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Uniparental disomy (UPD) is a rare type of chromosomal aberration that has sometimes been detected in paternity testing. We examined a 3-person family (father, mother, daughter) first by using short tandem repeat markers, which revealed 4 markers, TPOX, D2S1338, D2S1772, and D2S441, on chromosome 2 that were not transmitted in a Mendelian style. We...
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In paternity testing, when there are Mendelian errors in the alleles between the child and the parents, slippage mutation or silent allele may not fully explain the phenomenon. Sometimes, it is attributed to chromosomal abnormalities, such as uniparental disomy (UPD). Here, we present the investigation of two cases of suspected UPD in paternity tes...
DNA testing in cases of disputed paternity is a routine analysis carried out in genetic laboratories. The purpose of the test is to demonstrate similarities and differences in analyzed genetic markers between the alleged father, mother, and a child. The existence of differences in the examined loci between the child and the presumed father may indi...
Citations
... Two of these cases had complete maternal UPD2; four had complete paternal UPD2; one had complete maternal isodisomy resulting from two maternal isochromosomes i(2q) and i(2p). [23][24][25][26][27][28][29] Parental origin was not reported in one case. 30 The ages at which individuals with UPD2 and a normal phenotype was reported ranged from 18 months to 36 years. ...
We report a 4-year-old girl with neurodevelopmental abnormalities who has maternal uniparental isodisomy of chromosome 2 leading to homozygosity for a likely pathogenic variant in SPR , and a variant of uncertain significance in ZNF142 . Biallelic pathogenic variants in SPR lead to sepiapterin reductase deficiency (SRD), a dopa-responsive dystonia. Pathogenic variants in ZNF142 are associated with an autosomal recessive neurodevelopmental disorder characterized by impaired speech and hyperkinetic movements, which has significant clinical overlap with SRD. Our patient showed dramatic improvement in motor skills after treatment with levodopa. We also reviewed 67 published reports of uniparental disomy of chromosome 2 (UPD2) associated with various clinical outcomes. These include autosomal recessive disorders associated with loci on chromosome 2, infants with UPD2 whose gestations were associated with confined placental mosaicism for trisomy 2 leading to intrauterine growth restriction with good postnatal catchup growth, and normal phenotypes in children and adults with an incidental finding of either maternal or paternal UPD2. These latter reports provide support for the conclusion that genes located on chromosome 2 are not subject to imprinting. We also explore the mechanisms giving rise to UPD2.
... In this study, we aimed to display different clinical features between imprinting and nonimprinting UPDs. Besides our patUPD2 sample, several studies have showed that UPD2 patients exhibit normal phenotypes (Keller et al., 2009;Zhang et al., 2019;Song et al., 2021). However, rare matUPD2 patients accompanied with unspecific phenotypes, including severe IUGR, mild development delay (Ou et al., 2013;Zhou et al., 2017), oligohydramios and hypospadias (Hansen et al., 1997) (Table 2). ...
Uniparental disomy (UPD) refers to as both homologous chromosomes inherited from only one parent without identical copies from the other parent. Studies on clinical phenotypes in UPDs are usually focused on the documented UPD 6, 7, 11, 14, 15, and 20, which directly lead to imprinting disorders. This study describes clinical phenotypes and genetic findings of three patients with UPD 2, 9, and 14, respectively. Chromosomal microarray (CMA), UPDtool, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and whole-exome sequencing (WES) analysis were performed to characterize the genetic etiology. The CMA revealed a homozygous region involving the whole chromosome 2 and 9, a partial region of homozygosity in chromosome 14. UPD-tool revealed a paternal origin of the UPD2. MS-MLPA showed hypomethylation of imprinting gene MEG3 from maternal origin in the UPD14 case. In addition, UPD14 case displayed complex symptoms including growth failure, hypotonia and acute respiratory distress syndrome (ARDS), accompanied by several gene mutations with heterozygous genotype by WES analysis. Furthermore, we reviewed the documented UPDs and summarized the clinical characteristics and prognosis. This study highlighted the importance to confirm the diagnosis and origin of UPD using genetic testing. Therefore, it is suggested that expanding of the detailed phenotypes and genotypes provide effective guidance for molecule testing and genetic counseling, and promote further biological investigation to the underlying mechanisms of imprinted disorders and accompanied copy number variations.
... The concept of uniparental disomy (UPD) was first proposed by Engel [1] and refers to the phenomenon when all or part of an offspring's homologous chromosome are derived from only the father or mother. UPD is a relatively rare chromosomal abnormality [2]. The pathogenic mechanism of UPD causing severe clinical phenotypes is mostly related to monogenic homozygous mutations or the disruption of imprinted gene expression [3,4]. ...
... With the development of genetic diagnostic techniques, more chromosomal abnormalities or genetic abnormalities have been detected during prenatal diagnosis, and most prenatal diagnostic techniques such as karyotyping, quantitative fluorescence PCR, copy number variant sequencing (CNV-Seq), and array comparative genomic hybridization cannot be used to screen for UPD [12,13]. Using traditional genetic diagnosis methods, some cases of UPD may be overlooked [2]. Current genetic methods that can detect UPD with high accuracy include SNP arrays, short tandem repeat sequencing, and whole-exome sequencing (WES) [12,13]. ...
... UPD2 resulting in homozygosity of pathogenic mutations leads to certain diseases such as Catel-Manzke syndrome/VCRL syndrome, infantile hypotonia with psychomotor retardation and characteristic facies 2, and hepatocerebral mitochondrial DNA depletion syndrome [3,20,21]. Some UPD2 cases were discovered in normal individuals during paternity testing [2,22,23]. ...
Uniparental disomy (UPD) is when all or part of the homologous chromosomes are inherited from only one of the two parents. Currently, UPD has been reported to occur for almost all chromosomes. In this study, we report two cases of UPD for chromosome 2 (UPD2) encountered during prenatal diagnosis. The ultrasound findings of the fetuses from two unrelated families showed intrauterine growth restriction. The karyotype analyses were normal. The two fetuses both had complete paternal chromosome 2 uniparental disomy detected by whole-exome sequencing, but their clinical outcomes were significantly different, with fetal arrest in case 1 and birth in case 2. In this report, we analyzed and discussed the phenotypes of the fetuses in these two cases and reviewed the literature on UPD2.
... The current reports on a few complete paternal UPD cases and a partial maternal UPD case confirmed the lack of clinically conspicuous phenotype. This suggests the likelihood of few or no paternal imprinted genes in chromosome 2, which majorly affect growth and development (14)(15)(16)(17). In contrast, maternal UPD of chromosome 2 causes a variable phenotype (18,19). ...
Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare, inherited autosomal recessive disorder caused by fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or Klotho (KL) gene variants. Here, we report the case of a Japanese boy who presented with a mass in his left elbow at the age of three. Laboratory test results of the patient revealed normocalcemia (10.3 mg/dL) and hyperphosphatemia (8.7 mg/dL); however, despite hyperphosphatemia, serum intact FGF23 level was low, renal tubular reabsorption of phosphate (TRP) level was inappropriately increased, and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) level was inappropriately normal. Genetic analysis revealed maternal uniparental disomy (UPD) of chromosome 2, which included a novel GALNT3 variant(c.1780-1G>C). Reverse transcription-polymerase chain reaction (RT-PCR) analysis of GALNT3 mRNA confirmed that this variant resulted in the destruction of exon 11. We resected the mass when the patient was five years old, owing to its gradual enlargement. No relapse or new pathological lesions were observed four years after tumor resection. This is the first case report of a Japanese patient with HFTC associated with a novel GALNT3 variant, as well as the first case of HFTC caused by maternal UPD of chromosome 2 that includes the GALNT3 variant.
... Nevertheless, dual-variant carrier III.19 (proband/proposita's sister) did not transmit either variant to her eldest son (IV.11), although her youngest son (IV.12) did inherit the MSH6 variant ( Figure 1). Various hypotheses could explain such a finding of non-transmission, including: (1) a sampling error; (2) a de novo deletion encompassing and thereby removing either MSH2 or MSH6 variant in the son (IV.11), which would incur another cause for LS; (3) complete or segmental paternal uniparental disomy (pUPD) for chromosome 2, or Chr2p21-p16, such that IV.11 had inherited both copies of the Chr2p21-p16 region from his father with no maternal contribution, which has previously been described in healthy subjects [35][36][37]; or (4) a recombination event between the locations of the trans MSH2 c.2006G>T and MSH6 c.3936_4001+8dup (Intronic) variants in the maternal germline such that the son inherited the recombined wild-type allele from his mother. ...
Simple Summary
Lynch syndrome is a hereditary cancer condition caused by a pathogenic variant (mutation) within one of the mismatch repair (MMR) genes. Risks for cancer vary by which MMR gene is mutated and sex, although colorectal and uterine cancers are most common. A major challenge in genetic testing is that this frequently reveals a variant of uncertain significance (VUS), which hinders clinical decision-making. We describe a large, four-generation, 13-branched, cancer-affected family with a mutation in MSH2 (c.2006G>T) in which one branch also carries a VUS in MSH6 (c.3936_4001+8dup). Functional studies in samples from family members show this MSH6 VUS is likely to be pathogenic. In addition, other cancer-relevant mutations were identified in branches without either MMR gene mutation so genetic counseling was highly individualized. Our study suggests multi-cancer gene panel testing should be offered to all members of cancer-effected families rather than targeted testing for specific mutations for accurate genetic diagnosis.
Abstract
Lynch syndrome (LS), caused by heterozygous pathogenic variants affecting one of the mismatch repair (MMR) genes (MSH2, MLH1, MSH6, PMS2), confers moderate to high risks for colorectal, endometrial, and other cancers. We describe a four-generation, 13-branched pedigree in which multiple LS branches carry the MSH2 pathogenic variant c.2006G>T (p.Gly669Val), one branch has this and an additional novel MSH6 variant c.3936_4001+8dup (intronic), and other non-LS branches carry variants within other cancer-relevant genes (NBN, MC1R, PTPRJ). Both MSH2 c.2006G>T and MSH6 c.3936_4001+8dup caused aberrant RNA splicing in carriers, including out-of-frame exon-skipping, providing functional evidence of their pathogenicity. MSH2 and MSH6 are co-located on Chr2p21, but the two variants segregated independently (mapped in trans) within the digenic branch, with carriers of either or both variants. Thus, MSH2 c.2006G>T and MSH6 c.3936_4001+8dup independently confer LS with differing cancer risks among family members in the same branch. Carriers of both variants have near 100% risk of transmitting either one to offspring. Nevertheless, a female carrier of both variants did not transmit either to one son, due to a germline recombination within the intervening region. Genetic diagnosis, risk stratification, and counseling for cancer and inheritance were highly individualized in this family. The finding of multiple cancer-associated variants in this pedigree illustrates a need to consider offering multicancer gene panel testing, as opposed to targeted cascade testing, as additional cancer variants may be uncovered in relatives.
... The potential harmful effects of UPD include imprinted gene diseases, or activation of recessive pathogenic genes. Maternal and paternal UPD2, with normal phenotypes, have been reported previously, indicating the absence of genomic imprinting effects in UPD2 (Keller et al., 2009;Ou et al., 2013;Zhou et al., 2017;Zhang et al., 2019). Single conventional SNP-array analysis did not provide a conclusive diagnosis for the patient, therefore, an integrated approach is needed to determine the underlying genetic cause. ...
Background: Infantile hypotonia with psychomotor retardation and characteristic facies 2 (IHPRF2) is a rare autosomal recessive neurodevelopmental disorder caused by mutations in the UNC80 gene. It is characterized by severe global developmental delay, poor or absent speech and absent or limited walking abilities. The current study explored a case of a Chinese patient with IHPRF2 caused by a novel splicing variant of UNC80.
Case Report: The proband is a 8-year-old Chinese male manifested with global developmental delay, severe truncal hypotonia, absent speech and intellectual disability. SNP array analysis revealed a uniparental isodisomy of the entire chromosome 2 [UPD(2)] in the proband. Whole exome sequencing (WES) subsequently identified a novel mutation c.5609-4G>A in the UNC80 gene, which was inherited from his mother and was confirmed by Sanger sequencing, indicating that UPD(2) was of maternal origin.
Conclusion: A novel UNC80 homozygous splicing variant c.5609-4G>A associated with maternal UPD(2) was identified. These findings indicate that UPD poses a high risk of autosomal recessive diseases, and provides information on the variant spectrum for UNC80. Our findings elucidate on understanding of the genotype-phenotype associations that occur in IHPRF2 patients.
... Samples from 102 fetuses with negative CMA results were subsequently analyzed by WES. The fetuses were assessed at a median gestational age of 24 (range [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] weeks. The results of the Down syndrome maternal serum screening test or noninvasive prenatal screening test were recorded when available. ...
... WGS not only robustly detects SNVs but also performs well for the detection of CNVs and has the potential to detect SVs [15,32], specific repeat expansions [33,34], and noncoding variants [35,36]. There are possible reasons why the diagnostic rate (19.8%) in this study was lower than that (22% or 32%) in fetuses with structural anomalies in previous reports [11,15], specifically, the prenatal detection rate for P/LP CNVs (2.7%) in our study was significantly lower than those in previous large-scale studies (4.3%-8.2%) ...
Whole genome sequencing (WGS) is a powerful tool for postnatal genetic diagnosis, but relevant clinical studies in the field of prenatal diagnosis are limited. The present study aimed to prospectively evaluate the utility of WGS compared with chromosomal microarray (CMA) and whole exome sequencing (WES) in the prenatal diagnosis of fetal structural anomalies. We performed trio WGS (≈40-fold) in parallel with CMA in 111 fetuses with structural or growth anomalies, and sequentially performed WES when CMA was negative (CMA plus WES). In comparison, WGS not only detected all pathogenic genetic variants in 22 diagnosed cases identified by CMA plus WES, yielding a diagnostic rate of 19.8% (22/110), but also provided additional and clinically significant information, including a case of balanced translocations and a case of intrauterine infection, which might not be detectable by CMA or WES. WGS also required less DNA (100 ng) as input and could provide a rapid turnaround time (TAT, 18 ± 6 days) compared with that (31 ± 8 days) of the CMA plus WES. Our results showed that WGS provided more comprehensive and precise genetic information with a rapid TAT and less DNA required than CMA plus WES, which enables it as an alternative prenatal diagnosis test for fetal structural anomalies.
... While UPD is a rare event [15,16], in particular paternity cases, it might complicate the interpretation of paternity index (PI) statistics. This phenomenon might affect any chromosome [17][18][19], and in the worst-case scenario may lead to false exclusion of kinship. Thus, in paternity cases, more attention should be paid when loci that do not conform to Mendelian inheritance rules are restricted to a single region or chromosome. ...
DNA testing in cases of disputed paternity is a routine analysis carried out in genetic laboratories. The purpose of the test is to demonstrate similarities and differences in analyzed genetic markers between the alleged father, mother, and a child. The existence of differences in the examined loci between the child and the presumed father may indicate the exclusion of biological parenthood. However, another reason for such differences is genetic mutations, including chromosome aberrations and genome mutations. The presented results relate to genetic analyses carried out on three persons for the purposes of disputed paternity testing. A deviation from inheritance based on Mendel’s Law was found in 7 out of 53 STR-type loci examined. All polymorphic loci that ruled out the paternity of the alleged father were located on chromosome 2. Additional analysis of 32 insertion–deletion markers (DIPplex, Qiagen) and sequencing of 94 polymorphic positions of the single nucleotide polymorphism (SNP) type (Illumina, ForenSeq) did not exclude the defendant’s biological paternity. A sequence analysis of STR alleles and their flanking regions confirmed the hypothesis that the alleles on chromosome 2 of the child may originate only from the mother. The results of the tests did not allow exclusion of the paternity of the alleged father, but are an example of uniparental maternal disomy, which is briefly described in the literature.
... This platform can analyze 690,000 markers of each sample [18]. After the base quality score recalibration and insertion-deletion realignment were conducted with Genome Analysis Toolkit (GATK) [20], we used Burrows-Wheeler Alignment (BWA) [21] to compare the results with the hg19 reference genome. Variant quality score recalibration was used for genotyping [22]. ...
... UPD can occur on any chromosome according to the reports of last four decades [20,27,28]. The recognized mechanisms of UPD include gamete complementation, trisomic or monosomic self-rescue, monomer replication, mitotic abnormality, etc. [4], though the specific mechanism of UPD has not been fully understood so far. ...
Uniparental disomy (UPD) has attracted more attention recently in paternity testing, though it is an infrequent genetic event. Although short tandem repeat (STR) profiling has been widely used in paternity testing, it is not sufficient to use STR only to judge the genetic relationship, because the existence of UPD will inevitably affect the results of genotyping. Compared with complete UPD, segmental UPD is more difficult to detect because it does not affect all genotypes on the same chromosome. It is necessary to determine the type of UPD with multiple methods because a single method is not sufficient. Therefore, it is advisable to detect UPD in paternity testing with multiple methods. In this study, after autosomal STR profiling was used, we found that there were several gene loci on the same chromosome that did not conform to Mendelian genetic law, thus we highly suspected the existence of UPD and performed X-STR profiling immediately. Then whole-genome single nucleotide polymorphism (SNP) array analysis was performed to identify the type, and the results provided straightforward evidence for distinguishing complete from segmental UPD. Lastly, we used deletion insertion polymorphism (DIP)-SNP SNaPshot assay and Miseq FGx sequencing (for SNP and STR) to determine whether the mutation source is maternal uniparental disomy (mUPD) or paternal uniparental disomy (pUPD). To avoid false exclusion of kinship, it is vital to determine the type of UPD in paternity testing and effective strategies based on multiple methods to detect the type of UPD are provided in this study.
... This patient had additional features including spastic paraplegia, fatty liver, and developmental delay, while both his father and mother were phenotypically normal. Though the patient carried a large stretch of UPD on chromosome 2p22-2q37, complete UPD of chromosome 2 can be tolerated (Ou et al., 2013;Zhang et al., 2019). ...
Jalili syndrome is a rare multisystem disorder with the most prominent features consisting of cone‐rod dystrophy and amelogenesis imperfecta. Few cases have been reported in the Americas. Here we describe a case series of patients with Jalili syndrome examined at the National Eye Institute's Ophthalmic Genetics clinic between 2016 and 2018. Three unrelated sporadic cases were systematically evaluated for ocular phenotype and determined to have cone‐rod dystrophy with bull's eye maculopathy, photophobia, and nystagmus. All patients had amelogenesis imperfecta. Two of these patients had Guatemalan ancestry and the same novel homozygous CNNM4 variant (p.Arg236Trp c.706C > T) without evidence of consanguinity. This variant met likely pathogenic criteria by the American College of Medical Genetics guidelines. An additional patient had a homozygous deleterious variant in CNNM4 (c.279delC p.Phe93Leufs*31), which resulted from paternal uniparental isodisomy for chromosome 2p22‐2q37. This individual had additional syndromic features including developmental delay and spastic diplegia, likely related to mutations at other loci. Our work highlights the genotypic variability of Jalili syndrome and expands the genotypic spectrum of this condition by describing the first series of patients seen in the United States.
