Review and meta-analysis of systematic searches for uniparental disomy (UPD) other than UPD 15

All systematic searches for uniparental disomy (UPD) so far published and comprising clinically defined populations (Silver-Russell syndrome/primordial growth retardation (SRS/PGR) (n = 14), multiple malformations (n = 2), or rare syndromes (n = 12)) or situations at risk (confined placental mosaicism (CPM) (n = 13), spontaneous abortions (n = 6), additional marker chromosomes (n = 15), balanced non-Robertsonian translocations (n = 3), or balanced Robertsonian translocations (n = 15)) were reviewed. In many studies clinical and/or cytogenetic information on fluorescent in situ hybridization (FISH) results was very scarce. Meta-analysis concerning an adequate number of cases was possible for SRS/PGR, CPM, additional marker chromosomes, and balanced Robertsonian translocations only. As expected, the highest risk for UPD was found in cases with translocations between homologous acrocentric chromosomes (11 cases with UPD of 15 investigated) and in CPM due to a meiotic error (25 of 51 cases).In prenatal investigations or in cases with a normal phenotype, translocations between nonhomologous acrocentric chromosomes implied a risk for UPD of less than 0.5%. The risks for maternal UPD 7 in cases with SRS/PGR, for UPD 15 in cases with an additional inv dup(15) marker chromosome, and for UPD of any chromosome in cases with multiple malformation/mental retardation were approximately 5.5%, and approximately 1.3%, respectively. Searches for UPD in well-defined syndromes (Brachmann-De Lange syndrome, Sotos syndrome, Rett syndrome, Weaver syndrome, or XX true hermaphroditism) were disappointing. Not a single case was found.     

Identification of interstitial maternal uniparental disomy (UPD) (14) and complete maternal UPD(20) in a cohort of growth retarded patients

The association of uniparental disomy (UPD) and short stature has been reported for different chromosomes and in several conditions. Therefore, we investigated a cohort of 21 patients referred because of intrauterine and postnatal growth retardation for UPD of chromosomes 2, 7, 9, 14, 16, and 20. Typing of short tandem repeats showed maternal UPD(14) and maternal UPD(20) in two cases. In the first case, an interstitial UPD(14) was detected and the growth retarded newborn showed some additional clinical signs in common with the putative "maternal UPD(14) syndrome". The maternal UPD(20) patient showed minor features. However, since it is only the second maternal UPD(20) case it is too early to delineate a specific syndrome and the role of this constitution in growth remains to be investigated. Our data suggest that searching for UPD in growth retarded patients is a helpful approach to getting more information on the role of UPD in growth retardation. Based on our results, general considerations and indications for UPD testing are discussed.


Keywords: uniparental disomy 14; uniparental disomy 20; growth retardation; Silver-Russell syndrome     

Review and meta‐analysis of systematic searches for uniparental disomy (UPD) other than UPD 15

All systematic searches for uniparental disomy (UPD) so far published and comprising clinically defined populations (Silver‐Russell syndrome/primordial growth retardation (SRS/PGR) (n = 14), multiple malformations (n = 2), or rare syndromes (n = 12)) or situations at risk (confined placental mosaicism (CPM) (n = 13), spontaneous abortions (n = 6), additional marker chromosomes (n = 15), balanced non‐Robertsonian translocations (n = 3), or balanced Robertsonian translocations (n = 15)) were reviewed. In many studies clinical and/or cytogenetic information on fluorescent in situ hybridization (FISH) results was very scarce. Meta‐analysis concerning an adequate number of cases was possible for SRS/PGR, CPM, additional marker chromosomes, and balanced Robertsonian translocations only. As expected, the highest risk for UPD was found in cases with translocations between homologous acrocentric chromosomes (11 cases with UPD of 15 investigated) and in CPM due to a meiotic error (25 of 51 cases). In prenatal investigations or in cases with a normal phenotype, translocations between nonhomologous acrocentric chromosomes implied a risk for UPD of less than 0.5%. The risks for maternal UPD 7 in cases with SRS/PGR, for UPD 15 in cases with an additional inv dup(15) marker chromosome, and for UPD of any chromosome in cases with multiple malformation/mental retardation were approximately 5.5%, and approximately 1.3%, respectively. Searches for UPD in well‐defined syndromes (Brachmann‐De Lange syndrome, Sotos syndrome, Rett syndrome, Weaver syndrome, or XX true hermaphroditism) were disappointing. Not a single case was found. © 2002 Wiley‐Liss, Inc.     

Maternal uniparental heterodisomy of chromosome 14: chromosomal mechanism and clinical follow up

To our knowledge, 22 cases of chromosome 14 maternal uniparental disomy (UPD(14)mat) have been reported so far. The majority of cases were ascertained because of an abnormal phenotype associated with a Robertsonian translocation involving chromosome 14. We report here on a child with UPD(14)mat detected prenatally and resulting from trisomy rescue in a maternal meiosis I non-disjunction trisomic zygote. After four years of clinical follow up, in addition to intrauterine growth retardation (IUGR), only short stature and small hands and feet were observed. These clinical data as well as the ascertainment and mechanism of origin of UPD(14)mat were compared with those observed in previously reported cases. It appears that the clinical spectrum of UPD(14)mat is milder in our patient than in patients with UPD(14)mat resulting from other chromosomal mechanisms. In addition, a hypothesis based on abnormal imprinting is proposed to explain the variability of the UPD(14)mat.


Keywords: maternal UPD; chromosome 14; MCP; imprinting     

Maternal uniparental disomy for chromosome 14 in a boy with intrauterine growth retardation

Maternal uniparental disomy (UPD) for chromosome 14 [upd(14)mat] may cause a characteristic phenotype with growth and developmental deficiency and precocious puberty. We report the case of a Japanese infant with an isochromosome 14 [i(14q)] and intrauterine growth retardation (IUGR). The infant is one of triplets comprising a boy (the patient) and two karyotypically normal girls. We analyzed parent–child transmission modes of alleles on the i(14q) at 17 CA-repeat marker loci along the entire length of chromosome 14. Genotypes at 4 proximal and 5 distal loci on the i(14q) were consistent with maternal isodisomy, whereas those at an intervening region indicated maternal heterodisomy. Thus, the derivative chromosome 14 had arisen through a translocation between maternal homologous chromosomes 14 [t(14;14)(p10;q10)] after at least two crossing-over events at the first meiosis. This result also suggests that there must be maternally imprinted gene(s) on 14q, and that loss of the functionally active, paternally derived allele in the same locus may lead to IUGR. Alternatively, IUGR may be an autosomal recessive trait. In the latter case, the mother would be a heterozygote and the putative disease locus would be either at the most proximal or most distal region of 14q. Received: December 19, 1997 / Accepted: February 7, 1998     

The contribution of uniparental disomy to congenital development defects in children born to mothers at advanced childbearing age

Most instances of maternal uniparental disomy (UPD) start as trisomies and, similar to the latter, show a significant increase of mean maternal age at delivery. To investigate the incidence of UPD in offspring of older mothers, we investigated two groups of patients: 1) 50 patients with unclassified developmental defects born to mothers 35 years or older at delivery were tested for UPD for all autosomes by means of microsatellite marker analysis; 2) The incidence of UPD versus other etiologies in correlation, with maternal age below versus 35 years and above at delivery was studied in patients investigated in our laboratory for maternal UPD 15 (Prader-Willi syndrome, PWS), paternal UPD 15 (Angelman syndrome, AS), and maternal UPD 7 (Silver-Russell syndrome, SRS). In group 1, four patients of 50 showed UPD for an autosome that clarified the etiology of their developmental problems: a 27-year-old woman with growth retardation and early puberty disclosed maternal heterodisomy 14; a 15-year-old girl revealed paternal isodisomy 15; a 6-year-old boy with suspected Smith-Lemli-Opitz syndrome was shown to have maternal heterodisomy 16 with additional mosaic partial trisomy 16(pter-p13); a 16-month-old girl with intrauterine growth retardation and a dysmorphic pattern revealed maternal heterodisomy 7. In group 2 the offspring of older mothers showed a clear increase of UPD compared with the mothers below 35 years at delivery. The binomial distribution gave P-values of 1.9 x 10(-10), 2.6 x 10(-4), and 0.01 for PWS, AS, and SRS, respectively. The correlation between increase of paternal UPD 15 with advanced maternal age might be explained by maternal non-disjunction leading to hypohaploid gamete (nullisomy) for chromosome 15 with subsequent or concomitant duplication of the paternal homologue (paternal isodisomy). The three UPD 15 AS cases with mothers older than 35 years at delivery revealed isodisomy, whereas the three cases from younger mothers showed heterodisomy. This study confirms the hypothesis that uniparental disomy is a not negligible cause of congenital developmental anomalies in children of older mothers.     

Expression of insulin-like growth factor in the placenta of intrauterine growth-retarded human fetuses

Many cases of intrauterine growth retardation (IUGR) are the result of placental and fetal tissue insufficiency. Insulin-like growth factor-I (IGF-I) is known to play a role in placental and fetal growth. An immunocytochemical study was performed to localize IGF-I peptides in human placenta and umbilical cords of normal (n = 3) and IUGR (n = 3) fetuses. The peripartum fetal conditions were evaluated as well. Immunoreactive IGF-I was detected in the cytotrophoblast, syncytiotrophoblast, amnion, endothelial cells of fetal capillaries and in the decidua in both normal and IUGR placental tissue. A more robust immunostaining and increased numbers of positively stained cells were found in the decidua of IUGR placenta (p < 0.001). Intense immunostaining was also found in endothelial cells, smooth muscle cells and fibroblasts of the umbilical vein. IGF-I immunoreactivity was also present in stroma (Hofbauer cells and/or fibroblasts) of IUGR villi. Our results indicate that expression of IGF-I is high in specific sites in placenta and umbilical cords, which indicates a paracrine and/or endocrine function. The increased expression of IGF-I in placenta of IUGR fetuses indicates its involvement in restoring normal growth by means of a positive feed-back mechanism.     

Mosaic maternal uniparental isodisomy for chromosome 7q21-qter

Uniparental disomy (UPD) for several human chromosomes is associated with clinical abnormalities. We report the case of a 2-year-old boy with severe intrauterine and post-natal growth retardation (IUGR/PNGR) and highly variable sweat chloride concentrations. The patient was identified as heterozygous for the F508del mutation of the CFTR (cystic fibrosis transmembrane conductance regulator) gene. Unexpectedly, the signal corresponding to the maternally inherited F508del allele appeared much more intense than the paternally derived wild allele. Molecular analysis including polymorphic marker studies, microsatellites and single-nucleotide polymorphisms subsequently showed that the boy was a carrier of a de novo mosaic maternal isodisomy of a chromosome 7 segment while there was a biparental inheritance of the rest of the chromosome. This is the first report of a mosaic partial UPD7. The matUPD7 segment at 7q21-qter extends for 72.7 Mb. The karyotype (550 bands) of our patient was normal, and fluorescence in situ hybridization with probes mapping around the CFTR gene allowed us to rule out a partial duplication. The detection of this chromosomal rearrangement confirms the hypothesis that the 7q31-qter segment is a candidate for the localization of human imprinted genes involved in the control of IUGR and PNGR. It also emphasizes the importance of searching for UPD7 in severe, isolated and unexplained IUGR and PNGR.     

Is maternal duplication of 11p15 associated with Silver-Russell syndrome?

Background: Silver-Russell syndrome (SRS) is a heterogeneous malformation syndrome characterised by intrauterine and postnatal growth retardation (IUGR, PGR) and dysmorphisms. The basic causes are unknown, however in approximately 10% of patients a maternal uniparental disomy (UPD) of chromosome 7 or chromosomal aberrations can be detected. Four growth retarded children, two with SRS-like features, associated with maternal duplications of 11p15 have been described. Considering the involvement of this genomic region in Beckwith-Wiedemann overgrowth syndrome (BWS), we postulated that some cases of SRS—with an opposite phenotype to BWS—might also be caused by genomic disturbances in 11p15.

Methods: A total of 46 SRS patients were screened for genomic rearrangements in 11p15 by STR typing and FISH analysis.

Results: Two SRS patients with duplications of maternal 11p material in our study population (n = 46) were detected. In patient SR46, the duplicated region covered at least 9 Mb; FISH analysis revealed a translocation of 11p15 onto 10q. In patient SR90, additional 11p15 material (approximately 5 Mb) was translocated to the short arm of chromosome 15.

Conclusions: We suggest that diagnostic testing for duplication in 11p15 should be offered to patients with severe IUGR and PGR with clinical signs reminiscent of SRS. SRS is a genetically heterogeneous condition and patients with a maternal duplication of 11p15.5 may form an important subgroup.

     

The trisomy 4p syndrome: Case report and review

We report a further case of trisomy 4p: a 5-year-old mentally retarded boy with characteristic facial features, eye abnormalities, flexion contractures, several bone anomalies, and hyperactivity. In a review of 27 cases (11♂, 16♀, 22 families) the cytogenetic and clinical data were tabulated and analyzed. Diagnosis is established by karyotype: there is always partial or apparently “total” trisomy of the short arm of chromosome 4. In 19 families a parent carried either a balanced translocation (16 times) or a pericentric inversion (3 times); 3 patients had de novo duplication of 4p. In several cases, additional deletions or trisomies were present. From the analysis of all cases, but particularly of the “pure” trisomies, the phenotypic spectrum of this condition was observed and found to be a specific multiple congenital anomaly/mental retardation (MCA/MR) syndrome. Its main features are a characteristic facial appearance, postnatal growth retardation, severe psychomotor retardation with or without seizures, microcephaly, and various major and minor anomalies.     

Uniparental isodisomy of chromosome 14 in two cases: An abnormal child and a normal adult

Uniparental disomy (UPD) of a number of different chromosomes has been found in association with abnormal phenotypes. A growing body of evidence for an imprinting effect involving chromosome 14 has been accumulating. We report on a case of paternal UPD of chromosome 14 studied in late gestation due to polyhydramnios and a ventral wall hernia. A prenatal karyotype documented a balanced Robertsonian 14:14 translocation. The baby was born prematurely with hairy forehead, retrognathia, mild puckering of the lips and finger contractures. Hypotonia has persisted since birth and at age one year, a tracheostomy for laryngomalacia and gastrostomy for feeding remain necessary. Absence of maternal VNTR polymorphisms and homozygosity of paternal polymorphisms using chromosome 14 specific probes at D14S22 and D14S13 loci indicated paternal uniparental isodisomy (pUPID). Parental chromosomes were normal. We also report on a case of maternal UPD in a normal patient with a balanced Robertsonian 14:14 translocation and a history of multiple miscarriages. Five previous reports of chromosome 14 UPD suggest that an adverse developmental effect may be more severe whenever the UPD is paternal in origin. This is the second reported patient with paternal UPD and the fifth reported with maternal UPD, and only few phenotypic similarities are apparent. Examination of these chromosome 14 UPD cases of maternal and paternal origin suggests that there are syndromic imprinting effects. © 1995 Wiley-Liss, Inc.     

Ring chromosome 2 in a child with growth failure and few congenital abnormalities

A ring chromosome 2 mosaic [46,XX/46,XX,r(2)(p25q37)] was found in a newborn female with severe intrauterine growth retardation (IUGR), postnatal growth failure, and a few minor abnormalities. Psychomotor development has been normal to 19 months old. A ring chromosome 2 is present in 77.8% of the nuclei examined and is not found in the parents or a sibling. G- and R-banding reveal the break points to be p25q37. The presence of a normal cell line indicates that the chromosome abnormality arose after conception.     

Prenatal diagnosis of trisomy 6 rescue resulting in paternal UPD6 with novel placental findings

Uniparental disomy (UPD) is defined by the inheritance of both copies of a chromosome pair from one single parent. Although 23 cases of paternal UPD6 have been reported earlier, the occurrence of trisomy 6 rescue with paternal UPD6 has not been previously reported. The phenotype of paternal UPD6 results from biallelic expression of the maternally imprinted, paternally expressed ZAC and HYMAI genes, and includes transient neonatal diabetes mellitus (TNDM), intra-uterine growth restriction (IUGR), macroglossia, and minor anomalies. Trisomy rescue has been proposed as a pathogenic mechanism leading to UPD of other chromosomes. We report on the first case of a prenatally diagnosed infant with UPD6 and describe the clinical, cytogenetic, molecular, and novel placental findings in a female infant with paternal UPD6. Low-level trisomy 6 and paternal UPD6 were prenatally diagnosed through amniocentesis. After birth trisomy 6 was documented in the placenta but was not found in three different cell lines from the infant. The placenta was small with a peculiar pattern of vascular proliferation. Our results of trisomy 6 cells predominantly present in the placenta and only in low levels in the amniotic fluid suggest that the distribution and proportion of trisomic and diploid UPD cells contribute to the variability of fetal and placental phenotypes.     

妊娠中、晚期300例胎儿脐血染色体核型分析

目的 分析妊娠中、晚期胎儿脐血染色体核型,了解该时期异常核型出现的频率、类型及与各种产前诊断指征的关系。方法 ３００例有产前诊断指征的孕妇,在妊娠１８～３８孕周时穿刺胎儿脐带血管,帛脐箅查染色体核型。结果 发现异常核型２３例（７．７％）,其中２１三体占３９．１％（８／１２６）,Ｐ＝０．７７。三体为主要的染色体异常,占异常核型的６０．９％（１４／２３）。其中２１三体占３９．１％（９／２３）,平衡易位     

A multiplex methylation PCR assay for identification of uniparental disomy of chromosome 7

Uniparental disomy of chromosome 7 (UPD7) is associated with abnormal phenotypic effects because of inappropriate expression of imprinted genes on chromosome 7. Based on the differential methylation of the promoter region of the imprinted PEG1/MEST locus at 7q32, we designed a multiplex methylation PCR (mPCR) assay to rapidly distinguish UPD7 from biparental inheritance of chromosome 7. Primers were designed to produce different sized PCR amplicons based on the parent of origin-specific methylation at this locus; electrophoresis of PCR amplicons showed a 189-bp product from the methylated maternal allele and a 109-bp product from the unmethylated paternal allele. This mPCR assay correctly predicted the chromosome 7 imprinting status in normal control and UPD7 samples. Previous assays for UPD7 required genotyping of the proband and parents, or separate maternal- and paternal-specific mPCR reactions. The advantage of this assay is that parental samples are not required and that amplification of both alleles in the same reaction is simpler and provides an internal control. This multiplex mPCR assay will be useful in screening for UPD7 in patients with Silver-Russell syndrome (SRS; also Russell-Sliver syndrome, RSS), primordial growth retardation, and in patients with supernumerary marker chromosomes or chromosome rearrangements of chromosome 7 origin.     

47,XX,UPD(7)mat,+r(7)pat/46,XX,UPD(7)mat mosaicism in a girl with Silver-Russell syndrome (SRS): possible exclusion of the putative SRS gene from a 7p13-q11 region

Maternal uniparental disomy for chromosome 7 (UPD7) may present with a characteristic phenotype reminiscent of Silver-Russell syndrome (SRS). Previous studies have suggested that approximately 10% of SRS patients have maternal UPD7. We describe a girl with a mos47,XX,+mar/46,XX karyotype associated with the features of SRS. Chromosome painting using a chromosome 7 specific probe pool showed that the small marker was a ring chromosome 7 (r(7)). PCR based microsatellite marker analysis of the patient detected only one maternal allele at each of 16 telomeric loci examined on chromosome 7, but showed both paternal and maternal alleles at four centromeric loci. Considering her mosaic karyotype composed ofdiploid cells and cells with partial trisomy for 7p13-q11, the allele types obtained at the telomeric loci may reflect the transmission of one maternal allele in duplicate, that is, maternal UPD7 (complete isodisomy or homodisomy 7), whereas those at the centromeric loci were consistent with biparental contribution to the trisomic region. It is most likely that the patient originated in a 46,XX,r(7) zygote, followed by duplication of the maternally derived whole chromosome 7 in an early mitosis, and subsequent loss of the paternally derived ring chromosome 7 in a subset of somatic cells. The cell with 46,XX,r(7) did not survive thereafter because of the monosomy for most of chromosome 7. If the putative SRS gene is imprinted, it can be ruled out from the 7p11-q11 region, because biparental alleles contribute to the region in our patient.     

Silver-Russell syndrome due to maternal uniparental disomy 7 and a familial reciprocal translocation t(7;13)

Behnecke A, Hinderhofer K, Jauch A, Janssen JWG, Moog U. Silver-Russell syndrome due to maternal uniparental disomy 7 and a familial reciprocal translocation t(7;13). Silver-Russell syndrome (SRS) is a genetically heterogeneous disorder characterized by intrauterine and postnatal growth retardation, typical facial features and a spectrum of additional features including body and limb asymmetry and clinodactyly. Maternal uniparental disomy for chromosome 7 (upd(7)mat) was shown to occur in 5-10% of patients with SRS. Maternal UPD7 is clinically often associated with mild SRS. Parents of an affected child are given a negligible recurrence risk as all reported cases with upd(7)mat have been sporadic so far. In general, chromosomal rearrangements-like translocations increase the likelihood of uniparental disomy (UPD) for the chromosomes involved. However, SRS as the result of a upd(7)mat in association with an inherited chromosomal translocation involving chromosome 7 has only been reported once before. Here, we describe the second case of SRS with upd(7)mat due to a familial reciprocal translocation t(7;13). This emphasizes the importance of chromosome analysis in SRS patients with upd(7)mat to rule out chromosomal rearrangements despite their rare occurrence as they are of great relevance for genetic counseling of SRS families.     

upd(20)mat is a rare cause of the Silver-Russell-syndrome-like phenotype: Two unrelated cases and screening of large cohorts

Silver-Russell syndrome (SRS) is an imprinting disorder characterized by prenatal and postnatal growth retardation, relative macrocephaly, feeding difficulties and body asymmetry. Recently, upd(20)mat has been identified in few patients with SRS-like features, suggestive of a new imprinting disorder characterized by prenatal and postnatal growth failure. Here, we describe two male patients with upd(20) and feeding difficulties, prenatal and postnatal growth retardation and normal cognitive development. During pregnancy, confined placental mosaicism for trisomy 20 was detected in one of the patients but was not investigated further until identification of upd(20)mat in the neonatal period. To evaluate whether upd(20)mat should be part of the first trier genetic diagnostic in patients with growth retardation, we screened a large cohort of patients (n = 673) referred to our laboratories for SRS-testing without detecting any upd(20). Our results, along with the existing evidence, indicate that upd(20)mat is a very rare cause of growth retardation, but should be followed up when confined placental mosaicism for trisomy 20 mosaicism is observed during pregnancy.     

Trisomy 16 and trisomy 16 mosaicism: A review

A review of all prenatal and postnatal diagnoses of trisomy 16 and trisomy 16 mosaicism was carried out in the context of the current understanding of confined placental mosaicism and uniparental disomy (UPD). The prenatal detection of trisomy 16 cells is associated with a high probability of fetal death, preterm delivery, intrauterine growth retardation, and fetal anomalies. Birth defects were typical of those seen in nonmosaic partial duplications of chromosome 16. Surprisingly, anomalies were sometimes limited to a single organ and included some relatively common isolated defects such as a ventricular septal defect, hypospadias, imperforate anus, inguinal hernia, and clubfoot. The risk for abnormality appeared to be higher in those pregnancies in which trisomy 16 cells were identified in amniotic fluid compared to the detection in chorionic villi samples. Contrary to nonmosaic trisomy 16 with an excess of males, mosaic trisomy 16 shows an excess of female karyotypes. Following the prenatal detection of trisomy 16 cells, aneuploid cells are almost never found in fetal or neonatal lymphocytes. Studies on fibroblasts also often fail to confirm the presence of the abnormal cell line even in cases in which multiple anomalies are present. It is likely that trisomy 16 cells are sometimes present in the early developing embryo even though subsequent cytogenetic studies on fetal or neonatal tissues may not detect any aneuploid cells. UPD can be excluded as a mechanism for those anomalies that are common to mosaic trisomy 16 and nonmosaic partial duplications. The term “occult mosaicism” is suggested to describe the situation in which the presence of an abnormal cell line is suspected on the basis of clinical data but unproven by laboratory analysis. Am. J. Med. Genet. 79:121–133, 1998. © 1998 Wiley-Liss, Inc.     

Uniparental disomy in a population of 32,067 clinical exome trios

PurposeData on the clinical prevalence and spectrum of uniparental disomy (UPD) remain limited. Trio exome sequencing (ES) presents a comprehensive method for detection of UPD alongside sequence and copy-number variant analysis.MethodsWe analyzed 32,067 ES trios referred for diagnostic testing to create a profile of UPD events and their disease associations. ES single-nucleotide polymorphism (SNP) and copy-number data were used to identify both whole-chromosome and segmental UPD and to categorize whole-chromosome results as isodisomy, heterodisomy, or mixed.ResultsNinety-nine whole-chromosome and 13 segmental UPD events were identified. Of these, 29 were associated with an imprinting disorder, and 16 were associated with a positive test result through homozygous sequence variants. Isodisomy was more commonly observed in large chromosomes along with a higher rate of homozygous pathogenic variants, while heterodisomy was more frequent in chromosomes associated with imprinting or trisomy mosaicism (14, 15, 16, 20, 22).ConclusionWhole-chromosome UPD was observed in 0.31% of cases, resulting in a diagnostic finding in 0.14%. Only three UPD-positive cases had a diagnostic finding unrelated to the UPD. Thirteen UPD events were identified in cases with prior normal SNP chromosomal microarray results, demonstrating the additional diagnostic value of UPD detection by trio ES.