To date, there have been only a few reports of patients carrying a microdeletion in chromosome 12q14. These patients usually present with pre- and postnatal growth retardation, and developmental delay. Here we report on two additional patients with both genotype and phenotype differences. Similar to previously published cases, one patient has haploinsufficiency of the
Microarray technology has revolutionised the detection of human chromosomal abnormalities within cytogenetics by discovering new, as well as refining, existing syndromes. The technology has recently revealed the existence of a previously unknown deletion syndrome at 12q14. Initial case series have helped categorise and partially refine the genotype and phenotype correlations of this emerging syndrome [
Comparison of the main clinical indications of Patients 1 and 2 and six previously reported patients carrying 12q14 microdeletions.
Patient 1 | Patient 2 | Spengler et al. (2010) [ |
Takenouchi et al. (2012) [ |
Mari et al. (2009) [ |
Menten et al. (2007) [ |
Menten et al. (2007) [ |
Buysse et al. (2009) [ | |
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Hg |
63,169,460–66,983,229 | 60,220,054–65,843,601 | ~66,200,000–67,550,000 | 66,080,229–70,062,135 | ~66,173,733–68,023,733 | ~61,800,000–66,800,000 | ~65,100,000–68,500,000 | ~61,500,000–67,600,000 |
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Deletion size (Mb) | 3.8 | 5.6 | 1.35 | 4 | 1.8 | 5 | ~3.4 | ~6 |
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Pregnancy | IUGR | Uncomplicated | IUGR | Severe IUGR | Severe IUGR | Oligohydramnios | Hyperemesis | Uncomplicated |
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Birth measurements | Wgt.: 2550 g, Lgt.: 48 cm, HC: 35 cm | Wgt.: 2600 g (75th centile), HC: 33 cm (75th–91th centile) | Wgt.: 2700 g (−1.83 SD), Lgt.: 46 cm (−2.59 SD), HC: not noted | Wgt.: 527 g (−3.78 SD), Lgt.: 30.5 cm, HC: 22 cm | Wgt.: 1730 g (<10th centile), Lgt.: 43 cm (−4 SD), OFC: 29 cm (−3.66 SD) | Wt.: 2300 g (<P3), Lgt.: not noted, OFC: not noted | Wgt.: at 3rd centile, Lgt.: at 10th centile | Wgt.: 2060 g (<P3), Lgt. & HC not noted |
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Growth parameters | 3 years: Wgt.: 11 kg (0.5 kg <3rd centile), Hgt.: 82.6 cm (−3.5 SD), HC: 49.5 cm (40th percentile) | 3 years 8 months: Wgt.: 17.4 Kg, HC: 54 cm, Hgt.: 102.2 cm | 1 year 9 months: Wgt.: 6.8 Kg (−5.4 SD), Hgt.: 70.8 cm (−4.5 SD), OFC: 43.7 (−3.3 SD) | 29 months: Wgt.: 10.5 kg (−0.75 SD), Hgt. 76 cm (−3.13 SD), HC: 42.5 cm (−3.53 SD) | 3 years: Wgt.: 6.5 Kg (−5 SD), Hgt.: 77 cm (−4.85 SD), OFC: 44.5 cm (−5.1 SD) | 14 years: Wgt.: 51.3 kg (mean for age), Hgt.: 142.3 cm (−3.5 SD), HC: 53.3 cm (−0.66 SD) | 18 years, Wgt.: 41 kg, Hgt.: 152 cm (both below 3rd centile) | 16 years: Hgt. 131.5 cm (−6.2 SD), HC: 49 cm (−4.4 SD) |
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Clinical presentation | Severe SS, relative macrocephaly | Absolute macrocephaly | SS, FTT, relative macrocephaly | SS, severe FTT | Severe proportionate SS, FTT | SS | SS, FTT | Proportionate SS, FTT |
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Developmental delay | Mild | Yes | Mild | Not noted | Yes | Yes | Mild | Yes |
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Dysmorphic features | Alternating esotropia, severe myopia | Strabismus, prominent brow, large and slightly low set eyes | Prominent head, slight triangle face, dysplastic ears, clinodactyly of 5th finger | Cleft lip with alveolar cleft on the right, atrial septal defect | Triangle face with prominent forehead, low set ears, vaulted palate, micrognathia | Scoliosis, deep set eyes, bushy eyebrows, thin lips | Triangle face with wide spaced eyes | Synophrys, mild hypertelorism, broad & high nasal bridge, micrognathia & maxillary overbite |
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Behavioural issues | Possible ADHD, mild ASD | ASD | Not noted | No | Not noted | Not noted | Not noted | Not noted |
HC: head circumference, OFC: Occipital Frontal Circumference, IUGR: Intrauterine Growth Retardation, ASD: Autism Spectrum Disorder, ADHD: Attention Deficit Hyperactivity Disorder, FTT: failure to thrive, and SS: short stature.
Menten et al. [
The 12q14 interstitial deletions found in these initial cases encompassed two critical genes:
The study described here comprises an additional two patients with interstitial 12q14 microdeletions. Patient 1 carries a 3.8 Mb heterozygous deletion involving the interstitial region 12q14.2q14.3, and Patient 2 carries a 5.6 Mb heterozygous deletion involving the interstitial region 12q14.1q14.3.
A healthy male was born at 41-week gestation with asymmetrical growth restriction weighing 2550 g (<3rd centile), with length 48 cm (20th centile) and head circumference 35 cm (50th centile). The mother is a hyperactive, verbally aggressive and difficult individual who drank excessively during the pregnancy. She is also relatively short with a height of approximately 153 cm and has a strabismus. The father is approximately 183 cm tall, cannot read or write, and is socially reclusive. There were no concerns about the child’s motor skills and achieved expected milestones. He was noted to be a behaviourally difficult child, always on the go, demanding attention, and seemingly always talking. He understood language and could talk well although at times his speech was unclear and he spoke in an unusual voice.
Paediatric assessment of the proband at three years of age noted that he was short, with height 82.6 cm (3.5 SD below the mean), weight 11 kg (0.5 kg less than the 3rd percentile), and head circumference 49.5 cm (on the 40th percentile). He had deep set eyes and a thin upper lip but normal philtrum and palpebral fissures each 22 mm (−2 SD). He wore glasses suggesting severe myopia and manifested alternating esotropia. He had no clear features of Fetal Alcohol Syndrome, but there were concerns over possible mild dysmorphic features. It was noted that social communication was poor and that he talked in unusual voice prosody, with reasonable receptive and expressive language. He was diagnosed with mild Autism Spectrum Disorder (ASD), was hyperactive and aggressive, and had many features of ADHD. A final genetics consultation at four years of age confirmed previous findings and his guardians stated that he had problems with fine motor skills. Head circumference was near the 50th centile and height below the 3rd centile. He had the appearance of relative macrocephaly but little else to see from a dysmorphology perspective. The child never had X-rays so we cannot say if there were skeletal changes consistent with a diagnosis of Osteopoikilosis.
A female was delivered at 35-week gestation following a breech presentation. Family medical history was unremarkable. Birth head circumference was 33 cm (75th–91st percentile for 35-week gestation), birth weight was 2.6 kg (75th percentile), and she had some issues with poor feeding. By 2 months of age her head had grown to 38.5 cm on the 98th percentile for her corrected gestational age and accelerated further to the 99th percentile by 6 months of age.
She passed her developmental screen at one year of age but a further assessment at 19 months revealed developmental delay. Macrocephaly was also first noted at this visit. Her head circumference has been stable 1-2 cm above the 98th percentile since then. Her motor skills were delayed and speech was also delayed and she met the criteria for ASD. She received speech therapy for six months, but this was stopped because at three years of age she had hundreds of words, was speaking in 2-3-word phrases, and understood most of what was said.
An MRI was performed at 27 months of age showing mild hyperintensity in the deep white matter in the periventricular regions of the occipital area bilaterally, more so on the right. There was no mass effect and the brain was normally formed, with no hydrocephalus noted.
Further paediatric examination at 3 years 8 months of age showed height of 102.2 cm (75th centile), weight of 17.4 kg (75–90th centile), and head circumference of 54 cm (+3.5 SD). There were no obvious dysmorphic features or neurocutaneous stigmata and she was undergoing treatment for a strabismus. She had evidence of both gross motor/fine motor and language delay but was showing excellent catching up of her development with appropriate inputs. Her last review at 4 years 5 months showed that her head circumference continued to track above the centiles at 55 cm; she was 108 cm tall (75–90th centile) and weighed 20 kg (90th centile). She still met the criteria for a diagnosis of ASD and had global gross motor/fine motor and language delay but was showing very encouraging improvements in all aspects of her development. It was noted that she had mild plagiocephaly, a prominent brow, and mild hypertelorism (Figure
(a) Image of Patient 2. (b) Patient 2 exhibits frontal bossing and macrocephaly.
DNA was extracted from both Patients 1 and 2 with genome-wide copy number analysis determined using an Affymetrix Cytogenetics Whole-Genome 2.7M array and CytoScan 750K Array, respectively, according to the manufacturer’s instructions. Regions of copy number change were determined using the Affymetrix Chromosome Analysis Suite software (ChAS) either v.1.0.1 or v.1.2.2 and interpreted with the aid of the UCSC genome browser (
Schematic of chromosome 12q14 containing microdeletions. (a) shows an ideogram of chromosome 12. (b) shows the location and extent of the deletions detected in the patients described here and other cases reported in the literature, as well as RefSeq and OMIM genes that lie within 12q14. These graphics were taken from the UCSC genome browser (
Patient 1 carried a 3.8 Mb heterozygous deletion involving the interstitial chromosome region 12q14.2q14.3 (hg19 coordinates 63,169,460–66,983,229) encompassing 16 OMIM genes (
In the study described here, we report two patients with overlapping deletions in 12q14: a 3.8 Mb deletion in Patient 1 with extreme short stature, mild autism, behavioural problems, severe myopia, and esotropia and a 5.6 Mb deletion in Patient 2 with absolute macrocephaly, developmental delay, learning difficulties, and autism. The deletion in Patient 1 includes both the
Of the reported 12q14 interstitial deletion cases, only 5 (including one of the cases presented here) have not included the
The
Critically, Spengler et al. [
Patient 1, whose deletion includes the
OMIM genes that lie in the 12q14 interval bounded by
Gene | OMIM | Description |
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604731 | USP15 is required for TGFB and BMP responses in both mammalian cells and frog embryos. The |
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616016 | Knockdown of PPM1H significantly increases proliferation in BT474 breast cancer cells [ |
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600821 | The |
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613893 |
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605862 | The |
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606523 | SRGAP1 interacts with Roundabout transmembrane receptors, together with SLIT proteins, which guide neuronal and leukocyte migration [ |
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603180 | Exportin-t is a specific mediator of tRNA export [ |
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604834 | TBK1 is a binding partner for optineurin [ |
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607019 | The |
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607664 | The |
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615077 | TBC1D30 protein is predicted to be involved in cell signalling [ |
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605186 | WIF1 binds to WNT proteins and inhibits their extracellular signaling involved in the control of embryonic development [ |
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607844 |
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613719 | The |
Those genes in bold italics are implicated in bone morphogenesis.
TGFB: Transforming Growth Factor Beta.
BMP: Bone Morphogenetic Protein.
Our cases, together with those reported earlier, suggest that the SRS-like phenotype of patients with deletions in 12q14 can be refined to the following: Deletions that include (all or some of) the A macrocephaly region (~2 MB in length) proximal and independent of the Deletions involving both of these regions combine to form an SRS-like phenotype (see Patient 1).
In the future, smaller deletions within 12q14 may be uncovered in order to narrow down a macrocephaly locus. Of the genes described above, the most likely candidate gene appears to be
The authors declare that there is no conflict of interests regarding the publication of this paper.