Publications by authors named "Matthias Begemann"

59 Publications

C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation.

J Clin Invest 2021 May 4. Epub 2021 May 4.

Department of Pediatrics, RWTH Aachen University, Aachen, Germany.

Background: Deciphering the function of the many genes previously classified as uncharacterized "open reading frame" (orf) completes our understanding of cell function and its pathophysiology.

Methods: Whole-exome sequencing, yeast 2-hybrid and transcriptome analyses together with molecular characterization are used here to uncover the function of the C2orf69 gene.

Results: We identified loss-of-function mutations in the uncharacterized C2orf69 gene in eight individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial localization. Consistent with mitochondrial dysfunction, patients showed signs of respiratory chain defect and a CRISPR-Cas9 knockout cell model of C2orf69 had similar respiratory chain defects. Patient-derived cells revealed alterations in immunological signaling pathways. Deposits of PAS-positive material in tissues from affected individuals together with decreased glycogen branching enzyme 1 (GBE1) activity indicated an additional impact of C2orf69 on glycogen metabolism.

Conclusions: Our study identifies C2orf69 as an important regulator of human mitochondrial function and suggests an additional influence on other metabolic pathways.
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http://dx.doi.org/10.1172/JCI143078DOI Listing
May 2021

Unusual deletion of the maternal 11p15 allele in Beckwith-Wiedemann syndrome with an impact on both imprinting domains.

Clin Epigenetics 2021 Feb 4;13(1):30. Epub 2021 Feb 4.

MVZ Medicover Humangenetik Berlin Lichtenberg, Berlin, Germany.

Background: Whereas duplications in 11p15.5 covering both imprinting centers (ICs) and their subordinated genes account for up to 1% of Beckwith-Wiedemann and Silver-Russell syndrome patients (BWS, SRS), the deletions in 11p15.5 reported so far only affect one of the ICs. In these cases, not only the size and gene content had an impact on the phenotype, but also the sex of the contributing parent influences the clinical signs of the deletion carrier.

Results: We here report on the first case with a heterozygous deletion within the maternal allele affecting genes which are regulated by both ICs in 11p15.5 in a BWS patient, and describe the molecular and clinical consequences in case of its maternal or paternal inheritance.

Conclusions: The identification of a unique deletion affecting both 11p15.5 imprinting domains in a BWS patient illustrates the complexity of the regulation mechanisms in these key imprinting regions.
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http://dx.doi.org/10.1186/s13148-021-01020-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863277PMC
February 2021

One test for all: whole exome sequencing significantly improves the diagnostic yield in growth retarded patients referred for molecular testing for Silver-Russell syndrome.

Orphanet J Rare Dis 2021 01 22;16(1):42. Epub 2021 Jan 22.

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.

Background: Silver-Russell syndrome (SRS) is an imprinting disorder which is characterised by severe primordial growth retardation, relative macrocephaly and a typical facial gestalt. The clinical heterogeneity of SRS is reflected by a broad spectrum of molecular changes with hypomethylation in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat) as the most frequent findings. Monogenetic causes are rare, but a clinical overlap with numerous other disorders has been reported. However, a comprehensive overview on the contribution of mutations in differential diagnostic genes to phenotypes reminiscent to SRS is missing due to the lack of appropriate tests. With the implementation of next generation sequencing (NGS) tools this limitation can now be circumvented.

Main Body: We analysed 75 patients referred for molecular testing for SRS by a NGS-based multigene panel, whole exome sequencing (WES), and trio-based WES. In 21/75 patients a disease-causing variant could be identified among them variants in known SRS genes (IGF2, PLAG1, HMGA2). Several patients carried variants in genes which have not yet been considered as differential diagnoses of SRS.

Conclusions: WES approaches significantly increase the diagnostic yield in patients referred for SRS testing. Several of the identified monogenetic disorders have a major impact on clinical management and genetic counseling.
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http://dx.doi.org/10.1186/s13023-021-01683-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821667PMC
January 2021

Biallelic PADI6 variants cause multilocus imprinting disturbances and miscarriages in the same family.

Eur J Hum Genet 2021 Apr 21;29(4):575-580. Epub 2020 Nov 21.

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.

The term multilocus imprinting disturbance (MLID) describes the aberrant methylation of multiple imprinted loci in the genome, and MLID occurs in patients suffering from imprinting disorder carrying methylation defects. First data indicate that functional variants in factors expressed from both the fetal as well as the maternal genome cause MLID. Molecular changes in such genes of the maternal genome are called maternal effect variants, they affect members of the subcortical maternal complex (SCMC) in the oocyte which plays an important role during early embryonic development. Whereas the contribution of variants in the SCMC genes NLRP2, NLRP5, NLRP7, and KHDC3L to the etiology of reproductive failure and aberrant imprinting is widely accepted, the involvement of PADI6 variants in the formation of MLID is in discussion. We now report on the identification of biallelic variants in a woman suffering from different miscarriages and giving birth to two children with MLID. Thereby the role of PADI6 in maintaining the proper imprinting status during early development is confirmed. Thus, PADI6 variants do not only cause (early) pregnancy losses, but maternal effect variants in this gene cause the same spectrum of pregnancy outcomes as variants in other SCMC encoding genes, including chromosomal aberrations and disturbed imprinting. The identification of maternal effect variants requires genetic and reproductive counseling as carriers of these variants are at high risks for reproductive failure.
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http://dx.doi.org/10.1038/s41431-020-00762-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115525PMC
April 2021

Molecular characterization of temple syndrome families with 14q32 epimutations.

Eur J Med Genet 2020 Dec 30;63(12):104077. Epub 2020 Sep 30.

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany. Electronic address:

Temple Syndrome (TS14) is an imprinting disorder caused by molecular disruptions of the imprinted region in 14q32 (MEG3:TSS-DMR). The frequency of the three known TS14 subtypes (deletions, maternal uniparental disomy (upd(14)mat), loss of methylation (LOM)) is currently in discussion, and within the LOM group, the occurrence of Multilocus Imprinting Disturbances (MLID) has been identified. We present 16 TS14 patients with molecular alterations affecting the MEG3:TSS-DMR, comprising seven patients (43.8%) with LOM, six carriers with upd(14)mat (37.5%), and three cases (18.8%) with a deletion affecting the paternal MEG3:TSS-DMR. We did not find any evidence for MLID in the LOM group, including two cases in which different tissues were available. Whole exome sequencing (WES) in the MEG3:TSS-DMR LOM patients and their parents (Trio WES) did not reveal an obvious pathogenic variant which might cause aberrant methylation at imprinted loci. By summarizing our data with those from the literature, we could show that MLID affecting clinically relevant imprinted loci is rare in TS14 and therefore differs markedly from other imprinting disorders associated with MLID, e.g. Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS). However, consistent with the clinical overlap with TS14, in SRS patients carrying MLID the MEG3:TSS-DMR is frequently affected. Variants in the known candidate genes for maternal effect variants causing MLID and fetal MLID determinants could not be identified in TS14 patients. Thus, 14q32 epimutations probably have other molecular causes than epimutations in BWS or SRS patients.
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http://dx.doi.org/10.1016/j.ejmg.2020.104077DOI Listing
December 2020

Need for a precise molecular diagnosis in Beckwith-Wiedemann and Silver-Russell syndrome: what has to be considered and why it is important.

J Mol Med (Berl) 2020 10 24;98(10):1447-1455. Epub 2020 Aug 24.

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, D-52074, Aachen, Germany.

Molecular diagnostic testing of the 11p15.5-associated imprinting disorders Silver-Russell and Beckwith-Wiedemann syndrome (SRS, BWS) is challenging due to the broad spectrum of molecular defects and their mosaic occurrence. Additionally, the decision on the molecular testing algorithm is hindered by their clinical heterogeneity. However, the precise identification of the type of defect is often a prerequisite for the clinical management and genetic counselling. Four major molecular alterations (epimutations, uniparental disomies, copy number variants, single nucleotide variants) have been identified, but their frequencies vary between SRS and BWS. Due to their molecular aetiology, epimutations in both disorders as well as upd(11)pat in BWS are particular prone to mosaicism which might additionally complicate the interpretation of testing results. We report on our experience of molecular analysis in a total cohort of 1448 patients referred for diagnostic testing of BWS and SRS, comprising a dataset from 737 new patients and from 711 cases from a recent study. Though the majority of positively tested patients showed the expected molecular results, we identified a considerable number of clinically unexpected molecular alterations as well as not yet reported changes and discrepant mosaic distributions. Additionally, the rate of multilocus imprinting disturbances among the patients with epimutations and uniparental diploidies could be further specified. Altogether, these cases show that comprehensive testing strategies have to be applied in diagnostic testing of SRS and BWS. The precise molecular diagnosis is required as the basis for a targeted management (e.g. ECG (electrocardiogram) and tumour surveillance in BWS, growth treatment in SRS). The molecular diagnosis furthermore provides the basis for genetic counselling. However, it has to be considered that recurrence risk calculation is determined by the phenotypic consequences of each molecular alteration and mechanism by which the alteration arose. KEY MESSAGES: The detection rates for the typical molecular defects of Beckwith-Wiedemann syndrome or Silver-Russell syndrome (BWS, SRS) are lower in routine cohorts than in clinically well-characterised ones. A broad spectrum of (unexpected) molecular alterations in both disorders can be identified. Multilocus imprinting disturbances (MLID) are less frequent in SRS than expected. The frequency of MLID and uniparental diploidy in BWS is confirmed. Mosaicism is a diagnostic challenge in BWS and SRS. The precise determination of the molecular defects affecting is the basis for a targeted clinical management and genetic counselling.
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http://dx.doi.org/10.1007/s00109-020-01966-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524824PMC
October 2020

Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles.

Brain 2020 08;143(8):2406-2420

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.

The muscle specific isoform of the supervillin protein (SV2), encoded by the SVIL gene, is a large sarcolemmal myosin II- and F-actin-binding protein. Supervillin (SV2) binds and co-localizes with costameric dystrophin and binds nebulin, potentially attaching the sarcolemma to myofibrillar Z-lines. Despite its important role in muscle cell physiology suggested by various in vitro studies, there are so far no reports of any human disease caused by SVIL mutations. We here report four patients from two unrelated, consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. All patients showed increased levels of serum creatine kinase but no or minor muscle weakness. Mild cardiac manifestations were observed. Muscle biopsies showed complete loss of large supervillin isoforms in muscle fibres by western blot and immunohistochemical analyses. Light and electron microscopic investigations revealed a structural myopathy with numerous lobulated muscle fibres and considerable myofibrillar alterations with a coarse and irregular intermyofibrillar network. Autophagic vacuoles, as well as frequent and extensive deposits of lipoproteins, including immature lipofuscin, were observed. Several sarcolemma-associated proteins, including dystrophin and sarcoglycans, were partially mis-localized. The results demonstrate the importance of the supervillin (SV2) protein for the structural integrity of muscle fibres in humans and show that recessive loss-of-function mutations in SVIL cause a distinctive and novel myopathy.
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http://dx.doi.org/10.1093/brain/awaa206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447519PMC
August 2020

Inherited cases of CNOT3-associated intellectual developmental disorder with speech delay, autism, and dysmorphic facies.

Clin Genet 2020 10 19;98(4):408-412. Epub 2020 Aug 19.

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.

De novo pathogenic variants in CNOT3 have recently been reported in a developmental delay disorder (intellectual developmental disorder with speech delay, autism, and dysmorphic facies [IDDSADF, OMIM: #618672]). The patients present with a variable degree of developmental delay and behavioral problems. To date, all reported disease-causing variants occurred de novo and no parent-child transmission was observed. We report for the first time autosomal dominant transmissions of the CNOT3-associated developmental disorder in two unrelated families. The clinical characteristics in our patients match the IDDSADF features reported so far and suggest substantial variability of the phenotype within the same family.
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http://dx.doi.org/10.1111/cge.13819DOI Listing
October 2020

HMGA2 Variants in Silver-Russell Syndrome: Homozygous and Heterozygous Occurrence.

J Clin Endocrinol Metab 2020 07;105(7)

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Context: Silver-Russell syndrome (SRS) is a clinical and molecular heterogeneous disorder associated with short stature, typical facial gestalt, and body asymmetry. Though molecular causes of SRS can be identified in a significant number of patients, about one-half of patients currently remain without a molecular diagnosis. However, determination of the molecular cause is required for a targeted treatment and genetic counselling.

Objective: The aim of this study was to corroborate the role of HMGA2 as an SRS-causing gene and reevaluate its mode of inheritance.

Design, Setting, Patients: Patients were part of an ongoing study aiming on SRS-causing genes. They were classified according to the Netchine-Harbison clinical scoring system, and DNA samples were investigated by whole exome sequencing. Common molecular causes of SRS were excluded before.

Results: Three novel pathogenic HMGA2 variants were identified in 5 patients from 3 SRS families, and fulfilling diagnostic criteria of SRS. For the first time, homozygosity for a variant in HMGA2 could be identified in a severely affected sibpair, whereas parents carrying heterozygous variants had a mild phenotype. Treatment with recombinant growth hormone led to a catch-up growth in 1 patient, whereas all others did not receive growth hormone and stayed small. One patient developed type 2 diabetes at age 30 years.

Conclusions: Identification of novel pathogenic variants confirms HMGA2 as an SRS-causing gene; thus, HMGA2 testing should be implemented in molecular SRS diagnostic workup. Furthermore, inheritance of HMGA2 is variable depending on the severity of the variant and its consequence for protein function.
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http://dx.doi.org/10.1210/clinem/dgaa273DOI Listing
July 2020

Frequency of KCNQ1 variants causing loss of methylation of Imprinting Centre 2 in Beckwith-Wiedemann syndrome.

Clin Epigenetics 2020 05 11;12(1):63. Epub 2020 May 11.

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.

Background: Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder caused by disturbances of the chromosomal region 11p15.5. The most frequent molecular finding in BWS is loss of methylation (LOM) of the Imprinting Centre 2 (IC2) region on the maternal allele, which is localised in intron 10 of the KCNQ1 gene. In rare cases, LOM of IC2 has been reported in families with KCNQ1 germline variants which additionally cause long-QT syndrome (LQTS). Thus, a functional link between disrupted KCNQ1 transcripts and altered IC2 methylation has been suggested, resulting in the co-occurrence of LQTS and BWS in case of maternal inheritance. Whereas these cases were identified by chance or in patients with abnormal electrocardiograms, a systematic screen for KCNQ1 variants in IC2 LOM carriers has not yet been performed.

Results: We analysed 52 BWS patients with IC2 LOM to determine the frequency of germline variants in KCNQ1 by MLPA and an amplicon-based next generation sequencing approach. We identified one patient with a splice site variant causing premature transcription termination of KCNQ1.

Conclusions: Our study strengthens the hypothesis that proper KCNQ1 transcription is required for the establishment of IC2 methylation, but that KCNQ1 variants cause IC2 LOM only in a small number of BWS patients.
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http://dx.doi.org/10.1186/s13148-020-00856-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216698PMC
May 2020

Disturbed genomic imprinting and its relevance for human reproduction: causes and clinical consequences.

Hum Reprod Update 2020 02;26(2):197-213

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Background: Human reproductive issues affecting fetal and maternal health are caused by numerous exogenous and endogenous factors, of which the latter undoubtedly include genetic changes. Pathogenic variants in either maternal or offspring DNA are associated with effects on the offspring including clinical disorders and nonviable outcomes. Conversely, both fetal and maternal factors can affect maternal health during pregnancy. Recently, it has become evident that mammalian reproduction is influenced by genomic imprinting, an epigenetic phenomenon that regulates the expression of genes according to their parent from whom they are inherited. About 1% of human genes are normally expressed from only the maternally or paternally inherited gene copy. Since numerous imprinted genes are involved in (embryonic) growth and development, disturbance of their balanced expression can adversely affect these processes.

Objective And Rationale: This review summarises current our understanding of genomic imprinting in relation to human ontogenesis and pregnancy and its relevance for reproductive medicine.

Search Methods: Literature databases (Pubmed, Medline) were thoroughly searched for the role of imprinting in human reproductive failure. In particular, the terms 'multilocus imprinting disturbances, SCMC, NLRP/NALP, imprinting and reproduction' were used in various combinations.

Outcomes: A range of molecular changes to specific groups of imprinted genes are associated with imprinting disorders, i.e. syndromes with recognisable clinical features including distinctive prenatal features. Whereas the majority of affected individuals exhibit alterations at single imprinted loci, some have multi-locus imprinting disturbances (MLID) with less predictable clinical features. Imprinting disturbances are also seen in some nonviable pregnancy outcomes, such as (recurrent) hydatidiform moles, which can therefore be regarded as a severe form of imprinting disorders. There is growing evidence that MLID can be caused by variants in the maternal genome altering the imprinting status of the oocyte and the embryo, i.e. maternal effect mutations. Pregnancies of women carrying maternal affect mutations can have different courses, ranging from miscarriages to birth of children with clinical features of various imprinting disorders.

Wider Implications: Increasing understanding of imprinting disturbances and their clinical consequences have significant impacts on diagnostics, counselling and management in the context of human reproduction. Defining criteria for identifying pregnancies complicated by imprinting disorders facilitates early diagnosis and personalised management of both the mother and offspring. Identifying the molecular lesions underlying imprinting disturbances (e.g. maternal effect mutations) allows targeted counselling of the family and focused medical care in further pregnancies.
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http://dx.doi.org/10.1093/humupd/dmz045DOI Listing
February 2020

A novel homozygous splice-site mutation in the SPTBN4 gene causes axonal neuropathy without intellectual disability.

Eur J Med Genet 2020 Apr 16;63(4):103826. Epub 2019 Dec 16.

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Mutations in spectrin beta non-erythrocytic 4 (SPTBN4) have been linked to congenital hypotonia, intellectual disability and motor neuropathy. Here we report on two siblings with a homozygous splice-site mutation in the SPTBN4 gene, lacking previously reported features of the disorder such as seizures, feeding difficulties, respiratory difficulties or profound intellectual disability. Our findings indicate that muscular hypotonia, myopathic facies with ptosis and axonal neuropathy can be the core clinical features in the SPTBN4 disorder and suggest that SPTBN4 mutation analysis should be considered in infants with marked axonal neuropathy.
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http://dx.doi.org/10.1016/j.ejmg.2019.103826DOI Listing
April 2020

Comparison of flow-FISH and MM-qPCR telomere length assessment techniques for the screening of telomeropathies.

Ann N Y Acad Sci 2020 04 24;1466(1):93-103. Epub 2019 Oct 24.

Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, University Hospital Aachen, Aachen, Germany.

Assessment of telomere length (TL) in peripheral blood leukocytes is part of the diagnostic algorithm applied to patients with acquired bone marrow failure syndromes (BMFSs) and dyskeratosis congenita (DKC). Monochrome multiplex-quantitative polymerase chain reaction (MM-qPCR) and fluorescence in situ hybridization (flow-FISH) are methodologies available for TL screening. Dependent on TL expressed in relation to percentiles of healthy controls, further genetic testing for inherited mutations in telomere maintenance genes is recommended. However, the correct threshold to trigger this genetic workup is still under debate. Here, we prospectively compared MM-qPCR and flow-FISH regarding their capacity for accurate identification of DKC patients. All patients (n = 105) underwent genetic testing by next-generation sequencing and in 16 patients, mutations in DKC-relevant genes were identified. Whole leukocyte TL of patients measured by MM-qPCR was found to be moderately correlated with lymphocyte TL measured by flow-FISH (r² = 0.34; P < 0.0001). The sensitivity of both methods was high, but the specificity of MM-qPCR (29%) was significantly lower compared with flow-FISH (58%). These results suggest that MM-qPCR of peripheral blood cells is inferior to flow-FISH for clinical routine screening for suspected DKC in adult patients with BMFS due to lower specificity and a higher rate of false-positive results.
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http://dx.doi.org/10.1111/nyas.14248DOI Listing
April 2020

Germline Mutations Predispose to Pediatric Medulloblastoma.

J Clin Oncol 2020 01 14;38(1):43-50. Epub 2019 Oct 14.

RWTH Aachen University, Aachen, Germany.

Purpose: The identification of a heritable tumor predisposition often leads to changes in management and increased surveillance of individuals who are at risk; however, for many rare entities, our knowledge of heritable predisposition is incomplete.

Methods: Families with childhood medulloblastoma, one of the most prevalent childhood malignant brain tumors, were investigated to identify predisposing germline mutations. Initial findings were extended to genomes and epigenomes of 1,044 medulloblastoma cases from international multicenter cohorts, including retrospective and prospective clinical studies and patient series.

Results: We identified heterozygous germline mutations in the G protein-coupled receptor 161 () gene in six patients with infant-onset medulloblastoma (median age, 1.5 years). mutations were exclusively associated with the sonic hedgehog medulloblastoma (MB) subgroup and accounted for 5% of infant MB cases in our cohorts. Molecular tumor profiling revealed a loss of heterozygosity at in all affected MB tumors, atypical somatic copy number landscapes, and no additional somatic driver events. Analysis of 226 MB tumors revealed somatic copy-neutral loss of heterozygosity of chromosome 1q as the hallmark characteristic of deficiency and the primary mechanism for biallelic inactivation of in affected MB tumors.

Conclusion: Here, we describe a novel brain tumor predisposition syndrome that is caused by germline mutations and characterized by MB in infants. Additional studies are needed to identify a potential broader tumor spectrum associated with germline mutations.
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http://dx.doi.org/10.1200/JCO.19.00577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943973PMC
January 2020

Male infant with paternal uniparental diploidy mosaicism and a 46,XX/46,XY karyotype.

Am J Med Genet A 2019 11 1;179(11):2252-2256. Epub 2019 Aug 1.

Institute of Human Genetics, University Hospital, Technical University of Aachen, Aachen, Germany.

A male patient with mosaic paternal uniparental diploidy (PUD) is presented. After birth, the patient presented with hypoglycemia, hemihypertrophy, umbilical hernia, and hepatomegaly. Afterward pancreatic hypertrophy, liver hemangiomas, and cysts were detected sonographically. At the age of 3.5 months, hepatoblastoma was diagnosed. To investigate suspected Beckwith-Wiedemann syndrome (BWS), extensive genetic analyses were performed using DNA from chorionic villus sampling, amniocentesis, and peripheral blood lymphocytes (chromosome analysis, methylation-specific multiplex ligation-dependent probe amplification assays, microsatellite analyses, and single nucleotide polymorphism array analysis). These analyses led to the detection of mosaic PUD. In peripheral blood lymphocytes, a male cell line (46,XY[27]/46,XX[5]) predominated, suggesting a mixture of uniparental isodisomy and heterodisomy. The genetic analyses suggest that the mosaic PUD status was attributable to fertilization of an oocyte by two sperms, with subsequent triploidy rescue giving rise to haploidy, which in turn was rescued. Notably, in the majority of the 28 mosaic PUD patients reported to date, BWS was initially suspected. Mosaic PUD status is associated with a higher risk for a broad range of malignant and benign tumors than in BWS. As tumors can also occur after childhood surveillance into adolescence is indicated. Mosaic PUD must therefore be considered in patients with suspected BWS.
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http://dx.doi.org/10.1002/ajmg.a.61314DOI Listing
November 2019

Contribution of GRB10 to the prenatal phenotype in Silver-Russell syndrome? Lessons from 7p12 copy number variations.

Eur J Med Genet 2019 Jul 14;62(7):103671. Epub 2019 May 14.

Institute of Human Genetics, University Hospital, Technical University Aachen (RWTH), Aachen, Germany.

The growth factor binding protein 10 (GRB10) has been suggested as a candidate gene for Silver-Russell syndrome because of its localization in 7p12, its imprinting status, data from mice models and its putative role in growth. Based on a new patient with normal growth carrying a GRB10 deletion affecting the paternal allele and data from the literature, we conclude that the heterogeneous clinical findings in patients with copy number variations (CNVs) of GRB10 gene depend on the size and the gene content of the CNV. However, evidence from mouse and human cases indicate a growth suppressing role of GRB10 in prenatal development. As a result, an increase of active maternal GRB10 copies, e.g. by maternal uniparental disomy of chromosome 7 or duplications of the region results in intrauterine growth retardation. In contrast, a defective GRB10 copy might result in prenatal overgrowth, whereas the paternal GRB10 allele is not required for proper prenatal growth.
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http://dx.doi.org/10.1016/j.ejmg.2019.103671DOI Listing
July 2019

Identification of transcription factor binding sites using ATAC-seq.

Genome Biol 2019 02 26;20(1):45. Epub 2019 Feb 26.

Institute for Computational Genomics, Joint Research Center for Computational Biomedicine, RWTH Aachen University Medical School, Aachen, 52074, Germany.

Transposase-Accessible Chromatin followed by sequencing (ATAC-seq) is a simple protocol for detection of open chromatin. Computational footprinting, the search for regions with depletion of cleavage events due to transcription factor binding, is poorly understood for ATAC-seq. We propose the first footprinting method considering ATAC-seq protocol artifacts. HINT-ATAC uses a position dependency model to learn the cleavage preferences of the transposase. We observe strand-specific cleavage patterns around transcription factor binding sites, which are determined by local nucleosome architecture. By incorporating all these biases, HINT-ATAC is able to significantly outperform competing methods in the prediction of transcription factor binding sites with footprints.
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http://dx.doi.org/10.1186/s13059-019-1642-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391789PMC
February 2019

Novel familial distal imprinting centre 1 (11p15.5) deletion provides further insights in imprinting regulation.

Clin Epigenetics 2019 02 15;11(1):30. Epub 2019 Feb 15.

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, D-52074, Aachen, Germany.

Background: Deletions of the imprinting centre 1 (IC1) in 11p15.5 are rare and their clinical significance is not only influenced by their parental origin but also by their exact genomic localization. In case the maternal IC1 allele is affected, the deletion is associated with the overgrowth disorder Beckwith-Wiedemann syndrome (BWS) and a gain of methylation (GOM) of the IC1. The consequences of deletions of the paternal IC1 allele depend on the localization and probably the binding sites of methylation-specific DNA-binding factors affected by the change. It has been suggested that distal deletions of the paternal allele are associated with a normal IC1 methylation and phenotype, whereas proximal alterations cause a loss of methylation (LOM) and Silver-Russell syndrome (SRS) features.

Results: In a patient referred for molecular BWS testing and his family, a deletion within the IC1 was identified by MLPA. It was associated with a GOM, corresponding to the transmission of the alteration via the maternal germline. Accordingly, the deletion was also detectable in the maternal grandmother, but here the paternal chromosome 11p15.5 was affected and a IC1 LOM was observed. By nanopore sequencing, the localization of the deletion could be precisely determined.

Conclusions: We report for the first time both GOM and LOM of the IC1 in the same family, caused by transmission of a 2.2-kb deletion in 11p15.5. Nanopore sequencing allowed the precise characterization of the change by long-read sequencing and thereby provides further insights in the regulation of imprinting in the IC1.
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http://dx.doi.org/10.1186/s13148-019-0629-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377752PMC
February 2019

DEGS1-associated aberrant sphingolipid metabolism impairs nervous system function in humans.

J Clin Invest 2019 03 11;129(3):1229-1239. Epub 2019 Feb 11.

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Background: Sphingolipids are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling, and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids leads to various neurological pathologies; however, the entire spectrum of sphingolipid metabolism disorders remains elusive.

Methods: A combined approach of genomics and lipidomics was applied to identify and characterize a human sphingolipid metabolism disorder.

Results: By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous systems, we identified a homozygous p.Ala280Val variant in DEGS1, which catalyzes the last step in the ceramide synthesis pathway. The blood sphingolipid profile in the patient showed a significant increase in dihydro sphingolipid species that was further recapitulated in patient-derived fibroblasts, in CRISPR/Cas9-derived DEGS1-knockout cells, and by pharmacological inhibition of DEGS1. The enzymatic activity in patient fibroblasts was reduced by 80% compared with wild-type cells, which was in line with a reduced expression of mutant DEGS1 protein. Moreover, an atypical and potentially neurotoxic sphingosine isomer was identified in patient plasma and in cells expressing mutant DEGS1.

Conclusion: We report DEGS1 dysfunction as the cause of a sphingolipid disorder with hypomyelination and degeneration of both the central and peripheral nervous systems.

Trial Registration: Not applicable.

Funding: Seventh Framework Program of the European Commission, Swiss National Foundation, Rare Disease Initiative Zurich.
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http://dx.doi.org/10.1172/JCI124159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391115PMC
March 2019

Next generation sequencing and imprinting disorders: Current applications and future perspectives: Lessons from Silver-Russell syndrome.

Mol Cell Probes 2019 04 2;44:1-7. Epub 2019 Jan 2.

Institute of Human Genetics, University Hospital, Technical University RWTH, Aachen, Germany. Electronic address:

Imprinting Disorders are a group of rare diseases with overlapping phenotypes which are associated with similar molecular changes and affect imprinted chromosomal regions. Clinical features mainly occur prenatally or in childhood, but have a severe lifelong impact on health. Due to their clinical and molecular heterogeneity, the diagnosis of imprinting disorders is often challenging and requires testing of a broad spectrum of genomic variants and aberrant methylation of imprinted loci (epimutations). A significant number of patients suspicious for imprinting disorders remain without a molecular confirmation, and in these cases differential diagnoses have to be considered. In fact, in patients with clinical features suggestive for imprinting disorders, the precise identification of the molecular cause is relevant for both clinical management as well as for genetic counselling. Thus, a comprehensive testing approach has to be applied. Next generation sequencing (NGS) based studies show that this technique is a valuable tool to improve the diagnostic efficiency particularly in entities with broad differential diagnoses. Furthermore, the development of diverse NGS approaches allows new insights in the function of imprinted regions, their structures, interactions and regulation. Based on a large cohort of patients referred for routine Silver Russel syndrome testing, the appropriateness and limitations of first trial tests in imprinting disorders are demonstrated in this report, but the chances of genomic NGS approaches for diagnostics and research are elucidated as well. Finally, the significance of the precise molecular diagnosis for the personalized management of the patient, and genetic counselling of the family will be discussed.
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http://dx.doi.org/10.1016/j.mcp.2018.12.007DOI Listing
April 2019

Familial NEDD4L variant in periventricular nodular heterotopia and in a fetus with hypokinesia and flexion contractures.

Mol Genet Genomic Med 2018 11 4;6(6):1255-1260. Epub 2018 Nov 4.

Department of Human Genetics, Medical Center, University of Regensburg, Regensburg, Germany.

Background: Mutations in the HECT domain of NEDD4L have recently been identified in a cohort of eight patients with a syndromic form of bilateral periventricular nodular heterotopia (PVNH) in association with neurodevelopmental delay, cleft palate, and toe syndactyly (PVNH7).

Methods: Case report based on NGS sequencing.

Results: Here, we describe a girl with a novel heterozygous NEDD4L missense variant, p.Tyr679His, and characteristic clinical findings, including bilateral periventricular nodular heterotopia, cleft palate and mild toe syndactyly. Molecular testing from peripheral blood identified the healthy father to carry the NEDD4L variant in mosaic state. Notably, a previous pregnancy of the couple had been terminated due to a complex fetal developmental disorder, including hypokinesia and flexion contractures. Upon review, this affected fetus was also shown to carry the familial NEDD4L variant.

Conclusion: Our findings may suggest a broader spectrum of NEDD4L-associated phenotypes, including severe prenatal neurodevelopmental manifestations, which might represent yet another genetic form of fetal hypokinesia with flexion contractures.
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http://dx.doi.org/10.1002/mgg3.490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305664PMC
November 2018

Search for cis-acting factors and maternal effect variants in Silver-Russell patients with ICR1 hypomethylation and their mothers.

Eur J Hum Genet 2019 01 14;27(1):42-48. Epub 2018 Sep 14.

Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Silver-Russell syndrome is an imprinting disorder characterized by severe intrauterine and postnatal growth retardation. The majority of patients show loss of methylation (LOM) of the H19/IGF2 IG-DMR (ICR1) in 11p15.5. In ~10% of these patients aberrant methylation of additional imprinted loci on other chromosomes than 11 can be observed (multilocus imprinting defect - MLID). Recently, genomic variations in the ICR1 have been associated with disturbed methylation of the ICR1. In addition, variants in factors contributing to the life cycle of imprinting are discussed to cause aberrant imprinting, including MLID. These variants can either be identified in the patients with imprinting disorders themselves or in their mothers. We performed comprehensive studies to elucidate the role of both cis-acting variants in 11p15.5 as well as of maternal effect variants in the etiology of ICR1 LOM. Whereas copy number analysis and next generation sequencing in the ICR1 did not provide any evidence for a variant, search for maternal effect variants in 21 mothers of patients with ICR1 LOM identified two carriers of NLRP5 variants. By considering our results as well as those from the literature, we conclude that the causes for epimutations are heterogeneous. MLID might be regarded as an own etiological subgroup, associated with maternal effect variants in NLRP and functionally related genes. In addition, these variants might also contribute to LOM of single imprinted loci. Furthermore, genomic variants in the patients themselves might result in aberrant methylation patterns and need further investigation.
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http://dx.doi.org/10.1038/s41431-018-0269-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303262PMC
January 2019

Search for altered imprinting marks in Mayer-Rokitansky-Küster-Hauser patients.

Mol Genet Genomic Med 2018 11 11;6(6):1225-1228. Epub 2018 Aug 11.

Institute of Human Genetics, University of Münster, Münster, Germany.

Background: Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) is the second most common cause of primary amenorrhea and characterized by absence of the uterus and the upper part of the vagina. The etiology of MRKH is mainly unknown but a contribution of genomic alterations is probable. A molecular disturbance so far neglected in MRKH research is aberrant methylation at imprinted loci. In fact, MRKH has been reported in patients with the imprinting disorder Silver-Russell syndrome.

Methods: We report on a rare patient with MRKH and SRS due to an ICR1 hypomethylation in 11p15.5. On the basis of this observation we screened a large cohort of MRKH patients (n > 100) for aberrant methylation at nine imprinted loci.

Results: We failed to detect any epimutation, thus we conclude that imprinting defects at least at the currently known disease-relevant imprinted loci do not contribute to the isolated MRKH phenotype. However, it cannot be excluded that altered methylation marks at other loci are involved in the etiology of MRKH.

Conclusion: The molecular basis for MRKH remains unclear in the majority of patients, but future studies on the association between MRKH and ICR1 hypomethylation/SRS will to enlighten the role of epigenetics in the etiology of MRKH.
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http://dx.doi.org/10.1002/mgg3.426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305658PMC
November 2018

Recurrent somatic mutations are rare in patients with cryptic dyskeratosis congenita.

Leukemia 2018 08 2;32(8):1762-1767. Epub 2018 Apr 2.

Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Dyskeratosis congenita (DKC) is a paradigmatic telomere disorder characterized by substantial and premature telomere shortening, bone marrow failure, and a dramatically increased risk of developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). DKC can occur as a late-onset, so-called cryptic form, with first manifestation in adults. Somatic MDS-related mutations are found in up to 35% of patients with acquired aplastic anemia (AA), especially in patients with short telomeres. The aim of our study was to investigate whether cryptic DKC is associated with an increased incidence of MDS-related somatic mutations, thereby linking the accelerated telomere shortening with the increased risk of MDS/AML. Samples from 15 adult patients (median age: 42 years, range: 23-60 years) with molecularly confirmed cryptic DKC were screened using next-generation gene panel sequencing to detect MDS-related somatic variants. Only one of the 15 patients (7%) demonstrated a clinically relevant MDS-related somatic variant. This incidence was dramatically lower than formerly described in acquired AA. Based on our data, we conclude that clonal evolution of subclones carrying MDS-related mutations is not the predominant mechanism for MDS/AML initiation in adult cryptic DKC patients.
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http://dx.doi.org/10.1038/s41375-018-0125-xDOI Listing
August 2018

Maternal variants in and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring.

J Med Genet 2018 07 24;55(7):497-504. Epub 2018 Mar 24.

Faculty of Medicine, University of Southampton, Southampton, UK.

Background: Genomic imprinting results from the resistance of germline epigenetic marks to reprogramming in the early embryo for a small number of mammalian genes. Genetic, epigenetic or environmental insults that prevent imprints from evading reprogramming may result in imprinting disorders, which impact growth, development, behaviour and metabolism. We aimed to identify genetic defects causing imprinting disorders by whole-exome sequencing in families with one or more members affected by multilocus imprinting disturbance.

Methods: Whole-exome sequencing was performed in 38 pedigrees where probands had multilocus imprinting disturbance, in five of whom maternal variants in have previously been found.

Results: We now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal effect genes, including , and . As well as clinical features of well-recognised imprinting disorders, some offspring had additional features including developmental delay, behavioural problems and discordant monozygotic twinning, while some mothers had reproductive problems including pregnancy loss.

Conclusion: The identification of 20 putative maternal effect variants in 38 families affected by multilocus imprinting disorders adds to the evidence that maternal genetic factors affect oocyte fitness and thus offspring development. Testing for maternal-effect genetic variants should be considered in families affected by atypical imprinting disorders.
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http://dx.doi.org/10.1136/jmedgenet-2017-105190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047157PMC
July 2018

The maternal uniparental disomy of chromosome 6 (upd(6)mat) "phenotype": result of placental trisomy 6 mosaicism?

Mol Genet Genomic Med 2017 11 22;5(6):668-677. Epub 2017 Sep 22.

Institute of Human Genetics, University of Essen, Essen, Germany.

Background: Maternal uniparental disomy of chromosome 6 (upd(6)mat) is a rare finding and its clinical relevance is currently unclear. Based on clinical data from two new cases and patients from the literature, the pathogenetic significance of upd(6)mat is delineated.

Methods: Own cases were molecularly characterized for isodisomic uniparental regions on chromosome 6. For further cases with upd(6)mat, a literature search was conducted and genetic and clinical data were ascertained.

Results: Comparison of isodisomic regions between the new upd(6)mat cases and those from four reports did not reveal any common isodisomic region. Among the patients with available cytogenetic data, five had a normal karyotype in lymphocytes, whereas a trisomy 6 (mosaicism) was detected prenatally in four cases. A common clinical picture was not obvious in upd(6)mat, but intrauterine growth restriction (IUGR) and preterm delivery were frequent.

Conclusion: A common upd(6)mat phenotype is not obvious, but placental dysfunction due to trisomy 6 mosaicism probably contributes to IUGR and preterm delivery. In fact, other clinical features observed in upd(6)mat patients might be caused by homozygosity of recessive mutations or by an undetected trisomy 6 cell line. Upd(6)mat itself is not associated with clinical features, and can rather be regarded as a biomarker. In case upd(6)mat is detected, the cause for the phenotype is identified indirectly, but the UPD is not the basic cause.
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http://dx.doi.org/10.1002/mgg3.324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702562PMC
November 2017

Formation of upd(7)mat by trisomic rescue: SNP array typing provides new insights in chromosomal nondisjunction.

Mol Cytogenet 2017 25;10:28. Epub 2017 Jul 25.

Institute of Human Genetics, RWTH University Hospital Aachen, Pauwelsstr 30, D-52074 Aachen, Germany.

Background: Maternal uniparental disomy (UPD) of chromosome 7 (upd(7)mat) accounts for approximately 10% of patients with Silver-Russell syndrome (SRS). For upd(7)mat and trisomy 7, a significant number of mechanisms have been proposed to explain the postzygotic formation of these chromosomal compositions, but all have been based on as small number of cases. To obtain the ratio of isodisomy and heterodisomy in UPDs (hUPD, iUPD) and to determine the underlying formation mechanisms, we analysed a large cohort of upd(7)mat patients ( = 73) by SNP array typing. Based on these data, we discuss the UPDs and their underlying trisomy 7 formation mechanisms.

Results: A whole chromosome 7 maternal iUPD was confirmed in 28.8%, a mixture or complete maternal hUPD in 71.2% of patients.

Conclusions: We could demonstrate that nondisjunction mechanism affecting chromosome 7 are similar to that of the chromosomes more frequently involved in trisomy (and/or UPD), and that mechanisms other than trisomic rescue have a lower significance than previously suspected. Furthermore, we suggest SNP array typing for future parent- and cell-stage-of origin studies in human aneuploidies as they allow the definite classification of trisomies and UPDs, and provide information on recombinational events and their suggested association with aneuploidy formation.
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http://dx.doi.org/10.1186/s13039-017-0329-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526280PMC
July 2017

NLRP genes and their role in preeclampsia and multi-locus imprinting disorders.

J Perinat Med 2018 Feb;46(2):169-173

Institute of Human Genetics, University Hospital, Technical University (RWTH) Aachen, Aachen, Germany.

Preeclampsia (PE) affects 2-5% of all pregnancies. It is a multifactorial disease, but it has been estimated that 35% of the variance in liability of PE are attributable to maternal genetic effects and 20% to fetal genetic effects. PE has also been reported in women delivering children with Beckwith-Wiedemann syndrome (BWS, OMIM 130650), a disorder associated with aberrant methylation at genomically imprinted loci. Among others, members of the NLRP gene family are involved in the etiology of imprinting defects. Thus, a functional link between PE, NLRP gene mutations and aberrant imprinting can be assumed. Therefore we analyzed a cohort of 47 PE patients for NLRP gene mutations by next generation sequencing. In 25 fetuses where DNA was available we determined the methylation status at the imprinted locus. With the exception of one woman heterozygous for a missense variant in the NLRP7 gene (NM_001127255.1(NLRP7):c.542G>C) we could not identify further carriers, in the fetal DNA normal methylation patterns were observed. Thus, our negative screening results in a well-defined cohort indicate that NLRP mutations are not a relevant cause of PE, though strong evidence for a functional link between NLRP mutations, PE and aberrant methylation exist.
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http://dx.doi.org/10.1515/jpm-2016-0405DOI Listing
February 2018

Maternal heterozygous NLRP7 variant results in recurrent reproductive failure and imprinting disturbances in the offspring.

Eur J Hum Genet 2017 08 31;25(8):924-929. Epub 2017 May 31.

Institute of Human Genetics, University of Bonn, Bonn, Germany.

It has been shown previously that homozygous and compound-heterozygous variants affecting protein function in the human NLRP genes impact reproduction and/or fetal imprinting patterns. These variants represent so-called 'maternal effect mutations', that is, although female variant carriers are healthy, they are at risk of reproductive failure, and their offspring may develop aberrant methylation and imprinting disorders. In contrast, the relevance to reproductive failure of maternal heterozygous NLRP7 variants remains unclear. The present report describes the identification of a heterozygous NLRP7 variant in a healthy 28-year-old woman with a history of recurrent reproductive failure, and the molecular findings in two of the deceased offspring. Next-generation sequencing (NGS) for NLRP variants was performed. In the tissues of two offspring (one fetus; one deceased premature neonate) methylation of imprinted loci was tested using methylation-specific assays. Both pregnancies had been characterized by the presence of elevated human chorionic gonadotropin (hCG) levels and ovarian cysts. In the mother, a heterozygous nonsense 2-bp deletion in exon 5 of the NLRP7 gene was identified (NM_001127255.1:c.2010_2011del, p.(Phe671Glnfs*18)). In the two investigated offspring, heterogeneous aberrant methylation patterns were detected at imprinted loci. The present data support the hypothesis that heterozygous NLRP7 variants contribute to reproductive wastage, and that these variants represent autosomal dominant maternal effect variants which lead to aberrant imprinting marks in the offspring. Specific screening and close prenatal monitoring of NLRP7 variant carriers is proposed. Egg donation might facilitate successful pregnancy in heterozygous NLRP7 variant carriers.
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http://dx.doi.org/10.1038/ejhg.2017.94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567160PMC
August 2017

Targeted Next Generation Sequencing Approach in Patients Referred for Silver-Russell Syndrome Testing Increases the Mutation Detection Rate and Provides Decisive Information for Clinical Management.

J Pediatr 2017 08 19;187:206-212.e1. Epub 2017 May 19.

Institute of Human Genetics, University Hospital, Technical University Aachen (Rheinisch-Westfälische Technische Hochschule), Aachen, Germany. Electronic address:

Objective: To investigate the contribution of differential diagnoses to the mutation spectrum of patients referred for Silver-Russell syndrome (SRS) testing.

Study Design: Forty-seven patients referred for molecular testing for SRS were examined after exclusion of one of the SRS-associated alterations. After clinical classification, a targeted next generation sequencing approach comprising 25 genes associated with other diagnoses or postulated as SRS candidate genes was performed.

Results: By applying the Netchine-Harbinson clinical scoring system, indication for molecular testing for SRS was confirmed in 15 out of 47 patients. In 4 out of these 15 patients, disease-causing variants were found in genes associated with other diagnoses. These patients carried mutations associated with Bloom syndrome, Mulibrey nanism, KBG syndrome, or IGF1R-associated short stature. We could not detect any pathogenic mutation in patients with a negative clinical score.

Conclusions: Some of the differential diagnoses detected in the cohort presented here have a major impact on clinical management. Therefore, we emphasize that the molecular defects associated with these clinical pictures should be excluded before the clinical diagnosis "SRS" is made. Finally, we could show that a broad molecular approach including the differential diagnoses of SRS increases the detection rate.
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http://dx.doi.org/10.1016/j.jpeds.2017.04.018DOI Listing
August 2017