Diagnostic testing for uniparental disomy: a points to consider statement from the American College of Medical Genetics and Genomics (ACMG)
2020; Elsevier BV; Volume: 22; Issue: 7 Linguagem: Inglês
10.1038/s41436-020-0782-9
ISSN1530-0366
AutoresDaniela del Gaudio, Marwan Shinawi, Caroline Astbury, Marwan K. Tayeh, Kristen Deak, Gordana Raca,
Tópico(s)Genomic variations and chromosomal abnormalities
ResumoIn 1980, Eric Engel1.Engel E. [A new genetic concept: the uniparental disomy and its potential effect, the isodisomy (author’s transl)].1:STN:280:DyaL3c3ltV2ntw%3D%3DJ Genet Hum. 1980; 28: 11-22Google Scholar first proposed the concept of uniparental disomy (UPD), in which both homologous chromosomes are inherited from one parent, with no contribution (for that chromosome) from the other parent. In 1988, the first case of a Mendelian disorder associated with UPD was reported, in which a child with cystic fibrosis (MIM 219700) had inherited two copies of a pathogenic variant in CFTR (MIM 602421) from a heterozygous carrier mother, with no contribution from the biological father.2.Spence J.E. Perciaccante R.G. Greig G.M. et al.Uniparental disomy as a mechanism for human genetic disease.1:STN:280:DyaL1c7jtFSguw%3D%3D17152721715272Am J Hum Genet. 1988; 42: 217-226Google Scholar For the majority of chromosomes, UPD is without clinical consequence. However, for chromosomes 6, 7, 11, 14, 15, and 20, there are parent-of-origin or imprinting differences in gene expression in the context of UPD, which may lead to phenotypic abnormalities. In addition, UPD may uncover an autosomal recessive disorder on a chromosome that is not subject to imprinting, while UPD of the X chromosome may lead to X-linked recessive disorders in females. Rarely, inheritance of both sex chromosomes from the father, may result in father-to-son transmission of X-linked conditions.3.Ferrier R.A. Lowry R.B. Lemire E.G. Stoeber G.P. Howard J. Parboosingh J.S. Father-to-son transmission of an X-linked gene: a case of paternal sex chromosome heterodisomy.1:STN:280:DC%2BD1Mjos1ylsA%3D%3DAm J Med Genet A. 2009; 149A: 2871-2873Google Scholar UPD generally results from two nondisjunction events, with the first event occurring during meiosis and the second being a mitotic event. Nondisjunction in meiosis I constitutes a failure of two homologues to segregate, which may eventually give rise to the presence of two different homologues from the same parent or heterodisomy. Nondisjunction in meiosis II is a failure of sister chromatids to separate into daughter cells, which subsequently can result in isodisomy. The gametes resulting from meiosis complicated by nondisjunction may be disomic (containing two copies of the affected chromosome) or nullisomic (containing no copies of the affected chromosome). Following fertilization with a normal haploid gamete, the zygote is expected to have either a trisomy or a monosomy for the affected chromosome. Postzygotic mitotic nondisjunction may then occur as the second event resulting in a rescue of the aneuploidy by either loss of the third chromosome (trisomy rescue) or duplication of a monosomic chromosome (monosomy rescue).4.Ledbetter D.H. Engel E. Uniparental disomy in humans: development of an imprinting map and its implications for prenatal diagnosis.1:CAS:528:DyaK2MXos1ylsrY%3DHum Mol Genet. 1995; 4: 1757-1764Google Scholar In addition, anaphase lag (the delayed movement of a chromosome or chromatid during anaphase, leading to the loss of that chromosome in a daughter nucleus) may also be the second event leading to a trisomy rescue. Trisomy rescue with loss of the parental chromosome present in a single copy will result in the inheritance of both homologues of the affected chromosome from one parent or UPD (Fig. 1a). As the majority of nondisjunction occurs in maternal meiosis I,5.Koehler K.E. Hawley R.S. Sherman S. Hassold T. Recombination and nondisjunction in humans and flies.1:CAS:528:DyaK28XlsFylurs%3DHum Mol Genet. 1996; 5: 1495-1504Google Scholar it is more likely that a trisomy consists of two different maternal chromosomes and one paternal chromosome. Subsequent trisomy rescue through loss of a paternal chromosome will thus give rise to maternal heterodisomy. Meiotic recombination will often result in the presence of one or more regions of homozygosity (ROH) on the affected chromosome, but with retention of heterozygosity around the centromere where recombination is suppressed. Analogously, chromosomes inherited from the same parent in cases of isodisomy due to meiosis II errors often do not show complete homozygosity for all single-nucleotide polymorphism (SNP) markers. Due to meiotic recombination, such chromosomes may also have alternating regions of heterozygosity and homozygosity, but in meiosis II errors, there is always homozygosity around the centromere. Postzygotic monosomy rescue (which is more rare than trisomy rescue) will result in complete isodisomy of the same homologue, with no heterodisomic regions (Fig. 1b). There are also cases of mosaic, segmental UPD affecting terminal regions of chromosome arms; they arise as postzygotic events, due to mitotic recombination between chromatids occuring in early embryogenesis (Fig. 1c). This UPD mechanism is responsible for a subset of cases of Beckwith–Wiedemann syndrome (BWS), an imprinting disorder resulting from altered activity of one or more genes in the imprinted gene cluster in the p15.5 region of chromosome 11 (as discussed later).6.Slatter R.E. Elliott M. Welham K. et al.Mosaic uniparental disomy in Beckwith–Wiedemann syndrome.1:STN:280:DyaK2M7jvFSntw%3D%3D10501191050119J Med Genet. 1994; 31: 749-753Google Scholar Other rare mechanisms leading to UPD have been reported and include postfertilization error (via somatic recombination or gene conversion), gamete complementation, somatic replacement of a derivative chromosome, correction of interchange monosomy, and correction of a trisomy resulting in a small supernumerary marker chromosome (sSMC).4.Ledbetter D.H. Engel E. Uniparental disomy in humans: development of an imprinting map and its implications for prenatal diagnosis.1:CAS:528:DyaK2MXos1ylsrY%3DHum Mol Genet. 1995; 4: 1757-1764Google Scholar UPD has also been observed to result from the presence of structurally abnormal chromosomes, including Robertsonian translocations, isochromosomes, reciprocal translocations, derivative chromosomes, and inversions (Fig. 2). As mentioned above, for the majority of chromosomes, there is no apparent phenotypic effect from UPD.7.Kotzot D. Utermann G. Uniparental disomy (UPD) other than 15: phenotypes and bibliography updated.Am J Med Genet A. 2005; 136: 287-305Crossref PubMed Scopus (126) Google Scholar However, a few chromosomes contain regions with parent-specific gene expression (imprinting), and UPD of these chromosomes may lead to clinically recognizable consequences. Specific phenotypes have been well documented to date for maternal UPD for chromosomes 7, 11, 14, 15, and 20, and paternal UPD for chromosomes 6, 11, 14, 15, and 20. For some chromosomes (2 and 16 for example), it is still debated whether UPD has phenotypic effects attributable to imprinting. This uncertainty may be due to the subtle nature of the anomalies (e.g., maternal disomy 16),8.Scheuvens R. Begemann M. Soellner L. et al.Maternal uniparental disomy of chromosome 16 [upd(16)mat]: clinical features are rather caused by (hidden) trisomy 16 mosaicism than by upd(16)mat itself.1:CAS:528:DC%2BC2sXpvFehsrw%3DClin Genet. 2017; 92: 45-51Google Scholar conflicting reports in the literature (e.g., maternal disomy 2),9.Hansen W.F. Bernard L.E. Langlois S. et al.Maternal uniparental disomy of chromosome 2 and confined placental mosaicism for trisomy 2 in a fetus with intrauterine growth restriction, hypospadias, and oligohydramnios.1:CAS:528:DyaK2sXktVyru7s%3DPrenat Diagn. 1997; 17: 443-450Google Scholar confounding mosaicism (e.g., maternal disomy 2 and 16), or too few cases reported. The empiric risks for UPD following the observation of prenatal aneuploidy mosaicism for certain chromosomes or a prenatally diagnosed Robertsonian translocation have been reported. The chance that trisomy 15 mosaicism, observed prenatally as confined placental mosaicism on analysis of chorionic villus sampling (CVS), would result in UPD has been estimated to be 11% to 25%.10.Trisomy 15 CPM: probable origins, pregnancy outcome and risk of fetal UPD: European Collaborative Research on Mosaicism in CVS (EUCROMIC).Prenat Diagn. 1999; 19: 29-35Crossref PubMed Scopus (38) Google Scholar, 11.Christian S.L. Smith A.C. Macha M. et al.Prenatal diagnosis of uniparental disomy 15 following trisomy 15 mosaicism.1:STN:280:DyaK28zitFarsQ%3D%3DPrenat Diagn. 1996; 16: 323-332Google Scholar, 12.Robinson W.P. Langlois S. Schuffenhauer S. et al.Cytogenetic and age-dependent risk factors associated with uniparental disomy 15.1:STN:280:DyaK2s%2FmtFyluw%3D%3DPrenat Diagn. 1996; 16: 837-844Google Scholar For prenatally identified Robertsonian translocations (de novo or inherited) between nonhomologous chromosomes (e.g., der[13;14]), the risk of UPD in the translocation carrier fetus is approximately 0.6%.13.Berend S.A. Horwitz J. McCaskill C. Shaffer L.G. Identification of uniparental disomy following prenatal detection of Robertsonian translocations and isochromosomes.1:CAS:528:DC%2BD3cXntV2jtbs%3D13780341378034Am J Hum Genet. 2000; 66: 1787-1793Google Scholar,14.Silverstein S. Lerer I. Sagi M. Frumkin A. Ben-Neriah Z. Abeliovich D. Uniparental disomy in fetuses diagnosed with balanced Robertsonian translocations: risk estimate.Prenat Diagn. 2002; 22: 649-651Crossref PubMed Scopus (23) Google Scholar For homologous acrocentric rearrangements, for which the majority are de novo isochromosomes (i.e., chromosomes derived from a duplication of a single parental chromosome), the risk of UPD in the balanced carrier fetus is approximately 66%.13.Berend S.A. Horwitz J. McCaskill C. Shaffer L.G. Identification of uniparental disomy following prenatal detection of Robertsonian translocations and isochromosomes.1:CAS:528:DC%2BD3cXntV2jtbs%3D13780341378034Am J Hum Genet. 2000; 66: 1787-1793Google Scholar The prevalence of UPD associated with a clinical presentation due to imprinting disorders or recessive diseases ranges from 1 in 3500 to 1 in 5000.15.Liehr T. Cytogenetic contribution to uniparental disomy (UPD).28535542853554Mol Cytogenet. 2010; 3: 8Google Scholar,16.Robinson W.P. Mechanisms leading to uniparental disomy and their clinical consequences.1:CAS:528:DC%2BD3MXmslWlsbY%3DBioessays. 2000; 22: 452-459Google Scholar Recent data, collected using over four million consented research participants from the personal genetics company 23andMe and 431,094 northern European UK Biobank participants, estimated that UPD for all chromosomes (rather than just chromosomes carrying imprinted regions) occurs with an overall prevalence of 1 in 2000 births. Since the 23andMe database comprises, for the most part, healthy individuals from the general population, this is a more representative estimate of the overall UPD prevalence in the general population.17.Nakka P. Pattillo Smith S. O’Donnell-Luria A.H. et al.Characterization of prevalence and health consequences of uniparental disomy in four million individuals from the general population.1:CAS:528:DC%2BC1MXhvFKku73M68489966848996Am J Hum Genet. 2019; 105: 921-932Google Scholar Evaluation of DNA-based polymorphic markers is the typical approach to investigate UPD. Short tandem repeat (STR) markers are used for most UPD studies. These markers are abundant throughout the genome, many have very high heterozygosity values (a reflection of the allele frequency differences in the population), and they are ideally suited for multiplex polymerase chain reaction (PCR).18.Shaffer L.G. McCaskill C. Adkins K. Hassold T.J. Systematic search for uniparental disomy in early fetal losses: the results and a review of the literature.1:STN:280:DyaK1cvltFSrsQ%3D%3DAm J Med Genet. 1998; 79: 366-372Google Scholar, 19.Huang T.H. Cottingham R.W. Ledbetter D.H. Zoghbi H.Y. Genetic mapping of four dinucleotide repeat loci, DXS453, DXS458, DXS454, and DXS424, on the X chromosome using multiplex polymerase chain reaction.1:CAS:528:DyaK3sXjtlOrsw%3D%3DGenomics. 1992; 13: 375-380Google Scholar, 20.Shaffer L.G. Overhauser J. Jackson L.G. Ledbetter D.H. Genetic syndromes and uniparental disomy: a study of 16 cases of Brachmann-de Lange syndrome.1:STN:280:DyaK2c7ot1Knuw%3D%3DAm J Med Genet. 1993; 47: 383-386Google Scholar In addition to the proband’s DNA sample, a sample from both parents is required to delineate the parental origin of the detected STR alleles. If both parents are not available, testing can be performed using one parent; however, in some cases, testing of a single parent may not completely rule out heterodisomy of the other parent. Multiple markers should be tested for each chromosome of interest. It is strongly recommended that at least two fully informative loci, showing either UPD or biparental inheritance, should be identified for diagnostic reporting.21.Shaffer L.G. Agan N. Goldberg J.D. Ledbetter D.H. Longshore J.W. Cassidy S.B. American College of Medical Genetics statement of diagnostic testing for uniparental disomy.1:STN:280:DC%2BD3MzhsFOhug%3D%3D31110493111049Genet Med. 2001; 3: 206-211Google Scholar Multiple, highly polymorphic STR markers across each chromosome of interest should be selected based on their informativity and genomic location.22.Robinson W.P. Christian S.L. Kuchinka B.D. et al.Somatic segregation errors predominantly contribute to the gain or loss of a paternal chromosome leading to uniparental disomy for chromosome 15.1:STN:280:DC%2BD3cvls1Ogug%3D%3DClin Genet. 2000; 57: 349-358Google Scholar, 23.Eggermann K. Bliek J. Brioude F. et al.EMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver-Russell and Beckwith–Wiedemann syndrome.1:CAS:528:DC%2BC28XotV2ktL0%3D50276905027690Eur J Hum Genet. 2016; 24: 1377-1387Google Scholar, 24.Eggermann T. Mergenthaler S. Eggermann K. et al.Identification of interstitial maternal uniparental disomy (UPD) (14) and complete maternal UPD(20) in a cohort of growth retarded patients.1:STN:280:DC%2BD3M3msFeqtw%3D%3D17348071734807J Med Genet. 2001; 38: 86-89Google Scholar However, there are limitations to this technology in the detection of UPD in samples with somatic mosaicism, segmental UPD, and tissue-specific UPD. Diagnostic reporting should follow the International System for Human Cytogenomic Nomenclature (ISCN) 2016 guidelines: uniparental disomy is abbreviated as “upd” (lowercase), followed by the chromosome in parentheses, and then the parental origin.25.McGowan-Jordan J. Simons A. Schmid M. ISCN 2016: an international system for human cytogenetic nomenclature. Karger, Basel, Switzerland2016Crossref Google Scholar In clinical practice, UPD cases may be ascertained through testing for copy-number abnormalities using chromosomal microarray (CMA) platforms that have SNP probes. CMA can easily identify whole-chromosome isodisomy based on obligatory presence of extensive ROH on the affected chromosome including its pericentromeric region, but routine CMA analysis cannot determine the parental origin without testing parental samples. Furthermore, isodisomy constitutes only a small subset of UPD cases. Whole-chromosome heterodisomy is more common, and can be suspected in CMA testing based on its frequent association with ROH on the affected chromosome, generated by meiotic crossovers during meiosis in parental gametogenesis.26.Kearney H.M. Kearney J.B. Conlin L.K. Diagnostic implications of excessive homozygosity detected by SNP-based microarrays: consanguinity, uniparental disomy, and recessive single-gene mutations.Clin Lab Med. 2011; 31: 595-613Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar However, it has been shown that approximately one-third of all cases of molecularly confirmed UPD do not show extended ROH and are not detectable by CMA.27.Hoppman N. Rumilla K. Lauer E. Kearney H. Thorland E. Patterns of homozygosity in patients with uniparental disomy: detection rate and suggested reporting thresholds for SNP microarrays.1:CAS:528:DC%2BC1cXisFyksb%2FPGenet Med. 2018; 20: 1522-1527Google Scholar Even when present, ROH associated with heterodisomy varies in size, and overlap in the sizes has been demonstrated between ROH that was associated with UPD, and ROH that occurred due to chance (identity by state) or parental consanguinity (identity by descent).27.Hoppman N. Rumilla K. Lauer E. Kearney H. Thorland E. Patterns of homozygosity in patients with uniparental disomy: detection rate and suggested reporting thresholds for SNP microarrays.1:CAS:528:DC%2BC1cXisFyksb%2FPGenet Med. 2018; 20: 1522-1527Google Scholar Laboratories should define size thresholds and other criteria for reporting ROH and recommending follow-up UPD testing. Terminal ROH has been shown to rarely occur in non-UPD cases, and may warrant reporting even when it is relatively small (5Mb); for interstitial ROH, it has been proposed that larger size thresholds (15–20Mb) may provide sufficient sensitivity without resulting in high false-positive rates.27.Hoppman N. Rumilla K. Lauer E. Kearney H. Thorland E. Patterns of homozygosity in patients with uniparental disomy: detection rate and suggested reporting thresholds for SNP microarrays.1:CAS:528:DC%2BC1cXisFyksb%2FPGenet Med. 2018; 20: 1522-1527Google Scholar Follow-up testing is indicated primarily if the ROH region is confined to one chromosome, involves one of the chromosomes that contain imprinted regions, and UPD for that chromosome is expected to result in an abnormal phenotype. Importantly, the ROH identified by CMA does not have to (and typically does not) overlap with the imprinted region on the affected chromosome. Regardless of where it localizes on the chromosome, the ROH in this situation functions as a marker of potential whole-chromosome UPD, which if confirmed will be responsible for the imprinting disorder in the patient. The presence of extended ROH on multiple chromosomes most commonly indicates a familial relationship between the proband’s parents (consanguinity); recommendations for documenting suspected consanguinity as an incidental finding of genomic testing have been described elsewhere.28.Rehder C.W. David K.L. Hirsch B. Toriello H.V. Wilson C.M. Kearney H.M. American College of Medical Genetics and Genomics: standards and guidelines for documenting suspected consanguinity as an incidental finding of genomic testing.Genet Med. 2013; 15: 150-152Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar Computational algorithms can also be employed to detect UPD through analysis of SNP distribution from trio genotype data in the context of exome or genome sequencing.29.Magi A. Tattini L. Palombo F. et al.H3M2: detection of runs of homozygosity from whole-exome sequencing data.1:CAS:528:DC%2BC28Xhs1Oltb7LBioinformatics. 2014; 30: 2852-2859Google Scholar,30.King D.A. Fitzgerald T.W. Miller R. et al.A novel method for detecting uniparental disomy from trio genotypes identifies a significant excess in children with developmental disorders.1:CAS:528:DC%2BC2cXmt1CrsL0%3D39750663975066Genome Res. 2014; 24: 673-687Google Scholar These tools have been used to identify whole-chromosome UPD and segmental UPD greater than 10Mb from exome data.31.Bis D.M. Schüle R. Reichbauer J. et al.Uniparental disomy determined by whole-exome sequencing in a spectrum of rare motoneuron diseases and ataxias.1:CAS:528:DC%2BC2sXotFOqtLg%3D54414265441426Mol Genet Genomic Med. 2017; 5: 280-286Google Scholar Since heterozygous deletions can masquerade as segmental UPD, follow-up testing has to be performed to distinguish between these two abnormalities. In most clinical laboratories, evaluation for UPD is not routinely incorporated into clinical exome or genome sequencing assays. However, if UPD is detected during analysis, it can be reported as a secondary finding with a recommendation to confirm the finding with a clinically validated assay, for patients who consented to receive secondary findings. Since these methodologies can potentially uncover misattributed relationships, this possibility should be addressed during the consent or pretest counseling process. Laboratories should develop a process for appropriate follow-up when misattributed relationships are suspected based on the UPD testing results. In addition to techniques that directly detect UPD, multiple technologies are used in the diagnosis of imprinting disorders that can be caused by UPD for certain chromosomes but can also have other etiologies. Some of these techniques, like methylation-specific PCR (MS-PCR)32.Kubota T. Das S. Christian S.L. Baylin S.B. Herman J.G. Ledbetter D.H. Methylation-specific PCR simplifies imprinting analysis.1:CAS:528:DyaK2sXivFKhsLo%3DNat Genet. 1997; 16: 16-17Google Scholar and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA)33.Schouten J.P. McElgunn C.J. Waaijer R. Zwijnenburg D. Diepvens F. Pals G. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification.117299117299Nucleic Acids Res. 2002; 30: e57Google Scholar are based on interrogation of the methylation status of so-called differentially methylated regions (DMRs) or imprinting centers within the larger (typically several megabases in size) areas of chromosomes containing imprinted genes. DMRs have different methylation status on the maternal and the paternal homologue; they have been mapped, sequenced, and functionally characterized within well-known clinically significant imprinted chromosomal regions, and are thought to play a role in establishing and maintaining the parent-of-origin specific expression of the surrounding imprinted genes.34.Kaneko-Ishino T. Kohda T. Ishino F. The regulation and biological significance of genomic imprinting in mammals.1:CAS:528:DC%2BD3sXms1Wit70%3DJ Biochem. 2003; 133: 699-711Google Scholar MS-PCR and MS-MLPA assays are designed to distinguish between the normal methylation profile of the DMRs on the chromosome of interest and the abnormal profile associated with an imprinting disorder, without the need for parental samples. However, neither technique can distinguish between UPD and imprinting defects. Thus, STR marker analysis is required to determine if UPD is the cause of the observed aberrant methylation pattern. UPD for any chromosome is associated with an increased risk for a recessive disorder, since it can result in an affected child when only one parent is a carrier of a pathogenic variant. This is true even for cases of heterodisomy, due to isodisomic regions generated through meiotic crossovers during gametogenesis in the parent. Individuals at risk for a recessive disorder due to a UPD event may be ascertained by CMA testing. Further evaluation for a recessive disorder may be recommended if there is a concern for UPD based on large ROH on a single chromosome detected by CMA testing, in particular if there is also a clinical suspicion for a recessive condition based on a physical examination or results of other auxiliary diagnostic studies. More often the occurrence of a recessive disorder due to UPD is identified when sequencing based testing shows homozygosity for a pathogenic variant for which only one parent is a carrier. UPD for specific chromosomes results in abnormal phenotypes shown to be caused by imprinting. Transient neonatal diabetes mellitus (TNDM, MIM 601410) is a rare but well recognized type of diabetes caused by overexpression of the imprinted loci PLAGL1 and HYMAI at chromosome 6q24.2.35.Temple I.K. James R.S. Crolla J.A. et al.An imprinted gene(s) for diabetes?.1:CAS:528:DyaK2MXjsFOmsL8%3DNat Genet. 1995; 9: 110-112Google Scholar,36.Kamiya M. Judson H. Okazaki Y. et al.The cell cycle control gene ZAC/PLAGL1 is imprinted-a strong candidate gene for transient neonatal diabetes.1:CAS:528:DC%2BD3cXhsVOjurY%3DHum Mol Genet. 2000; 9: 453-460Google Scholar Partial or complete paternal UPD6 including PLAGL1 and HYMAI has been reported in approximately 40% of cases of TNDM.37.Docherty L.E. Kabwama S. Lehmann A. et al.Clinical presentation of 6q24 transient neonatal diabetes mellitus (6q24 TNDM) and genotype-phenotype correlation in an international cohort of patients.1:CAS:528:DC%2BC3sXjslehsrY%3DDiabetologia. 2013; 56: 758-762Google Scholar The finding of macroglossia or other congenital anomalies in addition to TNDM is a strong indicator to suspect UPD.37.Docherty L.E. Kabwama S. Lehmann A. et al.Clinical presentation of 6q24 transient neonatal diabetes mellitus (6q24 TNDM) and genotype-phenotype correlation in an international cohort of patients.1:CAS:528:DC%2BC3sXjslehsrY%3DDiabetologia. 2013; 56: 758-762Google Scholar The majority of paternal UPD6 is isodisomic and therefore affected individuals are at increased risk for rare autosomal recessive disorders including HFE-associated hereditary hemochromatosis (MIM 235200), methylmalonic acidemia (MIM 251000), and congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (MIM 201910).37.Docherty L.E. Kabwama S. Lehmann A. et al.Clinical presentation of 6q24 transient neonatal diabetes mellitus (6q24 TNDM) and genotype-phenotype correlation in an international cohort of patients.1:CAS:528:DC%2BC3sXjslehsrY%3DDiabetologia. 2013; 56: 758-762Google Scholar Russell–Silver syndrome (RSS, MIM 180860) is characterized by prenatal and postnatal poor growth, relative macrocephaly, and limb, body, and/or facial asymmetry. Complete and partial maternal UPD7 accounts for ~7–10% of patients with RSS.38.Kotzot D. Schmitt S. Bernasconi F. et al.Uniparental disomy 7 in Silver-Russell syndrome and primordial growth retardation.1:CAS:528:DyaK2MXltlSjuro%3DHum Mol Genet. 1995; 4: 583-587Google Scholar, 39.Preece M.A. Price S.M. Davies V. et al.Maternal uniparental disomy 7 in Silver-Russell syndrome.1:STN:280:DyaK2s7osVyksA%3D%3D10508381050838J Med Genet. 1997; 34: 6-9Google Scholar, 40.Eggermann T. Wollmann H.A. Kuner R. et al.Molecular studies in 37 Silver-Russell syndrome patients: frequency and etiology of uniparental disomy.1:STN:280:DyaK2svhvVWhug%3D%3DHum Genet. 1997; 100: 415-419Google Scholar, 41.Price S.M. Stanhope R. Garrett C. Preece M.A. Trembath R.C. The spectrum of Silver-Russell syndrome: a clinical and molecular genetic study and new diagnostic criteria.1:STN:280:DC%2BD3c%2FhtlSmtg%3D%3D17342671734267J Med Genet. 1999; 36: 837-842Google Scholar, 42.Eggermann T. Schneider-Rätzke B. Begemann M. Spengler S. Isolated hypermethylation of GRB10 (7p12.2) in a Silver-Russell syndrome patient carrying a 20p13 microdeletion.1:STN:280:DC%2BC3sjhtVWqsQ%3D%3DClin Genet. 2014; 85: 399-400Google Scholar Partial UPD7 due to segmental maternal UPD restricted to the long arm of chromosome 7, which results in hypermethylation of the imprinting center of the MEST gene within 7q32.2, was reported in several RSS patients.43.Hannula K. Kere J. Pirinen S. Holmberg C. Lipsanen-Nyman M. Do patients with maternal uniparental disomy for chromosome 7 have a distinct mild Silver-Russell phenotype?.1:CAS:528:DC%2BD3MXjtlKjurc%3D17348471734847J Med Genet. 2001; 38: 273-278Google Scholar Maternal UPD7 isodisomy and maternal heterodisomy have been reported in RSS patients.41.Price S.M. Stanhope R. Garrett C. Preece M.A. Trembath R.C. The spectrum of Silver-Russell syndrome: a clinical and molecular genetic study and new diagnostic criteria.1:STN:280:DC%2BD3c%2FhtlSmtg%3D%3D17342671734267J Med Genet. 1999; 36: 837-842Google Scholar,44.Bernard L.E. Peñaherrera M.S. Van Allen M.I. et al.Clinical and molecular findings in two patients with Russell–Silver syndrome and UPD7: comparison with non-UPD7 cases.1:STN:280:DC%2BD3c%2Fjtleqtw%3D%3DAm J Med Genet. 1999; 87: 230-236Google Scholar Mosaic maternal segmental UPD of 7q has also been reported in some cases.45.Reboul M.P. Tandonnet O. Biteau N. et al.Mosaic maternal uniparental isodisomy for chromosome 7q21-qter.Clin Genet. 2006; 70: 207-213Crossref PubMed Scopus (20) Google Scholar,46.Su J. Wang J. Fan X. et al.Mosaic UPD(7q)mat in a patient with Silver Russell syndrome.56459075645907Mol Cytogenet. 2017; 10: 36Google Scholar Beckwith–Wiedemann syndrome (BWS, MIM 130650) is a congenital overgrowth disorder with a predisposition to tumorigenesis. The disorder is caused by abnormalities within the two differentially methylated regions (DMRs) on the short arm of chromosome 11: imprinting center 1 (IC1), which regulates the expression of H19 and IGF2, and imprinting center 2 (IC2), which regulates the expression of CDKN1C, KCNQ1, and KCNQ10T1. The common causes of BWS are methylation abnormalities affecting the imprinting centers.47.Brioude F. Kalish J.M. Mussa A. et al.Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith–Wiedemann syndrome: an international consensus statement.60228486022848Nat Rev Endocrinol. 2018; 14: 229-249Google Scholar Segmental paternal UPD of 11p15 occurs in about 20% of BWS patients and results in biallelic expression of the normally paternally expressed IGF2 (in IC1 region), encoding a potent fetal growth factor.48.Choufani S. Shuman C. Weksberg R. Beckwith–Wiedemann syndrome.1:CAS:528:DC%2BC3cXhtFKqsr7JAm J Med Genet C Semin Med Genet. 2010; 154C: 343-354Google Scholar The UPD appears to consistently arise from a somatic recombination event resulting in paternal isodisomy (Fig. 1c). It has been hypothesized that nonmosaic whole-chromosome UPD11 may be lethal, and in fact, mosaicism is present in the majority of the cases, confirming the postzygotic origin of this UPD.6.Slatter R.E. Elliott M. Welham K. et al.Mosaic uniparental disomy in Beckwith–Wiedemann syndrome.1:STN:280:DyaK2M7jvFSntw%3D%3D10501191050119J Med Genet. 1994; 31: 749-753Google Scholar The detection of nonmosaic ROH involving chromosome 11 in a prenatal setting may be concerning about the high likelihood of fetus lethality. Maternal UPD of chromosome 11 has been rarely described as the cause of isolated cases of RSS.49.Luk H.M. Yeung K.S. Wong W.L. Chung B.H. Tong T.M. Lo I.F. Silver-Russell syndrome
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