Paternal UPD14 with sSMC derived from chromosome 14 in Kagami-Ogata syndrome

doi:10.21203/rs.3.rs-2251362/v1

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Paternal UPD14 with sSMC derived from chromosome 14 in Kagami-Ogata syndrome

https://doi.org/10.21203/rs.3.rs-2251362/v1

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published 19 Jan, 2023

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Uniparental disomy (UPD) has been associated with several well-characterized disorders due to abnormal imprinting of the underlying genes. Depending on the parent-of-origin, paternal and maternal UPD are frequently associated with clinically distinct imprinting disorders. Here we report a neonatal case that was referred to Greenwood Genetic Center for clinical genetic testing. Prenatal ultrasound identified polyhydramnios and congenital cardiac anomalies and neonatal examination revealed a prune-like belly and bowel obstruction. Taking advantage of a variety of cytogenetic and molecular genetic approaches, we identified the presence of a small supernumerary marker chromosome (sSMC) associated with a complex chromosomal rearrangement derived from 14q11.2 and absence of heterozygosity on the chromosome 14q, indicative of uniparental isodisomy for chromosome 14. In addition, microsatellite DNA analysis of chromosome 14 showed UPD14 in this patient is paternal in origin, which is consistent with a clinical diagnosis of Kagami-Ogata syndrome (KOS). To our knowledge, this is the first case report of KOS resulting from paternal UPD14 and presence of sSMC with complex chromosomal rearrangement involving 14q11.2 without evidence of mosaicism.

genomic imprinting

paternal uniparental disomy 14

small supernumerary marker chromosome

Kagami-Ogata syndrome

trisomy rescue

Genomic imprinting refers to an epigenetic phenomenon that leads to expression of certain genes in a parent-of-origin dependent manner. Altered gene imprinting has been associated with several well-described disorders, i.e., Beckwith–Wiedemann and Russell-Silver syndromes associated with chromosome 11p15 and Prader-Willi and Angelman syndromes associated with chromosome 15q11-q13 (Barlow and Bartolomei, 2014; Butler, 2009; Horsthemke and Buiting, 2008; Monk et al., 2019; Tucci et al., 2019). In humans, over 100 imprinting genes have been discovered in the past few decades (Baran et al., 2015; Court et al., 2014). There is increasing evidence that a variety of imprinting genes are highly expressed in the human placenta and play vital roles in embryogenesis (Hanna et al., 2016; Peters, 2014; Plasschaert and Bartolomei, 2014; Sanchez-Delgado et al., 2016; Smith et al., 2014; Tucci et al., 2019).

The molecular mechanisms underlying imprinting disorders include pathogenic genetic/epigenetic alterations of imprinted genes, copy number variants in the critical regions, and uniparental disomy (UPD)(Baran et al., 2015; Barlow and Bartolomei, 2014; Butler, 2009; Horsthemke and Buiting, 2008). Paternal and maternal UPD are frequently associated with clinically distinctive imprinting disorders. For instance, maternal UPD14 is associated with Temple syndrome (TS), whereas paternal UPD14 is associated with Kagami-Ogata syndrome (KOS)(Kagami et al., 2017; Ogata and Kagami, 2016; Prasasya et al., 2020). The common clinical features observed in patients with KOS and TS include feeding problems, short stature, growth retardation, hypotonia, developmental delay, intellectual disability, dysmorphic facial features, and kyphoscoliosis. Apart from the shared clinical features of these syndromes, oligohydramnios is present in the prenatal cases with TS while polyhydramnios occurs in the prenatal KOS cases. In addition, small bell-shaped thorax, cardiac defects, and abdominal wall defects are frequently observed in KOS but uncommon in TS (Ioannides et al., 2014; Kagami et al., 2015; Prasasya et al., 2020).

Interestingly, small supernumerary maker chromosomes (sSMCs) have been observed in a subset of cases with UPD. An sSMC is a structurally abnormal chromosome that is generally equal to or smaller than chromosome 20 in size and is generally unidentifiable by banding pattern alone. As the genomic content of sSMCs is variable, clinical phenotypes in patients with sSMCs are highly variable, ranging from clinically normal to severely affected (Liehr et al., 2011). To date, cases with either UPD or sSMC have been reported involving all of the autosomes and sex chromosomes; however, reports of cases with both UPD and sSMC are relatively rare(Liehr T. 2022). Liehr et al. (2011) reported 46 UPD + sSMC cases, among which, three cases involved maternal UPD14 + sSMC whereas only one case involved paternal UPD14 + sSMC (Liehr et al., 2011). To date, the vast majority of the patients with UPD14 and sSMC have been reported in association with TS resulting from maternal UPD14. Cases with paternal UPD14 and sSMC derived from chromosome 14 are rare.

In this study, we report a neonatal case with clinical features consistent with KOS. By utilizing cytogenetic and molecular techniques, we determined this patient is a carrier of both paternal UPD14 and an sSMC derived from chromosome 14. To our knowledge, this is the first case report of KOS resulting from paternal UPD14 and presence of sSMC with complex chromosomal rearrangement and no evidence of mosaicism.

The patient was initially referred to Greenwood Genetic Center for clinical genetic testing. She was born to a 42 year old G7 P1 Ab6 (spontaneous) female at 32 weeks gestation by Cesarean section because of worsening hypertension and poor fetal movements. The pregnancy was complicated by gestational diabetes requiring insulin and significant polyhydramnios. At birth, all growth parameters were normal with birth weight at 11–25 percentile, head circumference at 51–75 percentile, and height at 4–10 percentile. She was noted to have mild retrognathia, a bell-shaped chest with unusual appearing ribs, prune belly appearance to the abdomen, and significant hypotonia. The baby had no spontaneous movement breathing efforts at birth so she required intubation. She was weened to oxygen by nasal cannula and followed by a thoracic insufficiency team at another institution since hospital discharge. Since significant gastroesophageal reflux was present, a jejunostomy tube was placed for nutrition. During the initial hospitalization, the baby was noted to have several abdominal wall hernias that have required surgical repair. At chronologic age of 8 months, the baby was noted to have developmental delay in all domains for chronologic age and adjusted age. She is receiving appropriate therapies now.

G-banded chromosome analysis was initially performed and identified a small supernumerary marker chromosome (sSMC). The ISCN designation for the karyotype at this time was reported as 47,XX,+mar (Fig. 1A). To determine the chromosomal origin of the sSMC in this patient, centromeric heterochromatin staining (C-banding) was performed. The sSMC was C-band positive with limited light staining, indicating that it is mainly heterochromatic in origin (Fig. 1B). Concurrent chromosomal microarray analysis (CMA) using the Affymetrix CytoScan HD Microarray system showed complex copy number gains in the 14q11.2 region (chr14:20,511,672 − 21,560,602) consisting of a duplication followed by a region with a copy number state of approximately 3–6 (Fig. 2A), suggesting that the sSMC is composed of chromosomal material most likely derived from 14q11.2 resulting from a complex chromosome rearrangement. As shown in Fig. 2B, there are 57 genes in this interval, of which four have known genotype-phenotype associations in the Online Mendelian Inheritance in Man (OMIM; Supplemental Table 1). However, copy number gains of these genes have not been reported in association with any clinical phenotype as yet. In addition, the CMA results also showed absence of heterozygosity (AOH) on the q arm of chromosome 14, indicative of UPD14 (Fig. 3A). As UPD14 is associated with two clinically distinctive syndromes, TS and KOS, depending on the parent of origin, we performed microsatellite analysis of chromosome 14 and the results showed that nine fully informative microsatellite markers spanning the q arm of chromosome 14 confirm paternal isodisomy (iD) of chromosome 14 in this individual (Fig. 3B; Supplemental Table 2). Taken together, these results are consistent with the clinical diagnosis of KOS resulting from paternal UPiD14 and indicate that the sSMC is most likely derived from chromosome 14.

To date, the vast majority of the patients with UPD14 and sSMC have been reported in association with TS resulting from maternal UPD14. Cases with paternal UPD14 and sSMC derived from chromosome 14 are very limited. In this study, we illustrate the clinical features in a patient with paternal UPD14 and sSMC and demonstrate the mechanism underlying this condition for this patient utilizing cytogenetic and molecular techniques. This study not only provides comprehensive prenatal and postnatal clinical features associated with paternal UPD14 and sSMC but also raises the possibility that genes in the copy number gain region may contribute to some clinical characteristics that have not been discovered as yet.

KOS is a rare imprinting disorder characterized by dysmorphic facial features, small bell-shaped thorax, abdominal wall defects, congenital heart defects, and polyhydramnios prenatally. It is caused by abnormal epigenetic regulation in the differentially methylated region (DMR) at 14q32.2, resulting in alteration of gene expression in a parent-of-origin specific manner. The common mechanisms include paternal UPD14 involving 14q32.2, hypermethylation, and microdeletion of the maternally expressed genes. Here we report an infant with prenatal polyhydramnios, congenital heart defects, and small bell-shaped thorax. Taking advantage of cytogenetic and molecular genetic techniques, we characterize the underlying genetic cause of the clinical features observed in this individual leading to a clinical diagnosis of KOS as the result of paternal UPiD14.

In addition, we observed the presence of an sSMC in each cell examined which is most likely derived from 14q11.2 with complex chromosome rearrangement as indicated by the CMA results, although we cannot rule out the possibility of the presence of genomic material derived from other chromosomes or other regions of chromosome 14 on this marker chromosome. Interestingly, there are numerous evidences revealing that somatic mosaicism is not uncommon in individuals with sSMCs derived from various chromosomes (Kurtas et al., 2019; Liehr et al., 2011; Liehr et al., 2010; Liehr and Kosyakova, 2013; Ou et al., 2013; Recalcati et al., 2018; Rodriguez et al., 2007; Shao et al., 2020). In particular, mosaicism is more frequent in non-acrocentric-derived sSMCs. However, in our patient, we observed the presence of an sSMC in all 30 metaphase cells counted. To our knowledge, there are only two cases that have been reported with paternal UPD14 and sSMC as summarized in Table 1. First, an infant with a mosaic sSMC and paternal UPD14 has been reported (Mattes et al., 2007). Chromosome and FISH analyses demonstrated that the marker chromosome was bisatellited and composed entirely of heterochromatic material from chromosome 14. In addition, Li et al. reported a fetus with an sSMC and paternal UPD14 as determined by chromosome and CMA analyses. No copy number variations were detected in this fetus, indicating that the sSMC is likely to be centric minute-shaped or mainly heterochromatic with few euchromatic regions that are under the limit of detection for CMA with the chromosomal origin remaining unknown (Li et al., 2017). In contrast to the two reported cases, our case also harbors complex CNVs proximal to the centromeric region of chromosome 14, suggesting that complex chromosome rearrangement occurred involving chromosome 14. This is reminiscent of chromothripsis, the phenomenon of catastrophic structural alterations involving one or more chromosomes in cancer genome and in the germline (Kloosterman et al., 2011; Liu et al., 2011; Stephens et al., 2011). Chromothripsis occurs in micronuclei, the aberrant nuclear structures where one or more chromosomes are fragmented and resembled. As trisomy rescue is one of the well-known mechanisms underlying sSMC, it has been proposed that chromothripsis-mediated partial trisomy rescue results in formation of sSMC with massive chromosome rearrangements and loss of other chromosomal material (Al-Rikabi et al., 2018; Crasta et al., 2012; Kurtas et al., 2019; Matsubara et al., 2020; Zhang et al., 2015). Additionally, several different mechanisms of co-occurrence of UPiD and an sSMC has been proposed as well (Kotzot, 2002; Liehr et al., 2011). The most straightforward mechanism is that due to an error in meiosis II: sister chromatids of one chromosome in a gamete are not separated normally resulting in trisomy after fertilization with a normal gamete, which subsequently triggers trisomy rescue that partially eliminates the extra chromosome leading to co-occurrence of UPiD and an sSMC (Kotzot, 2002; Liehr et al., 2011).

As reports with paternal UPiD14 and sSMC are extremely rare, it is hard to determine the contribution of sSMCs to the clinical features of each case in addition to those observed in individuals with classic KOS. Thus, further characterization of dosage sensitivity of the genes that are present on sSMCs could provide more insight into variability of clinical findings in individuals with paternal UPD14 and sSMC.

G-banding and C-banding chromosome analysis

The specimen was cultured and harvested as per standard laboratory procedures. G-banding and C-banding were performed on metaphase spreads (The AGT Cytogenetics Laboratory Manual, 3rd ed., 1997). The karyotyping of metaphases was performed using the Leica CytoVysion system (Leica IL, USA).

Chromosomal microarray analysis

The isolated DNA was analyzed using the Affymetrix CytoScan HD Microarray system. This platform consists of 2.67 million markers (comprised of ~1.9 million non-polymorphic copy number and ~750,000 single nucleotide polymorphism (SNP) probes) at an average spacing of 1 probe every 800 bp throughout the entire human genome. This test compares the patient sample to control samples from the HapMap set of 270 individuals. The Affymetrix CytoScan HD microarray is a diagnostic assay used by the Greenwood Genetic Center for the identification of genomic copy number variations and loss of heterozygosity regions. Chromosome Analysis Suite (ChAS) software has been utilized for the analysis of this microarray. SNP genotyping on this platform has the enhanced ability to identify long contiguous stretches of homozygosity (LCSH) and uniparental disomy. All copy number changes were determined using the human genome build 19 (hg19/NCBI build 37).

STR analysis for UPD14

Genomic DNA from this individual and peripheral blood samples from the parents, were received for analysis. DNA was isolated from peripheral blood samples by routine laboratory procedures and all three samples were subjected to polymerase chain reaction (PCR) analysis of several short tandem repeat loci along the q arm of chromosome 14. At each of the fully informative loci, the individual had two alleles that were identical to both of the father's alleles and no alleles that matched the mother's alleles. The results from the fully informative loci indicate paternal uniparental disomy of chromosome 14. Primer sequences used in this analysis were indicated in Supplemental Table 2.

UPD14 uniparental disomy 14

sSMC small supernumerary marker chromosome

KOS Kagami-Ogata syndrome

AOH absence of heterozygosity

CMA chromosomal microarray

Ethical Approval: This research study was conducted retrospectively from data obtained for clinical purposes. We consulted with the institutional review board of Self Regional Medical Center/Greenwood Genetic Center who determined that our study did not need ethical approval.

Consent to Participate and Publish: The sample was deidentified prior to performing this study and patient pictures have not been included in this study; therefore, no consent was obtained or required per the institutional review board. This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki.

Author Contributions: JW and BAH conceived and designed research. JJ, CC, and KH conducted experiments. JW, MAM, BH, JAL, BD, and BAH analyzed data. JW and BAH wrote the manuscript. All authors read and approved the manuscript.

Funding: No funds, grants, or other support was received for conducting this study.

Competing Interests: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. The authors are all employed at the Greenwood Genetic Center.

Availability of Data and Materials: All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Table 1 is available in the Supplementary Files section.

No competing interests reported.

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You are reading this latest preprint version

Paternal UPD14 with sSMC derived from chromosome 14 in Kagami-Ogata syndrome

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