Prenatal Detection of Uniparental Disomies (UPD): Intended and Incidental Finding in the Era of Next Generation Genomics

Eggermann, Thomas

doi:10.3390/genes11121454

Cited by 31 publications

(24 citation statements)

References 43 publications

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“…Upd can arise as meiotic or mitotic errors [ 25 , 26 ]. In our probands, somatic mosaicism and isodisomy suggest post-fertilization errors that might derive from mitotic nondisjunction followed by trisomic rescue in the case of complete upd or mitotic recombination between non-sister chromatids in the case of segmental upd.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, loss of one of the supernumerary chromosomes is a prerequisite for the survival of trisomic embryos. In one-third of these cases, the homolog that is present in single copy is lost, thus giving rise to a upd [ 25 ]. It is plausible that the chromosome that is lost is the maternal or paternal one by chance, determining mosaic complete maternal or paternal UPiD 11 with the same probability.…”

Section: Discussionmentioning

confidence: 99%

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Mosaic Segmental and Whole-Chromosome Upd(11)mat in Silver-Russell Syndrome

Pignata

Sparago

Palumbo

et al. 2021

Genes

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Molecular defects altering the expression of the imprinted genes of the 11p15.5 cluster are responsible for the etiology of two congenital disorders characterized by opposite growth disturbances, Silver–Russell syndrome (SRS), associated with growth restriction, and Beckwith–Wiedemann syndrome (BWS), associated with overgrowth. At the molecular level, SRS and BWS are characterized by defects of opposite sign, including loss (LoM) or gain (GoM) of methylation at the H19/IGF2:intergenic differentially methylated region (H19/IGF2:IG-DMR), maternal or paternal duplication (dup) of 11p15.5, maternal (mat) or paternal (pat) uniparental disomy (upd), and gain or loss of function mutations of CDKN1C. However, while upd(11)pat is found in 20% of BWS cases and in the majority of them it is segmental, upd(11)mat is extremely rare, being reported in only two SRS cases to date, and in both of them is extended to the whole chromosome. Here, we report on two novel cases of mosaic upd(11)mat with SRS phenotype. The upd is mosaic and isodisomic in both cases but covers the entire chromosome in one case and is restricted to 11p14.1-pter in the other case. The segmental upd(11)mat adds further to the list of molecular defects of opposite sign in SRS and BWS, making these two imprinting disorders even more specular than previously described.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mosaic Segmental and Whole-Chromosome Upd(11)mat in Silver-Russell Syndrome

Pignata

Sparago

Palumbo

et al. 2021

Genes

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“…Chromosomal microarray can detect clinically relevant submicroscopic copy number variants and may change surveillance and decision making in the affected pregnancy [ 23 , 24 , 25 ]. Furthermore, single nucleotide polymorphism (SNP)-based arrays also allow the detection of triploidy and uniparental disomy [ 26 ]. The additional diagnostic yield is dependent on the indication for testing.…”

Section: Introduction and Overviewmentioning

confidence: 99%

Chances and Challenges of New Genetic Screening Technologies (NIPT) in Prenatal Medicine from a Clinical Perspective: A Narrative Review

Bedei

Wolter

Weber

et al. 2021

Genes

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In 1959, 63 years after the death of John Langdon Down, Jérôme Lejeune discovered trisomy 21 as the genetic reason for Down syndrome. Screening for Down syndrome has been applied since the 1960s by using maternal age as the risk parameter. Since then, several advances have been made. First trimester screening, combining maternal age, maternal serum parameters and ultrasound findings, emerged in the 1990s with a detection rate (DR) of around 90–95% and a false positive rate (FPR) of around 5%, also looking for trisomy 13 and 18. With the development of high-resolution ultrasound, around 50% of fetal anomalies are now detected in the first trimester. Non-invasive prenatal testing (NIPT) for trisomy 21, 13 and 18 is a highly efficient screening method and has been applied as a first-line or a contingent screening approach all over the world since 2012, in some countries without a systematic screening program. Concomitant with the rise in technology, the possibility of screening for other genetic conditions by analysis of cfDNA, such as sex chromosome anomalies (SCAs), rare autosomal anomalies (RATs) and microdeletions and duplications, is offered by different providers to an often not preselected population of pregnant women. Most of the research in the field is done by commercial providers, and some of the tests are on the market without validated data on test performance. This raises difficulties in the counseling process and makes it nearly impossible to obtain informed consent. In parallel with the advent of new screening technologies, an expansion of diagnostic methods has begun to be applied after invasive procedures. The karyotype has been the gold standard for decades. Chromosomal microarrays (CMAs) able to detect deletions and duplications on a submicroscopic level have replaced the conventional karyotyping in many countries. Sequencing methods such as whole exome sequencing (WES) and whole genome sequencing (WGS) tremendously amplify the diagnostic yield in fetuses with ultrasound anomalies.

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“…UPD is rare in health populations. In fact, it could become a pathogenic event, when UPD involves imprinted chromosomal region or gene (chromosomes 6, 7, 11, 14, 15, or 20) (Eggermann, 2020), or results in the homozygosity of recessive mutation (Yamazawa et al, 2010). This occurs as a consequence of isodisomy, when one of the parents is a carrier for recessive disorder (Yamazawa et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Case Report: A Case of Epileptic Disorder Associated With a Novel CNTN2 Frameshift Variant in Homozygosity due to Maternal Uniparental Disomy

Chen

Shen

et al. 2021

Front. Genet.

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Background: Contactin 2, encoded by CNTN2 on chromosome 1q32.1, is a neural-specific glycoprotein and plays important roles in neurodevelopment. A deleterious homozygous variant in the CNTN2 gene was previously reported to cause autosomal recessive cortical myoclonic tremor and epilepsy. Since then, there has been no further report confirming the association of CNTN2 and epilepsy. Here, we reported one new case, who presented with epilepsy, carrying a novel homozygous frameshift variant in CNTN2. The clinical and genetic features of the patient were reviewed.Case presentation: The male patient presented with preschool age-of-onset neurodevelopmental impairment and focal seizures of temporal origin, and responded to valproate. A trio-whole exome sequencing revealed a novel homozygous frameshift variant in CNTN2 (c.2873_c.2874delCT, p.Thr958Thrfs). The patient’s mother was a heterozygous carrier while his father was wild-type; they were both unaffected and non-consanguineous. Further study revealed that maternal uniparental disomy (1q32.1) unmasked the heterozygous variant of CNTN2 in the proband.Conclusions: This case enhanced the gene–disease relationship between CNTN2 and epilepsy, which will help to further understand this emerging disorder.

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Prenatal Detection of Uniparental Disomies (UPD): Intended and Incidental Finding in the Era of Next Generation Genomics

Cited by 31 publications

References 43 publications

Mosaic Segmental and Whole-Chromosome Upd(11)mat in Silver-Russell Syndrome

Mosaic Segmental and Whole-Chromosome Upd(11)mat in Silver-Russell Syndrome

Chances and Challenges of New Genetic Screening Technologies (NIPT) in Prenatal Medicine from a Clinical Perspective: A Narrative Review

Case Report: A Case of Epileptic Disorder Associated With a Novel CNTN2 Frameshift Variant in Homozygosity due to Maternal Uniparental Disomy

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