontal head circumference (36.5 cm) were below the second percentile. Dysmorphic features included anterior fontanel with dimension like one finger, bilateral epicanthal folds, upslanting palpebral fissures, bulbous nasal tip, enlarged columela, large symmetric and posteriorly rotated ears. Limbs, hands and feet were symmetric. Hallux vagus and overlapping of the left third toe on the second toe were observed. Finger and toe nails were hyperconvex. Thorax and lombo-sacral radiographies revealed no abnormalities.
Additional aCGH and MLPA investigations were conducted. Patient and progenitors DNA samples were extracted from blood with Qiamp Dna Blood Midi (Qiagen, Germany). aCGH procedures were performed as recommended by manufacturer (Perkin Elmer, Norwalk). Constitutional Chip 4.0 (Perkin Elmer, Norwalk) was employed and was comprised of 5000 BAC clones spotted in duplicate, with resolution lower than 650 kb and segments arranged from 100 to 300 kb of human DNA, distributed through whole genome.
Clones that presented copy number variation detected through aCGH screening of patient genome
Status of alteration
Genomic coordinates (GRCh36 hg18)
Genes present in the region
PRKAG2, GALNTL5, LOC100505483
DPP6, LOC100132707, PAXIP1
Clinical manifestations of 7q deletion cases
Frühmesser et al. 2012
Ponnala and Dalal, 2011
Vorsanova et al. 2008
Ahn et al. 2003
Nowaczyk et al. 2000
Chen et al. 1999
Savage et al. 1997
Hara et al. 1986
46,XY, der (7), t(7;9) (q36;p22), 9 ph
46,XX, der(7), t(7;17) (q36;p13)
46, XY, der (7), t(7;14), (q33-q32.2)
45,XX, der(7), t(7;21) (q34;q22.13),-21
46,XX, der(7), t(2;7) (q37.3;q34)
46,XY, der(7), t(2;7) (p23.2;q36.1)
46,XX, der(7), t(3;7) (p23;q36)
46,XX, der (7), t(7; 19) (q36.1;q13.43)
46, XX, der(7), t(5;7) (q31:q22)
Age at diagnosis
5 months §
21 years §
2 years §
Up slanting palpebral fissures
Broad/bulbous nasal tip
Multiple skeletal abnormalities
Hypoplasia of the corpus callosum
Maternal age at conception
Although HPE was not pointed as a feature of the case here shown, MRI scan of the brain of the patient disclosed hypoplasia of corpus callosum, which may be considered a minimal finding of HPE . In fact, 7q36.3 region encloses the gene SHH- Sonic Hedgehog, which haploinsufficiency was previously associated with HPE [29, 30], microcephaly and cerebral midline defects . Some characteristics as mental retardation, microcephaly, hypotonia and failure to thrive are common features of 9p duplication syndrome, also exhibited by this patient.
Duplication of 9p was recognized as a syndrome in 1970 , since then, more than one hundred cases were described and additional findings comprise mental retardation, failure to thrive, hypotonia, microcephaly, hypertelorism, deep set eyes in non-horizontal position, cup-shaped ears, kyphoscholiosis, cryptorchidism in males and syndactily of toes . Moreover, 9p duplication was already associated to HPE  and epilepsy , also observed in this case.
In fact, double imbalances, as the present one, may confer phenotypic variability to described syndromes, turning it difficult to predict the characteristics that evolved as a result of the global gene imbalance, caused by the concomitant duplication and deletion, and the contribution of each isolated alteration to resulting phenotype.
Actually, chromosomes 7 and 9 are grouped among those frequently involved in karyotype alterations leading to pregnancies losses, mental retardation and multiple congenital abnormalities . Chromosome 7 is also observed as one of the three preferentially involved in reciprocal  and complex translocations , while 9p23-24 is suggested as hotspot for chromosome breaking .
Interestingly, reciprocal translocation t(7;9) leading to 7q33 → qter duplication and pter → 9p23 deletion was also described and phenotype involved prominent metopic suture, epicanthal folds, strabismus, low-set ears, microretrognathia, large anterior fontanel, bilateral simian creases, muscular hypotonia, severe psychomotor retardation  and hermaphroditism . Additional cases may help to evaluate if t(7;9) is a recurrent translocation correlated to miscarriages, MRDD and congenital birth defects.
Aneuploidy together with segmental aneusomy constitute the mainly cause of pregnancy losses in humans. Additionally, among 5% of all pregnancies present aneusomies  and the resulting children can show malformations and MRDD. It is estimated that 1 out of 150 liveborn babies present chromosomal abnormalities , but this number might rise with the employment of arrays and next generation sequencing. In fact, the advent of these high throughput techniques has permitted whole genome scanning with finer resolution, leading to detection of subtelomeric rearrangements and microalterations previously undetectable through conventional approaches, as G-band karyotyping and FISH . Furthermore, DNA arrays have been useful for breakpoint site determination and copy number evaluation improving correlation among chromosomal region alteration and resulting phenotype.
We present the case of a patient exhibiting deletion of 7q36.1 → 36.3 and duplication of 9p22.3 → 23 as a result of an unbalanced translocation from paternal origin. Breakpoint delimitation was achieved with array comparative genomic hybridization analyzes and MLPA assays confirmed the alterations found. Patient presented development delay and facial dysmorphisms, among other abnormalities, consistent with both 7q deletion and 9p duplication syndromes. Reciprocal translocation leading to 9p deletion and 7q duplication had already been reported in two unrelated cases, indicating that t(7;9)(q36;p23) may occur more frequently than expected. Further cases may confirm these results. Finally, the increasing use of high throughput platforms for genomic studies tends to refine chromosome breakpoint analyses, evaluate critical regions involved in genetic disorders and disclose micro rearrangements firstly inaccessible through conventional approaches.
Written informed consent was obtained from patient’s progenitors for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
We would like to thank patient and her parents for accepting participate in the research. ML Chauffaille received CNPq Produtividade em Pesquisa grant number 309932/2009-2.
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