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Prenatal diagnosis of paternal uniparental disomy for chromosome 14 using a single-nucleotide-polymorphism-based microarray analysis: A case report
Journal of the Formosan Medical Association (2019) 118, 739e742
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.jfma-online.com
Case Report
Prenatal diagnosis of paternal uniparental disomy for chromosome 14 using a singlenucleotide-polymorphism-based microarray analysis: A case report Chih-Ling Chen, Chien-Nan Lee, Ming-Wei Lin, Wen-Wei Hsu, Yi-Yun Tai, Shin-Yu Lin* Department of Obstetrics and Gynecology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan Received 10 September 2018; received in revised form 22 November 2018; accepted 14 December 2018
KEYWORDS Paternal uniparental disomy 14; Prenatal diagnosis; Uniparental disomy
Paternal uniparental disomy 14 (UDP(14)pat) is a rare imprinting disorder with a set of unique neonatal clinical features documented, including craniofacial abnormalities, thoracic and abdominal wall defects, and polyhydraminos. To date, no studies focus on prenatal diagnosis of uniparental disomy have been published. We report a case of a fetus with abnormal ultrasound features at 18 weeks of gestation and normal karyotype result. Subsequent Single nucleotide polymorphism (SNP)-based Affymetrix 750K Microarray analysis revealed the complete loss of heterozygosity for chromosome 14, identifying a case of uniparental disomy. Postmortem examination of the aborted fetus at 21 weeks, coupled with further Affymetrix 750K microarray analysis on the parents, confirmed the diagnosis of parental uniparental disomy for chromosome 14. Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
Introduction
* Corresponding author. Department of Obstetrics and Gynecology, National Taiwan University Hospital, No. 8, Zhongshan South Road, Zhongzheng District, Taipei 10041, Taiwan. Fax: þ886 2 23934197. E-mail address: [email protected] (S.-Y. Lin).
A rare genomic imprinting disorder of chromosome 14, namely, uniparental disomy (UPD(14)), describes the inheritance of two homologous chromosome 14 from either the maternal or the paternal side. Depending on whether maternal or paternal UPD is present, distinct resultant phenotypes have been documented.
https://doi.org/10.1016/j.jfma.2018.12.010 0929-6646/Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
740 Paternal uniparental disomy 14 (UPD(14)pat) is a more severe form of UPD disorder affected by the 14q32.2 imprinted region, resulting in a collection of unique phenotypical features, such as polyhydraminos, and craniofacial, thoracic, abdominal anomalities or defects, as well as severe developmental delay.1 Through a combination of prenatal ultrasonographic findings (Fig. 1a and b), and amniocentesis with single nucleotide polymorphism (SNP)-based Affymetrix 750K microarray analysis, and clinical features, UDP for chromosome 14 was ascertained. The SNP-based microarray analysis revealed a loss of heterozygosity in the long q arm of chromosome 14, involving chromosome band 11.2 to 32.33. Further Affymetrix 750K microarray analyses of both parents were used to confirm paternal-origined isodisomy for chromosome 14.
Case presentation A healthy 32-year-old gravida-4-para-1 pregnant woman was referred to the Department of Medical Genetics at National Taiwan University Hospital for second opinion counseling at 18 weeks and 2 days of gestation. She had an uncomplicated vaginal delivery of a normal male infant 13 years ago. She was referred to our center this time due to fetal abnormalities noted on prenatal screening ultrasound at 18 weeks of gestation. Detailed ultrasound exam revealed relative polyhydraminos, absence of stomach, and a 2.4*2.7 cm mass protruding from the abdomen, containing liver (Fig. 1a) and abnormal spine curvature (Fig. 1b). Tracheoesophageal fistula was initially suspected. Amniocentesis was arranged at 19 weeks, and standard cytogenetic analysis revealed a 46, XX female karyotype with no numerical or structural chromosome aberrations. Single nucleotide polymorphism (SNP)-based Affymetrix 750K microarray analysis revealed a loss of heterozygosity in chromosome 14 (Fig. 1f), which was indicative of Uniparental Disomy, UPD(14). Follow up ultrasound at 21 weeks revealed persistent omphalocele with liver protrusion, abnormal spine curvature, skin edema, ventricular septal defect, and polyhydraminos. In light of abnormal genetic results and ultrasound findings, the parents opted for termination of pregnancy at 21 weeks of gestation. Following induction with misoprostol vaginal suppositories, a deceased immature female fetus, weighing 582 g, was delivered in vertex position. The fetus was born with prominent philtrum, micrognathia, short webbed neck, omphalocele, and abnormal spine curvature (Fig. 1c and d).
Discussion The clinical manifestations of UDP(14)pat patients have been well-documented. The neonatal phenotypes are characterized by short stature with mildly short limbs, small bell-shaped thorax, short webbed neck, diastasis recti or omphalocele, and facial features of hirsute forehead, short palpebral fissures, depressed nasal bridge, prominent philtrum, micrognathia, and small
C.-L. Chen et al. ears.2 Other minor joint contractures, hand anomalies, kyphoscoliosis, hypospadias, and congenital heart disease have also been documented, along with severe developmental delay and metal retardation.1e3 There were no obvious phenotypic differences between UPD(14) pat patients with complete paternal isodisomy, mixed iso-and heterodisomy, and Robertsonian translocation.1 Many of the UPD(14)pat patients suffered from respiratory distress syndrome and hepatoblastoma in infancy, with an overall survival rate of 78% to childhood.4 Postmortem examination of our 21-week aborted fetus exhibited similar craniofacial features including prominent philtrum, micrognathia, and short webbed neck. Other features such as omphalocele, and abnormal spine curvature were also noted. Uniparental disomy can arise via gamete complementation, trisomy rescue, compensatory UPD (monosomy rescue), or post-fertilization error.5 However, both gamete complementation and trisomy rescue usually result in a mixture of hetero- and iso-disomy as a consequence of recombination in meiosis I prior to non-disjunction in meiosis II.5,1 Our case presents a fetus with normal karyotype, and apparently complete parental isodisomy based on the result of single nucleotide polymorphism (SNP)-based Affymetrix 750K microarray analysis. The complete loss of heterozygosity for chromosome 14 was unlikely resulted from gamete complementation or trisomy rescue, unless no recombination of chromosome 14 during meiosis I took place. Isodisomy is better justified by compensatory UPD or a post-fertilization event involving mitotic errors. Compensatory UPD occurs when an abnormal or absent chromosome in the zygote is replaced by a copy of the remaining homolog through mitotic duplication.6 Alternatively, UPD could also arise from a normal biparentalinherited cell line at birth, with the loss of one chromosome followed by duplication of the remaining homologue during early mitotic division.5 A very early postzygotic mitotic error could have produced two cell lines, one with uniparental isodisomy which affects the embryo, and the other with original biparental inheritance which persists in trophoblast and subsequently constitutes the placenta.1 However, no UPD studies have been done on the placenta to confirm. As uniparental disomy does not involve a copy number change, it cannot be detected by chromosomal microarray for copy number variation analysis.3,7 Testing for uniparental disomy is usually warranted when cytogenetic analysis reveals no visible copy number alternation, but a methylation alternation is identified. It is also recommended if there is a presence of structural or numerical abnormalities involving imprinted chromosomes regions.8 The result of our SNP-based Affymetrix 750K microarray analysis detected a loss of heterozygosity at the entire chromosome 14, which confirms isodisomy of chromosome 14, and effectively rules out that the abnormal phenotype is a result of mosacism, or homozygosity for a recessive mutation.7 Limitation of the SNP-based array include its inability to detect balanced chromosome anomalies such as balanced translocation, balanced inversion, low level mosaicism,
Prenatal diagnosis of paternal UDP 14 using SNP-based Affymetrix 750K microarray
741
Figure 1 Ultrasound imaging of the fetus at 18th week of gestation. Omphalocele with liver protruding in axial view of abdomen (a,*), and abnormal spine curvature via longitudinal view of the spine (b) were identified. The aborted fetus at 21 weeks of gestation showed features of omphalocele and abnormal spine curvature (c) and prominent philtrum, micrognathia, and short webbed neck (d). The graph (e) shows the result of copy number variation analysis (CNV). The horizontal axis lists the number of chromosome (1e22, X, Y), and the vertical axis represents chromosome copy number (0, 1, 2, 3). The blue line reflects copy number distributed along chromosome lengths. Whole-genome view shows a complete diploid set of human chromosomes. The lower graph (f) shows the results of SNP mapping. Absence of heterozygosity was noted on chromosome 14 (red box).
742 tetraploidy, uniparental heterodisomy and heterochromatin variation without combination with other techniques. To date, no studies focus on prenatal diagnosis of uniparental disomy have been published. Postmortem autopsy or genetic analysis of the aborted fetus is rarely performed. In our case, omphalocele with liver protruding, abnormal spine curvature, skin edema, ventricular septal defect, and polyhydraminos were the abnormal features documented at 21 weeks of gestation. Previous clinical studies revealed ultrasound findings of polyhydraminos in all patients with UPD(14)pat since 25 weeks of gestation.2 However, ultrasound findings of thoracic and abdominal anomalies were only found in about 40% of the patients at 25 weeks in this Japanese study.2 More cases with confirmed diagnosis of uniparental disomy need to be collected, and the results of their prenatal ultrasound exam reviewed, in order to make conclusions about any uniform appearance under prenatal ultrasonography.
Conclusion In summary, this case report is the first prenatal diagnosis of paternal UPD 14, supported by abnormal prenatal ultrasound findings, and confirmed via amniocentesis and results of SNP-based Affymetrix 750K microarray analysis, with UPD(14)pat-compatible phenotype recognized on postmortem examination. Normal karyotyping result combined with loss of heterozygosity in SNP-based microarray indicates paternal isodisomy, which further suggests compensatory UPD or post-fertilization mitotic error as the most likely cause.1 When a fetus with normal karyotype presents with abnormalities noted during second-trimester prenatal ultrasound screening, SNP-based microarray can be considered as the next step to rule out or confirm the diagnosis of uniparental disomy.
Ethical approval No ethical committee approval was necessary for this case report.
Funding statement No external funding was received for this work.
C.-L. Chen et al.
Disclosure statement The authors declare no conflicts of interest in connection with this article.
Acknowledgments We thank the parents of the subject who kindly participate in this study. This work was supported by the National Taiwan University Hospital [grant number 107-N4040].
References 1. Dietz LG, Wylie AA, Rauen KA, Murphy SK, Jirtle RL, Cotter PD. Exclusion of maternal uniparental disomy of chromosome 14 in patients referred for Prader-Willi syndrome using a multiplex methylation polymerase chain reaction assay. J Med Genet [Internet] 2003;40(4):e46. Available from: http://jmg.bmj. com/cgi/doi/10.1136/jmg.40.4.e46. 2. Kagami M, Kurosawa K, Miyazaki O, Ishino F, Matsuoka K, Ogata T. Comprehensive clinical studies in 34 patients with molecularly defined UPD(14)pat and related conditions (KagamieOgata syndrome) [cited 2017 Sep 11]; Eur J Hum Genet [Internet] 2015 Oct 18;23(11):1488e98. Available from:, http://www.nature.com/doifinder/10.1038/ejhg.2015.13. 3. Yuan H, Xie Y, Li Q, Hu X, Li X, Sun X, et al. Paternal uniparental disomy of chromosome 14 with hypospadias. Cytogenet Genome Res 2016;(148):256e61. 4. Ogata T, Kagami M. KagamieOgata syndrome: a clinically recognizable upd(14)pat and related disorder affecting the chromosome 14q32.2 imprinted region. J Hum Genet [Internet] 2016;61(2):87e94. Available from: http://www.nature.com/ doifinder/10.1038/jhg.2015.113. 5. Robinson WP. Mechanisms leading to uniparental disomy and their clinical consequences. Bioessays [Internet] 2000;22(5): 452e9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 10797485. 6. Chu C, Schwartz S, McPherson E. Paternal uniparental isodisomy for chromosome 14 in a patient with a normal 46,XY karyotype. Am J Med Genet A 2004;127A(2):167e71. 7. Liu W, Zhang R, Wei J, Zhang H, Yu G, Li Z, et al. Rapid diagnosis of imprinting disorders involving copy number variation and uniparental disomy using genome-wide SNP microarrays. Cytogenet Genome Res 2015;146:9e18. 8. Grafodatskaya D, Choufani S, Basran R, Weksberg R. An update on molecular diagnostic testing of human imprinting disorders. J Pediatr Genet 2017 Mar;6(1):3e17.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.jfma-online.com
Case Report
Prenatal diagnosis of paternal uniparental disomy for chromosome 14 using a singlenucleotide-polymorphism-based microarray analysis: A case report Chih-Ling Chen, Chien-Nan Lee, Ming-Wei Lin, Wen-Wei Hsu, Yi-Yun Tai, Shin-Yu Lin* Department of Obstetrics and Gynecology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan Received 10 September 2018; received in revised form 22 November 2018; accepted 14 December 2018
KEYWORDS Paternal uniparental disomy 14; Prenatal diagnosis; Uniparental disomy
Paternal uniparental disomy 14 (UDP(14)pat) is a rare imprinting disorder with a set of unique neonatal clinical features documented, including craniofacial abnormalities, thoracic and abdominal wall defects, and polyhydraminos. To date, no studies focus on prenatal diagnosis of uniparental disomy have been published. We report a case of a fetus with abnormal ultrasound features at 18 weeks of gestation and normal karyotype result. Subsequent Single nucleotide polymorphism (SNP)-based Affymetrix 750K Microarray analysis revealed the complete loss of heterozygosity for chromosome 14, identifying a case of uniparental disomy. Postmortem examination of the aborted fetus at 21 weeks, coupled with further Affymetrix 750K microarray analysis on the parents, confirmed the diagnosis of parental uniparental disomy for chromosome 14. Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
Introduction
* Corresponding author. Department of Obstetrics and Gynecology, National Taiwan University Hospital, No. 8, Zhongshan South Road, Zhongzheng District, Taipei 10041, Taiwan. Fax: þ886 2 23934197. E-mail address: [email protected] (S.-Y. Lin).
A rare genomic imprinting disorder of chromosome 14, namely, uniparental disomy (UPD(14)), describes the inheritance of two homologous chromosome 14 from either the maternal or the paternal side. Depending on whether maternal or paternal UPD is present, distinct resultant phenotypes have been documented.
https://doi.org/10.1016/j.jfma.2018.12.010 0929-6646/Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
740 Paternal uniparental disomy 14 (UPD(14)pat) is a more severe form of UPD disorder affected by the 14q32.2 imprinted region, resulting in a collection of unique phenotypical features, such as polyhydraminos, and craniofacial, thoracic, abdominal anomalities or defects, as well as severe developmental delay.1 Through a combination of prenatal ultrasonographic findings (Fig. 1a and b), and amniocentesis with single nucleotide polymorphism (SNP)-based Affymetrix 750K microarray analysis, and clinical features, UDP for chromosome 14 was ascertained. The SNP-based microarray analysis revealed a loss of heterozygosity in the long q arm of chromosome 14, involving chromosome band 11.2 to 32.33. Further Affymetrix 750K microarray analyses of both parents were used to confirm paternal-origined isodisomy for chromosome 14.
Case presentation A healthy 32-year-old gravida-4-para-1 pregnant woman was referred to the Department of Medical Genetics at National Taiwan University Hospital for second opinion counseling at 18 weeks and 2 days of gestation. She had an uncomplicated vaginal delivery of a normal male infant 13 years ago. She was referred to our center this time due to fetal abnormalities noted on prenatal screening ultrasound at 18 weeks of gestation. Detailed ultrasound exam revealed relative polyhydraminos, absence of stomach, and a 2.4*2.7 cm mass protruding from the abdomen, containing liver (Fig. 1a) and abnormal spine curvature (Fig. 1b). Tracheoesophageal fistula was initially suspected. Amniocentesis was arranged at 19 weeks, and standard cytogenetic analysis revealed a 46, XX female karyotype with no numerical or structural chromosome aberrations. Single nucleotide polymorphism (SNP)-based Affymetrix 750K microarray analysis revealed a loss of heterozygosity in chromosome 14 (Fig. 1f), which was indicative of Uniparental Disomy, UPD(14). Follow up ultrasound at 21 weeks revealed persistent omphalocele with liver protrusion, abnormal spine curvature, skin edema, ventricular septal defect, and polyhydraminos. In light of abnormal genetic results and ultrasound findings, the parents opted for termination of pregnancy at 21 weeks of gestation. Following induction with misoprostol vaginal suppositories, a deceased immature female fetus, weighing 582 g, was delivered in vertex position. The fetus was born with prominent philtrum, micrognathia, short webbed neck, omphalocele, and abnormal spine curvature (Fig. 1c and d).
Discussion The clinical manifestations of UDP(14)pat patients have been well-documented. The neonatal phenotypes are characterized by short stature with mildly short limbs, small bell-shaped thorax, short webbed neck, diastasis recti or omphalocele, and facial features of hirsute forehead, short palpebral fissures, depressed nasal bridge, prominent philtrum, micrognathia, and small
C.-L. Chen et al. ears.2 Other minor joint contractures, hand anomalies, kyphoscoliosis, hypospadias, and congenital heart disease have also been documented, along with severe developmental delay and metal retardation.1e3 There were no obvious phenotypic differences between UPD(14) pat patients with complete paternal isodisomy, mixed iso-and heterodisomy, and Robertsonian translocation.1 Many of the UPD(14)pat patients suffered from respiratory distress syndrome and hepatoblastoma in infancy, with an overall survival rate of 78% to childhood.4 Postmortem examination of our 21-week aborted fetus exhibited similar craniofacial features including prominent philtrum, micrognathia, and short webbed neck. Other features such as omphalocele, and abnormal spine curvature were also noted. Uniparental disomy can arise via gamete complementation, trisomy rescue, compensatory UPD (monosomy rescue), or post-fertilization error.5 However, both gamete complementation and trisomy rescue usually result in a mixture of hetero- and iso-disomy as a consequence of recombination in meiosis I prior to non-disjunction in meiosis II.5,1 Our case presents a fetus with normal karyotype, and apparently complete parental isodisomy based on the result of single nucleotide polymorphism (SNP)-based Affymetrix 750K microarray analysis. The complete loss of heterozygosity for chromosome 14 was unlikely resulted from gamete complementation or trisomy rescue, unless no recombination of chromosome 14 during meiosis I took place. Isodisomy is better justified by compensatory UPD or a post-fertilization event involving mitotic errors. Compensatory UPD occurs when an abnormal or absent chromosome in the zygote is replaced by a copy of the remaining homolog through mitotic duplication.6 Alternatively, UPD could also arise from a normal biparentalinherited cell line at birth, with the loss of one chromosome followed by duplication of the remaining homologue during early mitotic division.5 A very early postzygotic mitotic error could have produced two cell lines, one with uniparental isodisomy which affects the embryo, and the other with original biparental inheritance which persists in trophoblast and subsequently constitutes the placenta.1 However, no UPD studies have been done on the placenta to confirm. As uniparental disomy does not involve a copy number change, it cannot be detected by chromosomal microarray for copy number variation analysis.3,7 Testing for uniparental disomy is usually warranted when cytogenetic analysis reveals no visible copy number alternation, but a methylation alternation is identified. It is also recommended if there is a presence of structural or numerical abnormalities involving imprinted chromosomes regions.8 The result of our SNP-based Affymetrix 750K microarray analysis detected a loss of heterozygosity at the entire chromosome 14, which confirms isodisomy of chromosome 14, and effectively rules out that the abnormal phenotype is a result of mosacism, or homozygosity for a recessive mutation.7 Limitation of the SNP-based array include its inability to detect balanced chromosome anomalies such as balanced translocation, balanced inversion, low level mosaicism,
Prenatal diagnosis of paternal UDP 14 using SNP-based Affymetrix 750K microarray
741
Figure 1 Ultrasound imaging of the fetus at 18th week of gestation. Omphalocele with liver protruding in axial view of abdomen (a,*), and abnormal spine curvature via longitudinal view of the spine (b) were identified. The aborted fetus at 21 weeks of gestation showed features of omphalocele and abnormal spine curvature (c) and prominent philtrum, micrognathia, and short webbed neck (d). The graph (e) shows the result of copy number variation analysis (CNV). The horizontal axis lists the number of chromosome (1e22, X, Y), and the vertical axis represents chromosome copy number (0, 1, 2, 3). The blue line reflects copy number distributed along chromosome lengths. Whole-genome view shows a complete diploid set of human chromosomes. The lower graph (f) shows the results of SNP mapping. Absence of heterozygosity was noted on chromosome 14 (red box).
742 tetraploidy, uniparental heterodisomy and heterochromatin variation without combination with other techniques. To date, no studies focus on prenatal diagnosis of uniparental disomy have been published. Postmortem autopsy or genetic analysis of the aborted fetus is rarely performed. In our case, omphalocele with liver protruding, abnormal spine curvature, skin edema, ventricular septal defect, and polyhydraminos were the abnormal features documented at 21 weeks of gestation. Previous clinical studies revealed ultrasound findings of polyhydraminos in all patients with UPD(14)pat since 25 weeks of gestation.2 However, ultrasound findings of thoracic and abdominal anomalies were only found in about 40% of the patients at 25 weeks in this Japanese study.2 More cases with confirmed diagnosis of uniparental disomy need to be collected, and the results of their prenatal ultrasound exam reviewed, in order to make conclusions about any uniform appearance under prenatal ultrasonography.
Conclusion In summary, this case report is the first prenatal diagnosis of paternal UPD 14, supported by abnormal prenatal ultrasound findings, and confirmed via amniocentesis and results of SNP-based Affymetrix 750K microarray analysis, with UPD(14)pat-compatible phenotype recognized on postmortem examination. Normal karyotyping result combined with loss of heterozygosity in SNP-based microarray indicates paternal isodisomy, which further suggests compensatory UPD or post-fertilization mitotic error as the most likely cause.1 When a fetus with normal karyotype presents with abnormalities noted during second-trimester prenatal ultrasound screening, SNP-based microarray can be considered as the next step to rule out or confirm the diagnosis of uniparental disomy.
Ethical approval No ethical committee approval was necessary for this case report.
Funding statement No external funding was received for this work.
C.-L. Chen et al.
Disclosure statement The authors declare no conflicts of interest in connection with this article.
Acknowledgments We thank the parents of the subject who kindly participate in this study. This work was supported by the National Taiwan University Hospital [grant number 107-N4040].
References 1. Dietz LG, Wylie AA, Rauen KA, Murphy SK, Jirtle RL, Cotter PD. Exclusion of maternal uniparental disomy of chromosome 14 in patients referred for Prader-Willi syndrome using a multiplex methylation polymerase chain reaction assay. J Med Genet [Internet] 2003;40(4):e46. Available from: http://jmg.bmj. com/cgi/doi/10.1136/jmg.40.4.e46. 2. Kagami M, Kurosawa K, Miyazaki O, Ishino F, Matsuoka K, Ogata T. Comprehensive clinical studies in 34 patients with molecularly defined UPD(14)pat and related conditions (KagamieOgata syndrome) [cited 2017 Sep 11]; Eur J Hum Genet [Internet] 2015 Oct 18;23(11):1488e98. Available from:, http://www.nature.com/doifinder/10.1038/ejhg.2015.13. 3. Yuan H, Xie Y, Li Q, Hu X, Li X, Sun X, et al. Paternal uniparental disomy of chromosome 14 with hypospadias. Cytogenet Genome Res 2016;(148):256e61. 4. Ogata T, Kagami M. KagamieOgata syndrome: a clinically recognizable upd(14)pat and related disorder affecting the chromosome 14q32.2 imprinted region. J Hum Genet [Internet] 2016;61(2):87e94. Available from: http://www.nature.com/ doifinder/10.1038/jhg.2015.113. 5. Robinson WP. Mechanisms leading to uniparental disomy and their clinical consequences. Bioessays [Internet] 2000;22(5): 452e9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 10797485. 6. Chu C, Schwartz S, McPherson E. Paternal uniparental isodisomy for chromosome 14 in a patient with a normal 46,XY karyotype. Am J Med Genet A 2004;127A(2):167e71. 7. Liu W, Zhang R, Wei J, Zhang H, Yu G, Li Z, et al. Rapid diagnosis of imprinting disorders involving copy number variation and uniparental disomy using genome-wide SNP microarrays. Cytogenet Genome Res 2015;146:9e18. 8. Grafodatskaya D, Choufani S, Basran R, Weksberg R. An update on molecular diagnostic testing of human imprinting disorders. J Pediatr Genet 2017 Mar;6(1):3e17.