Maternal uniparental disomy 14 and mosaic trisomy 14 in a Chinese boy with moderate to severe intellectual disability
- Shujie Zhang†1,
- Haisong Qin†1,
- Jin Wang1,
- Luping OuYang1,
- Shiyu Luo1,
- Chunyun Fu1,
- Xin Fan1,
- Jiasun Su1,
- Rongyu Chen1,
- Bobo Xie1,
- Xuyun Hu1,
- Shaoke Chen1Email author and
- Yiping Shen1, 2Email author
© The Author(s). 2016
Received: 26 May 2016
Accepted: 2 August 2016
Published: 24 August 2016
Both maternal uniparental disomy 14 (UPD(14)mat) and mosaic trisomy 14 are rare events in live individuals. A combination of the two events in one individual is rarely encountered. Only six live-born cases have so far been reported.
Here we reported a case of concomitant UPD(14)mat and mosaic trisomy 14 in a 10-year-old Chinese patient. Most clinical features of our patient were consistent with those previous reported for UPD(14)mat cases, which include prenatal and postnatal growth retardation, neonatal hypotonia, feeding difficulty, intellectual disability, truncal obesity, small hands and feet, short stature, and mild facial dysmorphism, but our patient showed more severe intellectual disability and no sign of precocious puberty. SNP array analysis revealed a mixture of chromosome 14 maternal isodisomy with heterodisomy and a low level trisomy mosaicism of whole chromsome 14 in blood and hyperpigmented skin samples, whereas only UPD(14)mat was detected in normal skin sample. Cytogenetic analysis identified one trisomy 14 cell in 100 metaphase of peripheral blood lymphocytes (47,XX, +14/46,XX).
To our knowledge, this is the first case of a patient with UPD(14)mat and mosaic trisomy 14 reported in a Chinese patient. The definitive genetic diagnosis is beneficial for genetic counseling and clinical management of our patient, and for improving our understanding of the genotype-phenotype correlations of concomitant UPD(14)mat and mosaic trisomy 14.
Uniparental disomy refers to the inheritance of two homologous chromosomes from one parent . Maternal uniparental disomy 14 (UPD(14)mat) is a rare but clinically well-established disorder which is characterized with prenatal and postnatal growth retardation, neonatal hypotonia, feeding difficulty, motor development delay, mild to moderate intellectual disability, precocious puberty, truncal obesity, small hands and feet, short stature, hyperextensible joints, and mild facial dysmorphism [2, 3]. Since it was firstly described by Temple et al., 81 cases have been reported to date [4–11] (http://upd-tl.com/upd.html [accessed 24/07/2016]). Most UPD(14)mat cases were found with balanced Robertsonian translocations or extra structurally abnormal chromosomes (ESACs), however UPD(14)mat also occurred with normal karyotype [12, 13]. UPD(14)mat may be presented as isodisomy or heterodisomy or as a mixture of both. Both maternal iso- and heterodisomy of chromosome 14 were observed with the similar clinical findings, which indicated that the phenotypes were due to genomic imprinting rather than homozygosity for a recessive gene .
Trisomy 14 mosaicism is a rare chromosomal abnormality with distinct and recognizable clinical features, including growth and psychomotor retardation, short neck, congenital heart defect, genitourinary abnormalities, body asymmetry, abnormal skin pigmentation and craniofacial dysmorphism . So far, 42 live-born cases have been reported [15, 16].
The first case of UPD(14)mat with mosaic trisomy 14 confirmed at peripheral blood lymphocytes level was described by Antonarakis et al. . So far only six live-born patients have been previously reported [4, 17–21], four out of the six patients involved no Robertsonian translocations or ESACs. Here we reported a seventh live case of UPD(14)mat and mosaicism for trisomy 14 (the fifth case without involvement of Robertsonian translocations or ESACs).
Cytogenetic and molecular analyses
Peripheral blood lymphocytes, hyperpigmented and normal skin samples were collected from the patient and genomic DNA was extracted using Lab-Aid DNA kit (Zeesan Biotech Co., Ltd, China). G-banding was performed on metaphase chromosomes of cultured peripheral blood lymphocytes of the family trio. FISH was directly conducted on interphases chromosomes 14 of peripheral blood lymphocytes with probe specific for the region 14q11.2 (Agilent, USA, Spectrum red) on the patient. Genomic profiling were performed on blood, hyperpigmented and normal skin samples of the patient and his parents’ blood samples using Illumina Human CytoSNP 12 BeadChip array (Illumina, San Diego, CA). The SNP array data was analyzed with GenomeStudio and KaryoStudio software. All operative procedures fully followed the manufacturer’s instructions.
This is the seventh liveborn reported with a combination of UPD(14)mat and mosaic trisomy 14 and the first case in a Chinese patient. The presence of mosaic trisomy suggest that UPD was formed by trisomy rescue. The finding of tissue restricted trisomy mosaic pattern further suggested somewhat delayed post-zygotic trisomy rescue. In addition, the UPD(14)mat presented as a mixture of isodisomy and heterodisomy in our patient, we speculated that at least two crossover events had happened between the two non-sister chromatids of homologous chromosomes at the maternal meiosis I and a disomic gamete arose from nondisjunction in maternal meiosis II .
Summary of the clinical features in UPD(14)mat or Trisomy 14 mosaicism and the clinical features of liveborn previously reported with UPD(14)mat and trisomy 14 mosaicism
 patient A
Age at Diagnosis
Paternal chr14 in some cells
T14 = 2-49 %
T14 = 15-20 % (SNP array)
T14 = 1 % (100 cells)
Premature birth (12/30)
Intrauterine growth retardation (IUGR) (23/29); Low birth weight (24/28);
Short stature (30/37);
Truncal obesity (15/30);
Growth retardation (17/24)
1,870 g (<3rd);
2,350 g (<3rd);
Head and Neck
Relative macrocephaly (38/68)
Frontal bossing (11/40);
Short philtrum (7/40);
Recurrent otitis media (8/40);
Broad nose (5/40);
Depressed nasal bridge (in some patients);
Anteverted nares (in some patients);
High arch palate (11/40);
Frontal bossing (12/24);
Abnormal palpebral fissures(15/24);
Mouth abnormalities (32/40);
High arch palate(8/24);
Square and low-set ears;
Small up-turned nose;
Recurrent ear infections;
Broad and depressed nasal bridge; Short nose;
Upslanting palpebral fissures;
Small palpebral fissures;
Depressed nasal bridge;
Feeding difficulty (16/40)
Congenital heart defect (24/40)
Atrial septal defect
Small testes (rare);
Cryptorchidism on the right side
Hyperextensible joints (9/15);
Joint contractures (4/51);
Small hands (25/30) and feet (19/20);
Small hands and feet
Left hand agenesis
Loose hand joints;
Buffalo bump; barrel chest;
Small hands and feet;
Inapparent fifth finger;
Motor development delay (26/32);
Speech delay (9/20);
Mild to moderate intellectual disability (11/26);
Fine motor/coordination problems (3/40);
Moderate degree developmental disability;
Motor development delay;
Speech development delay;
Moderate intellectual impairment;
Severe learning difficulties; Hypotonia;
Less communication with his peers;
Moderate to severe intellectual disability; WISC:35-55-38; RSPM:6 %;
Early onset/Premature puberty (13/15); Maturity-onset diabetes of the young (rare);
Low serum GH level
Abnormal skin pigmentation(11/24)
Abnormal skin pigmentation
Abnormal skin pigmentation
Interestingly, both UPD(14)mat and trisomy 14 mosaicism were detected in the hyperpigmented skin of our patient whereas only the UPD(14)mat was detected in his normal skin. Balbeur et al. detected a similar low level trisomy 14 mosaicism in both hyperpigmented and normal skin . Thus it is not known if trisomy 14 mosaicism directly contributed to the abnormal skin pigmentation phenotype.
UPD(14)mat patients demonstrated overlapping features with Prader-Willi syndrome (PWS) including hypotonia, neonatal feeding difficulty and obesity. UPD(14)mat should be considered as a differential for patients with suspected PWS. Indeed, Mitter et al. detected four UPD(14)mat from 33 patients who were suspected to have PWS . Similarly, Hosoki et al. identified four UPD(14)mat patients from a 78 patient cohort with PWS-like phenotype without known molecular defects for PWS . However, Cox et al. did not find any UPD(14)mat in 35 patients suspected with PWS . Further studies could help to identify other distinguishing features such as facial characteristics and precocious puberty for differential diagnosis.
Four UPD(14)mat patients had been previously described with GH treatment, and all patients showed beneficial effects. But only one patient was known to have growth hormone deficiency , and other three cases were treated because of short stature without data regarding the GH level [19, 22]. The height SDS (HSDS) of patient with growth hormone deficiency increased from −2.5SD at age of 6 to −1.5SD at age of 12 . Two patients presented a considerable increase in height (from −2.3SD at age of 6.9 to −1.2SD at age of 8.9, from −1.2SD at age of 9.3 to −0.6SD at age of 11.4, respectively) and IGF-1 level (from +0.1SD to +1.3SD, from −1.4SD to +0.9SD, respectively) . The remaining patient received growth hormone therapy at age of 4 because of short stature (−3.9SD at 3 years 11 months) and obtained effective result without specific data about height . The treatment effect on body composition was less consistent among them. In one patient, her weight decreased from +1.2SD to −0.7SD and the body composition was improved (fat percentage from 51.5 % to 45.4 %), and in other patient, his weight and body composition remained stable . The GH level was rarely measured among the UPD(14)mat patients, our patient was the second case to undergo growth hormone provocative test. Due to the complete growth hormone deficiency, our patient started the recombinant human growth hormone replacement treatment at the age of 9 years and 9 months. After five months of treatment, his height increased from −6.0SD to −5.0SD. Contrary to previous reports, his weight increased from −1.5SD to −0.5SD which may be caused by other unknown endocrine problems or overeating behavior. The clinical presentation described for this patient and his response to GH treatment is useful for future patient counseling and care.
In summary, we described the first Chinese patient with UPD(14)mat and mosaic trisomy 14. Our patient presented with prenatal and postnatal growth retardation, neonatal hypotonia, feeding difficulty, intellectual disability, short stature, truncal obesity, small hands and feet, and mild facial dysmorphism, mostly consistent with features known to be associated with UPD(14)mat. The patient had complete GH deficiency and benefited for growth hormone replacement treatment. The definitive genetic diagnosis is beneficial for genetic counseling and clinical management of our patient, and for improving our understanding of the genotype-phenotype correlations of concomitant UPD(14)mat and mosaic trisomy 14.
Written informed consent was obtained from the parents of the patient for publication of this Case report and any accompanying images. The study was approved by the ethical committee of Guangxi Maternal and Child Health Hospital, China. A copy of the written consent is available for review upon request.
AOH, absence of heterozygosity; C-WISC, Chinese Wechsler intelligence scale for children; ESACs, extra structurally abnormal chromosomes; FISH, fluorescent in situ hybridization; GH, growth hormone; GHD, growth hormone deficiency; PWS, Prader-Willi syndrome; RSPM, Raven’s standard progressive matrices; SNP array, single nucleotide polymorphism array; TSH, thyroid-stimulating hormone; UPD(14)mat, maternal uniparental disomy 14.
The authors appreciate the patient and his parents for this study.
This study was supported by grants from Self-Financed Program of Guangxi (Z2015238), and there is no role for funding agent in this study.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and its additional file (Additional file 1). More details are available on request.
SJZ and HSQ wrote the manuscript and analyzed the SNP array results; RYC, CYF and SJS performed the SNP array experiments; JW, XYH and XF were involved in SNP array analysis; LPOY, BBX and SYL performed the cytogenetic and FISH experiments; SKC and YPS initiated the study, made substantial contribution to study design and revised the manuscript critically. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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