A rare de novo interstitial duplication of 15q15.3q21.2 in a boy with severe short stature, hypogonadism, global developmental delay and intellectual disability
© Yuan et al. 2016
Received: 28 October 2015
Accepted: 7 January 2016
Published: 11 January 2016
Interstitial duplications distal to 15q13 are very rare.
Here, we reported a 14-year-old boy with severe short stature, delayed bone age, hypogonadism, global developmental delay and intellectual disability. His had distinctive facial features including macrocephaly, broad forehead, deep-set and widely spaced eyes, broad nose bridge, shallow philtrum and thick lips. A de novo 6.4 Mb interstitial duplication of 15q15.3q21.2 was detected by chromosomal microarray analysis. We compared our patient’s clinical phenotypes with those of several individuals with overlapping duplications and several candidate genes responsible for the phenotypes were identified as well.
The results suggest a novel contiguous gene duplication syndrome characterized with shared features including short stature, hypogonadism, global developmental delay and other congenital anomalies.
Microdeletions and microduplications are recurrent for the proximal region of 15q. Five common breakpoints (BP1–BP5) exist in the 15q11.2-q13 region. Deletions between BP1–BP3 are responsible for the Prader-Willi and Angelman syndromes, depending on the parent-of-origin, whereas the reciprocal duplications of the region, particular the gains of maternal copy of 15q11.2-q13, are known as 15q duplication syndrome (Dup15q) characterized by global developmental delay, autism spectrum disorder and epilepsy [1–3]. 15q13.3 microdeletions and microduplications between BP4–BP5 are enriched in neurodevelopmental and neuropsychiatric disorders [4, 5]. On the other end of the 15q, the terminal trisomy or tetrasomy of 15q, including IGF1R gene, is named as 15q26 overgrowth syndrome consisting of overgrowth, learning difficulties, distinctive facial features and multiple congenital anomalies . The monosomy of 15q26 shows the opposite growth features, such as pre- and postnatal growth retardation, as well as some different dysmorphic features . A few proximal microdeletions at 15q25.2 have been reported to be associated with congenital diaphragmatic hernia, cognitive deficits and Diamond-Blackfan anemia and some more distal deletions to neurodevelopmental and neuropsychiatric disorders [8–11]. Whereas duplications distal to 15q13 are very rare. Elcioglu (1997) described a patient with hypogonadism, skeletal anomalies, Marfan-like features, developmental delay and intellectual disability, who carried a de novo interstitial inverted duplication involving bands of 15q13.3-q21.3 . Herr (1983) reported a patient with a de novo interstitial duplication of 15q14-q21.1, who presented with hypogonadism, skeletal problems, short stature, delayed bone age, global developmental delay and intellectual disability . Both of the duplications were uncovered by high-resolution G-banded cytogenetics analysis, so the precise locations and sizes of the duplications were not determined [12, 13]. Here, we reported a de novo 6.4 Mb interstitial duplication of 15q15.3q21.1 in a 14-year-old boy with hypogonadism, short stature, global developmental delay and multiple congenital anomalies.
The proband is the fourth child of healthy unrelated parents with negative family history. His siblings are all healthy. Intrauterine growth retardation was noticed by ultrasound examination at 7 months of pregnancy. He was born by vaginal delivery at 38 weeks of gestation. Birth weight was 2.9 kg (<-1SD), length 47 cm (<-2SD) and head circumference 34 cm. Apgar scores were all 9. No feeding difficulty was noted at all times.
Chromosomal microarray analysis
Chromosomal microarray analysis was performed for the proband and both parents by Affymetrix Cytoscan HD Array (Affymetrix, USA). Genomic DNA was extracted from peripheral blood using a commercial kit (Qiagen). The labeling and hybridization procedures were performed following manufacturer’s instructions. The raw data of chromosomal microarray was analyzed by Affymetrix Chromosome Analysis Suite Software.
Confirmation of 15q15.3q21.2 duplication
The duplication was further confirmed using quantitative real-time PCR analysis. Primer sequences and descriptions were included in Additional file 1: Table S1.
Genomic and clinical information of patients with duplication of 15q13.3q22. The genomic coordinates are based on GRCH37/hg19
Herr et al., 1983
Elcioglu et al., 1997
chr15q13.3q21.3 inverted duplication
high resolution G-banding analysis
high resolution G-banding analysis
inherited from parent with similar phenotype
ID, language delay,
delayed bone age,
delayed bone age,
delayed cranial suture closure,
distinctive facial features, macrocephaly,
distinctive facial features, seizure
thyroid and growth hormone are normal
thyroid and growth hormone are normal
Elcioglu (1997)  and Herr (1983)  each reported a case with a de novo interstitial duplication on 15q13.3q21.3 and 15q14q21.1 respectively. The Decipher case 260222 largely overlapped with the duplication detected in our patient. Our patient had the smallest duplication among these four patients with large duplication centered on 15q21.1. We noticed that three patients (our patient, Decipher case 260222 and the patient reported by Herr) had strikingly similar clinical features including hypogonadism, short stature, delayed bone age, global developmental delay and intellectual disability. Interestingly, the patient reported by Elcioglu shared most of similar phenotypes, but presented with Marfan-like features such as tall stature. All duplications were de novo except for Decipher case 260222 without parental tests and not reported in DGV database, as well as these patients had similar clinical conditions especially hypogonadism and skeletal problems, which further suggested a likely pathogenic nature of these duplications.
To further support this notion, we identified several candidate genes responsible for complex clinical phenotypes. The FBN1 (134797) gene is involved in these duplications. As we know that different mutations of FBN1 gene cause different dominant genetic diseases characterized with opposite stature. For example, acromicric dysplasia caused by FBN1 mutations is characterized by severe short stature, short limbs, delayed bone age, stiff joints and facial dysmorphism . Weill-Marchesani syndrome caused by FBN1 mutations consists of short stature, eye abnormalities, unusually brachydactyly, joint stiffness and heart disease . Marfan syndrome caused by FBN1 mutations on the other hand is charaterized by tall and slender stature with arachnodactyly, as well as ocular and cardiovascular defects . Thus, skeletal anomalies could be explained by FBN1 gene duplication at this interval.
Other than the FBN1 gene that was known to cause skeletal problems, no other known disease gene at this interval could explain all clinical phenotypes of these patients. Smaller overlapping duplications shared by Decipher cases 250560 and 303564 and an ISCA case 1602971 involved the NOX family genes such as DUOX2, DUOXA2, DUOXA1 and DUOX1. The loss of function mutations in these genes could cause permanent congenital hypothyroidism [17–20]. However, thyroid examinations of our patient and the one reported by Herr were both normal and other patients were lack of this information, it may be inferred that the clinical consequence of genes duplication was not known. And there was no additional evidence to support the pathogenicity of these small duplications.
Among other genes at the interval, we identified the EID1 gene as an interesting candidate gene. EID1 was shown to be expressed ubiquitously in human tissues with high expression in neuron, cardiac and skeletal muscle [21, 22]. Liu et al. generated an EID1 transgenic mouse model that exhibited neuron-specific overexpression of human EID1 gene in the brain, and overexpression of EID1 reduced hippocampal long-term potentiation and impaired spatial learning and memory function . EID1 tightly interacted with CBP/p300 in the nuclei and had been identified as an inhibitory protein of CBP/P300 . CBP/p300, a family of CREB-binding proteins, was associated with Rubinstein–Taybi syndrome characterized by short stature, intellectual disability, developmental delay and distinctive facial features . Overexpression of EID1 in human brain could negatively regulate CBP/p300 activity and lead to the impairment of neuronal function. In addition, EID-1 was known to be co-expressed with the Steroidogenic factor-1 (SF-1) which played a critical role in adrenal and reproductive development and function [25, 26]. Park et al. provided convincing evidence demonstrating that EID-1 strongly inhibited the transcriptional activity of SF-1 . It was tempting to speculate that duplication of EID-1 may also be responsible for the hypogonadism phenotype.
Finally, we identified the SEMA6D gene as another candidate gene. SEMA6D gene, one member of the class VI subgroup of the semaphorin family, was expressed abundantly in kidney, brain, and placenta and moderately in the heart and skeletal muscles. The expression of SEMA6D predominantly in the adult tissues made them potentially important molecules in nervous system maintenance and repair. This profile was consistent with a more general role of the proteins in neurogenesis and organogenesis as well as in regenerative and degenerative processes . Therefore, we hypothesized that overexpression of SEMA6D may play a role in neurodevelopmental anomalies of our patient.
In conclusion, we reported a de novo duplication of 15q15.3q21.2 in a patient with skeletal problems, hypogonadism, global developmental delay, intellectual disability and facial dysmorphism. Several candidate genes responsible for the complex clinical features were identified and critical region centered on 15q21.1 was defined as well, thus we proposed a novel contiguous gene duplication syndrome at this genomic interval. Further studies on duplications involving this region will be necessary.
Written informed consent was obtained from the patient 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.
This study makes use of data generated by the DECIPHER Consortium. A full list of centres who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from firstname.lastname@example.org. We would like to thank the family of the proband for their cooperation with this study. We cherish our sincerest gratitude for Dr. Yiping Shen’s guidance and selfless help who is employed by Boston Children’s Hospital.
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